AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression.

Early metastasis of pancreatic cancer (PaC) is a major cause of its high mortality rate. Previous studies have shown that AHNAK2 is involved in the progression of some tumors and is predicted to be an independent prognostic factor for PaC; however, the specific mechanisms through which AHNAK2 regulates PaC remain unclear. In this study, we examined the role of AHNAK2 in PaC and its potential molecular mechanisms. AHNAK2 mRNA and protein expression in PaC tissues and cells were measured using qRT-PCR and western blot analysis. After AHNAK2 knockdown using small interfering RNA, PaC cells were subjected to CCK-8 scratch, and Transwell assays to assess cell proliferation, migration, and invasion, respectively. Furthermore, the validation of the mechanistic pathway was achieved by western blot analysis. AHNAK2 mRNA and protein levels were up-regulated in PaC and silencing AHNAK2 significantly inhibited the proliferation, migration, and invasion of PaC cells. Mechanistically, AHNAK2 knockdown decreased the expression of phosphorylated p65, phosphorylated IκBα, and matrix metalloproteinase-9 (MMP-9), suggesting that activation of the NF-κB/MMP-9 signaling pathway was inhibited. Importantly, activation of NF-κB reversed the effects of AHNAK2 knockdown. Our findings indicate that AHNAK2 promotes PaC progression through the NF-kB/MMP-9 pathway and provides a theoretical basis for targeting AHNAK2 for the treatment of PaC.

Rheumatoid arthritis and changes on spirometry by smoking status in two prospective longitudinal cohorts.

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.

FOXK2 amplification promotes breast cancer development and chemoresistance.

Oncogene activation through DNA amplification or overexpression is a crucial driver of cancer initiation and progression. The FOXK2 gene, located on chromosome 17q25, encodes a transcription factor with a forkhead DNA-binding domain. Analysis of genomic datasets reveals that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor patient survival. Knockdown of FOXK2 significantly inhibited breast cancer cell proliferation, migration, anchorage-independent growth, and delayed tumor growth in a xenograft mouse model. Additionally, inhibiting FOXK2 sensitized breast cancer cells to chemotherapy. Co-overexpression of FOXK2 and mutant PI3KCA transformed non-tumorigenic MCF-10A cells, suggesting a role for FOXK2 in PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as transcriptional targets of FOXK2 in MCF-7 cells. Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer.

iGenSig-Rx: an integral genomic signature based white-box tool for modeling cancer therapeutic responses using multi-omics data.

Multi-omics sequencing is poised to revolutionize clinical care in the coming decade. However, there is a lack of effective and interpretable genome-wide modeling methods for the rational selection of patients for personalized interventions. To address this, we present iGenSig-Rx, an integral genomic signature-based approach, as a transparent tool for modeling therapeutic response using clinical trial datasets. This method adeptly addresses challenges related to cross-dataset modeling by capitalizing on high-dimensional redundant genomic features, analogous to reinforcing building pillars with redundant steel rods. Moreover, it integrates adaptive penalization of feature redundancy on a per-sample basis to prevent score flattening and mitigate overfitting. We then developed a purpose-built R package to implement this method for modeling clinical trial datasets. When applied to genomic datasets for HER2 targeted therapies, iGenSig-Rx model demonstrates consistent and reliable predictive power across four independent clinical trials. More importantly, the iGenSig-Rx model offers the level of transparency much needed for clinical application, allowing for clear explanations as to how the predictions are produced, how the features contribute to the prediction, and what are the key underlying pathways. We anticipate that iGenSig-Rx, as an interpretable class of multi-omics modeling methods, will find broad applications in big-data based precision oncology. The R package is available: https://github.com/wangxlab/iGenSig-Rx .

Assessing the association between a sedentary lifestyle and prevalence of primary osteoporosis: a community-based cross-sectional study among Chinese population.

OBJECTIVES: To reveal the association between a sedentary lifestyle and the prevalence of primary osteoporosis (POP). DESIGN: A community-based cross-sectional study was conducted. SETTING: This study was conducted in communities in Hefei city, Anhui province, China. PARTICIPANTS: A total of 1346 residents aged 40 and above underwent POP screening via calcaneus ultrasound bone mineral density (BMD) testing and completed a questionnaire survey. OUTCOME MEASURES: The average daily sitting time was included in the study variable and used to assess sedentary behaviour. The 15 control variables included general information, dietary information and life behaviour information. Logistic regression was used to analyse the association between the POP prevalence and study or control variables in different models. RESULTS: 1346 participants were finally included in the study. According to the 15 control variables, the crude model and 4 models were established. The analysis revealed that the average daily sitting time showed a significant correlation with the prevalence of POP in the crude model (OR=2.02, 95% CI=1.74 to 2.36, p<0.001), Model 1 (OR=2.65, 95% CI=2.21 to 3.17, p<0.001), Model 2 (OR=2.63, 95% CI=2.19 to 3.15, p<0.001), Model 3 (OR=2.62, 95% CI=2.18 to 3.15, p<0.001) and Model 4 (OR=2.58, 95% CI=2.14 to 3.11, p<0.001). Besides, gender, age and body mass index showed a significant correlation with the POP prevalence in all models. CONCLUSIONS: This study suggests a potential association between a sedentary lifestyle and the prevalence of POP within the Chinese population. Modifying sedentary behaviours could contribute to a reduction in POP risk. However, longitudinal cohort studies are necessary to confirm this hypothesis in the future.

Highly Efficient Nitrogen Reduction to Ammonia through the Cooperation of Plasma and Porous Metal-Organic Framework Reactors with Confined Water.

While the ambient N2 reduction to ammonia (NH3) using H2O as hydrogen source (2N2+6H2O=4NH3+3O2) is known as a promising alternative to the Haber-Bosch process, the high bond energy of N≡N bond leads to the extremely low NH3 yield. Herein, we report a highly efficient catalytic system for ammonia synthesis using the low-temperature dielectric barrier discharge plasma to activate inert N2 molecules into the activated nitrogen species, which can efficiently react with the confined and concentrated H2O molecules in porous metal-organic framework (MOF) reactors with V3+, Cr3+, Mn3+, Fe3+, Co2+, Ni2+ and Cu2+ ions. Specially, the Fe-based catalyst MIL-100(Fe) causes a superhigh NH3 yield of 22.4 mmol g-1 h-1. The investigation of catalytic performance and systematic characterizations of MIL-100(Fe) during the plasma-driven catalytic reaction unveils that the in situ generated defective Fe-O clusters are the highly active sites and NH3 molecules indeed form inside the MIL-100(Fe) reactor. The theoretical calculation reveals that the porous MOF catalysts have different adsorption capacity for nitrogen species on different catalytic metal sites, where the optimal MIL-100(Fe) has the lowest energy barrier for the rate-limiting *NNH formation step, significantly enhancing efficiency of nitrogen fixation.

Forced vital capacity trajectories and risk of lung transplant and ILD-related mortality among patients with rheumatoid arthritis-associated interstitial lung disease.

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes.

ColorNetVis: An Interactive Color Network Analysis System for Exploring the Color Composition of Traditional Chinese Painting.

In the field of digital humanities, color research aims to discover explanations for painting history and color usage habits. However, researchers analyzing color relationships is challenging and time-consuming, as it requires color extraction and a detailed review of many painting images for reference and comparison of color relationships. In our work, we propose ColorNetVis, an interactive color network analysis tool that enables researchers to explore color relationships through color networks. The core of ColorNetVis is a bipartite network model that establishes a bipartite relationship between colors and Chinese painting within a scope based on color difference measurement. It constructs a one-mode color network through projection algorithms and similarity calculation methods to discover the relationship between colors. We propose a coordinated set of views to demonstrate the combination of determined color networks with painting types and real-world attributes. We use color space view, color attribute distribution view, and single color query components to assist researchers in conducting detailed color analysis and validation. Through case studies, researcher reviews, and user studies, we demonstrate that ColorNetVis can effectively help researchers discover knowledge of color relationships and potential color research directions.

CircRNA circRREB1 promotes tumorigenesis and progression of breast cancer by activating Erk1/2 signaling through interacting with GNB4.

Current investigations have illuminated the essential roles played by circular RNAs (circRNAs) in driving breast cancer (BC) tumorigenesis. However, the functional implications and molecular underpinnings of most circRNAs in BC are not well characterized. Here, Circular RNA (circRNA) expression profiles were analyzed in four surgically resected BC cases along with adjacent non-cancerous tissues applying RNA microarray analysis. The levels and prognostic implications of circRREB1 in BC were subjected to quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Experimental manipulation of circRREB1 levels in both in vivo and in vitro settings further delineated its role in BC cell growth, invasion, and metastasis. The mechanical verification of circRREB1's interaction with GNB4 was established through RNA pull-down, mass spectrometry, Western blot analysis, RNA immunoprecipitation assays (RIP), fluorescence ISH (FISH), and rescue experiments. We found that circRREB1 exhibited significant upregulation in BC tissues and cells, implicating its association with an unfavorable prognosis in BC patients. CircRREB1 knockdown elicited anti-proliferative, anti-migratory, anti-invasive, and pro-apoptotic effects in BC cells, whereas its upregulation exerted opposing influences. Follow-up mechanistic examinations suggested that circRREB1 might interact with GNB4 directly, inducing the activation of Erk1/2 signaling and driving BC progression. Our findings collectively indicate that the interplay of circRREB1 with GNB4 promotes Erk1/2 signaling, thereby fostering BC progression, and positioning circRREB1 as a candidate therapeutic target for intervention in BC.

Factors Associated With an Electronic Health Record-Based Definition of Postacute Sequelae of COVID-19 in Patients With Systemic Autoimmune Rheumatic Disease.

OBJECTIVE: Many individuals with rheumatic disease are at higher risk for severe acute coronavirus disease 2019 (COVID-19). We aimed to evaluate risk factors for postacute sequelae of COVID-19 (PASC) using an electronic health record (EHR)-based definition. METHODS: We identified patients with prevalent rheumatic diseases and COVID-19 within the Mass General Brigham healthcare system. PASC was defined by the International Classification of Diseases, 10th revision (ICD-10) codes, relevant labs, vital signs, and medications at least 30 days following the first COVID-19 infection. Patients were followed until the earliest of incident PASC, repeat COVID-19 infection, 1 year of follow-up, death, or February 19, 2023. We used multivariable Cox regression to estimate the association of baseline characteristics with PASC risk. RESULTS: Among 2459 patients (76.37% female, mean age 57.4 years), the most common incident PASC manifestations were cough (14.56%), dyspnea (12.36%), constipation (11.39%), and fatigue (10.70%). Serious manifestations including acute coronary disease (4.43%), thromboembolism (3.09%), hypoxemia (3.09%), stroke (1.75%), and myocarditis (0.12%) were rare. The Delta wave (adjusted hazard ratio [aHR] 0.63, 95% CI 0.49-0.82) and Omicron era (aHR 0.50, 95% CI 0.41-0.62) were associated with lower risk of PASC than the early pandemic period (March 2020-June 2021). Age, obesity, comorbidity burden, race, and hospitalization for acute COVID-19 infection were associated with greater risk of PASC. Glucocorticoid (GC) use (aHR 1.19, 95% CI 1.05-1.34 compared to no use) was associated with greater risk of PASC. CONCLUSION: Among patients with rheumatic diseases, following their first COVID-19 infection, we found a decreased risk of PASC over calendar time using an EHR-based definition. Aside from GCs, no specific immunomodulatory medications were associated with increased risk, and risk factors were otherwise similar to those seen in the general population.

Regulated Dual Defects of Bridging Organic and Terminal Inorganic Ligands in Iron-based Metal-Organic Framework Nodes for Efficient Photocatalytic Ammonia Synthesis.

Engineering advantageous defects to construct well-defined active sites in catalysts is promising but challenging to achieve efficient photocatalytic NH3 synthesis from N2 and H2O due to the chemical inertness of N2 molecule. Here, we report defective Fe-based metal-organic framework (MOF) photocatalysts via a non-thermal plasma-assisted synthesis strategy, where their NH3 production capability is synergistically regulated by two types of defects, namely, bridging organic ligands and terminal inorganic ligands (OH- and H2O). Specially, the optimized MIL-100(Fe) catalysts, where there are only terminal inorganic ligand defects and coexistence of dual defects, exhibit the respective 1.7- and 7.7-fold activity enhancement comparable to the pristine catalyst under visible light irradiation. As revealed by experimental and theoretical calculation results, the dual defects in the catalyst induce the formation of abundant and highly accessible coordinatively unsaturated Fe active sites and synergistically optimize their geometric and electronic structures, which favors the injection of more d-orbital electrons in Fe sites into the N2 π* antibonding orbital to achieve N2 activation and the formation of a key intermediate *NNH in the reaction. This work provides a guidance on the rational design and accurate construction of porous catalysts with precise defective structures for high-performance activation of catalytic molecules.

Pharmacokinetics of polymyxin B in different populations: a systematic review.

BACKGROUND AND OBJECTIVES: Despite being clinically utilized for the treatment of infections, the limited therapeutic range of polymyxin B (PMB), along with considerable interpatient variability in its pharmacokinetics and frequent occurrence of acute kidney injury, has significantly hindered its widespread utilization. Recent research on the population pharmacokinetics of PMB has provided valuable insights. This study aims to review relevant literature to establish a theoretical foundation for individualized clinical management. METHODS: Follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, Pop-PK studies of PMB were searched in PubMed and EMBASE database systems from the inception of the database until March 2023. RESULT: To date, a total of 22 population-based studies have been conducted, encompassing 756 subjects across six different countries. The recruited population in these studies consisted of critically infected individuals with multidrug-resistant bacteria, patients with varying renal functions, those with cystic fibrosis, kidney or lung transplant recipients, patients undergoing extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT), as well as individuals with obesity or pediatric populations. Among these studies, seven employed a one-compartmental model, with the range of typical clearance (CL) and volume (Vc) being 1.18-2.5L /h and 12.09-47.2 L, respectively. Fifteen studies employed a two-compartmental model, with the ranges of the clearance (CL) and volume of the central compartment (Vc), the volume of the peripheral compartment (Vp), and the intercompartment clearance (Q) were 1.27-8.65 L/h, 5.47-38.6 L, 4.52-174.69 L, and 1.34-24.3 L/h, respectively. Primary covariates identified in these studies included creatinine clearance and body weight, while other covariates considered were CRRT, albumin, age, and SOFA scores. Internal evaluation was conducted in 19 studies, with only one study being externally validated using an independent external dataset. CONCLUSION: We conclude that small sample sizes, lack of multicentre collaboration, and patient homogeneity are the primary reasons for the discrepancies in the results of the current studies. In addition, most of the studies limited in the internal evaluation, which confined the implementation of model-informed precision dosing strategies.

Uncovering lupus nephritis-specific genes and the potential of TNFRSF17-targeted immunotherapy: a high-throughput sequencing study.

Introduction: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets. Methods: We performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry. Results: Our analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the 'regulation of biological quality' GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells. Discussion: Our findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN.

Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.

Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.

Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer.

Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.

Surgical management of nervus intermedius neuralgia: A report of 4 cases and literature review.

BACKGROUND: Nervus intermedius neuralgia (NIN) is characterized by paroxysmal episodes of sharp, lancinating pain in the deep ear. Unfortunately, only a few studies exist in the literature on this pain syndrome, its pathology and postoperative outcomes. METHOD: We conducted a retrospective review of four cases diagnosed with NIN who underwent a neurosurgical intervention at our center from January 2015 to January 2023. Detailed information on their MRI examinations, intraoperative findings and other clinical presentations were obtained, and the glossopharyngeal and vagus nerves were isolated for immunohistochemistry examination. RESULTS: A total of 4 NIN patients who underwent a microsurgical intervention at our institution were included in this report. The NI was sectioned in all patients and 3 of them underwent a microvascular decompression. Of these 4 patients, 1 had a concomitant trigeminal neuralgia (TN), and 1 a concomitant glossopharyngeal neuralgia (GPN). Three patients underwent treatment for TN and 2 for GPN. Follow-up assessments ranged from 8 to 99 months. Three patients reported complete pain relief immediately after the surgery until last follow-up, while in the remaining patient the preoperative pain gradually resolved over the 3 month period. Immunohistochemistry revealed that a greater amount of CD4+ and CD8+ T cells had infiltrated the glossopharyngeal versus vagus nerve. CONCLUSIONS: NIN is an extremely rare condition showing a high degree of overlap with TN/GPN. An in depth neurosurgical intervention is effective to completely relieve NIN pain, without any serious complications. It appears that T cells may play regulatory role in the pathophysiology of CN neuralgia.

Method for reconstructing femoral head blood supply by anastomosing the intraosseous artery.

Background: The reconstruction of femoral head blood supply is crucial in the management of avascular necrosis and related conditions. This study presents a method for reconstructing the femoral head blood supply by anastomosing the intraosseous artery. Methods: The femoral heads of six male Landrace swine were surgically exposed, and subcranial fractures of the femoral neck were intentionally created. Under microscopic guidance, the trophoblastic foramen of the posterior supporting artery was identified. Subsequently, a triangular bone window was carefully crafted to expose the intraosseous artery. Following the fixation of the femoral head, an anastomosis was performed between the intraosseous artery and the posterior inferior supporting artery located at the distal end of the fracture. The assessment of femoral head blood supply was conducted using Kirschner's pinhole and angiography techniques. Results: The anastomotic intraosseous artery exhibited a vibrant red color, indicating adequate blood perfusion, and demonstrated pulsatile flow. Observation through pinholes in the surface of the femoral head revealed continuous blood flow. Angiography further confirmed the successful circulation, as the contrast agent entered the inferior retinacular artery branch originating from the deep femoral artery. The contrast agent then proceeded to enter the femoral head through the retinacular artery, reaching the anastomosis site of the intraosseous artery. Notably, the angiography also revealed the presence of visible internal branches, highlighting the establishment of a functional vascular network. Discussion: The method of reconstructing the blood supply to the femoral head through anastomosis of the intraosseous artery enables utilization of the existing blood supply system within the femoral head. This study is just a preliminary study of this innovative technique that has the potential to prevent and/or treat femoral head necrosis following a femoral neck fracture. By restoring adequate blood flow to the affected area, this approach holds promise in preserving the viability and functionality of the femoral head, ultimately improving patient outcomes.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial.

BACKGROUND: Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy. METHODS: We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models. FINDINGS: We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85]). INTERPRETATION: In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations. FUNDING: The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.