Interrogating post-transplant donor HLA-specific antibody characteristics and effector functions using clinical bead assays.

Single antigen bead (SAB) assays are the most common and sensitive method used to detect and monitor post-transplant donor specific HLA antibodies (DSA). However, a direct comparison across traditional and modified SAB assays to improve routine DSA monitoring using pre-treated IgG sera to eliminate interference has not been performed. We performed a technical comparison of 251 post-transplant DSA from n = 91 serum samples tested neat (pre-treated, undiluted), at a single 1:16 dilution, in the C1q bead assay, and for IgG subclasses (IgG1, IgG2, IgG3, IgG4) with IgG-enriched sera. We found that DSAs that are detectable by 1:16 dilution and/or C1q are associated with higher IgG MFI values and results could be predicted by testing neat sera. DSA detected at 1:16 dilution correlated with >7000 IgG MFI in neat sera and identified DSA that exceeded the SAB linear range for semiquantitative measurements. C1q positive DSA correlated with >15,000 IgG MFI in neat sera. C1q binding correlated most strongly with total IgG MFI (Spearman r = 0.82, p = 0.002) and not specific subclasses, demonstrating that DSA C1q binding capacity in this cohort is driven by HLA-specific IgG concentration. Evaluation of engineered pan-HLA class I-specific human IgG1 and IgG2 subclass monoclonal antibodies by SAB C1q and C3d assays revealed that IgG2 antibodies can bind complement at higher concentrations. The strengths and limitations of modified SAB assays must be considered to optimize efficient testing and accurate clinical interpretation.

Angioedema due to acquired C1-inhibitor deficiency associated with monoclonal gammopathies of undetermined significance.

BACKGROUND: No specific description of monoclonal gammopathies of undetermined significance (MGUS)-associated angioedema due to acquired C1 inhibitor deficiency (AAE-C1-INH) has been reported yet. OBJECTIVE: Describe the biological and clinical characteristics, evolution and response to treatment of MGUS-associated AAE-C1-INH. MATERIAL AND METHODS: We conducted a French national retrospective observational study on MGUS-associated acquired angioedema spanning a 30-year period. RESULTS: Forty-one patients with MGUS-associated AAE-C1-INH at diagnosis were included; 68% displayed anti-C1INH antibodies. The monoclonal component was an IgM in 24 patients, IgG in 11 and IgA in 6 patients. Mean age at first angioedema attack was 63 years (SD = 13) and at diagnosis 66 years (SD = 11). 88 % of patients benefited from acute attack treatments, and 77% from long-term prophylaxis, either danazol, tranexamic acid or lanadelumab. Median follow-up was 7 years, during which 14 patients (33%) evolved into well-defined malignant hemopathies. 50 % of patients were given a hematological treatment, either rituximab alone, indicated by recurrent attacks of angioedema in patients with AAE-C1-INH with anti-C1-INH antibodies, or validated combinations of chemotherapies, indicated by evolution into a lymphoma in 7 patients and a myeloma in 3 patients. Fifteen patients (35%) were in clinical complete remission of angioedema at last visit, of which 60% had an undetectable serum monoclonal immunoglobulin. CONCLUSION: Complete remission of AAE-C1-INH is correlated to complete remission of the underlying hematological malignancy, as defined by an undetectable serum monoclonal immunoglobulin. In our MGUS-associated acquired angioedema cohort, we recorded an incidence of evolution into hematological malignancy of 4% per patient-year. It is therefore crucial to conduct full hematological workup during follow-up at an annual rate, and earlier if AAE relapses or if acute attacks frequency increases.

Single-cell sequencing in diffuse large B-cell lymphoma: C1qC is a potential tumor-promoting factor.

BACKGROUND: Complement component 1q (C1q) is central to the classical complement pathway. High C1q expression has been linked to poor prognosis in patients with cancer. However, the precise mechanism via which C1q contributes to diffuse large B-cell lymphoma (DLBCL) is still unknown. We aimed to explore the potential mechanism by which C1qC promoting DLBCL. METHODS: Using multiplex immunohistochemistry (mIHC) to identify immunocyte subgroups associated with prognosis in DLBCL tissues. Constructing a risk prediction model based on immunocytes using least absolute shrinkage and selection operator (LASSO) regression. Single-cell sequencing detects the expression level of C1qC in immunocytes in the DLBCL microenvironment. Using Wb and qPCR to detect markers of M2 macrophages after knocking down C1qC, and exploring the interactions between lymphoma cells and macrophages through co-culture. Analyzing clinical data from DLBCL patients to investigate the clinical significance of C1qC+ M2 macrophages. Lastly, using bioinformatics in conjunction with mIHC to elucidate the potential pro-tumor mechanism of C1qC. RESULTS: First, we found T cell subtypes, neutrophils, and M2 macrophages are associated with prognosis. Subsequently, the risk model identified C1qC as a differential gene relevant to DLBCL prognosis. Furthermore, single-cell sequencing suggested high C1qC expression in M2 macrophages. The expression level of CD163 is significantly lower following siC1qC. Co-culture experiments have shown that M2 macrophages can promote the proliferation of tumor cells and reduce their drug sensitivity. Furthermore, as an independent predictive indicator, high expression of C1qC+ M2 macrophages is associated with poor prognosis in patients. Finally, a positive correlation between increased C1qC expression and immune checkpoints, as well as an increase in the infiltration of regulatory T cells (Tregs) and M2 macrophages. CONCLUSIONS: C1qC offering new insights into pathogenesis and presenting a potential therapeutic target in DLBCL.

Case Report: Hypocomplementemic urticarial vasculitis syndrome in a pediatric patient with complement factor 1 deficiency.

Urticarial vasculitis (UV) is a type III hypersensitivity reaction, characterized by immune complex deposition in small vessels leading to complement activation. Hypocomplementemic urticarial vasculitis syndrome (HUVS) represents the most severe form of UV, manifesting as chronic and recurrent urticarial skin lesions with leukocytoclastic vasculitis on histology, hypocomplementemia, anti-C1q antibodies, and systemic organ involvement. This case study focuses on an adolescent who initially presented with invasive pneumococcal infection and was later diagnosed with two rare disorders: HUVS and coexisting complement factor 1 (CF1) deficiency by genotyping. The role of CF1 deficiency in the development of HUVS in this patient is uncertain but has not previously been described.

Exploring the genetic expression of Sdf1, Foxc1 and histologic changes following mandibular advancement and recovery phase in Wistar rats.

PURPOSE: This study evaluated the impact of mandibular advancement on Sdf1 and Foxc1 gene expression in the mandibular condylar cartilage of young Wistar rats. By examining the changes that occur during a unique one-month recovery period, it highlights the critical role of gene expression and condylar adaptation during the recovery phase. The analysis focused on whether, during the recovery period, reversal changes occur when functional appliances are removed and whether genetic expression important for condyle growth and adaptation downregulates. MATERIAL AND METHODS: The study involved 30 male Wistar rats divided into 2 control groups Appliance Control and Recovery Control groups, and 2 experimental groups, the Appliance group with mandibular advancement bite-jumping appliance for 30 days, and the Recovery group with appliance for 30 days followed by a 30-day recovery. Molecular analysis of condylar cartilage using real-time RT-PCR and histological assessments was conducted. RESULTS: Significant genetic expression alterations were noted in both the experimental groups for Sdf1 (p < 0.05) and Foxc1 (p < 0.05). According to histological investigations, significant alterations with an increase in the proliferative and hypertrophic layer in condylar cartilage were seen. CONCLUSION: Mandibular advancement bite-jumping appliances induce proliferative and hypertrophic layer changes in mandibular condylar cartilage, shown by elevated Foxc1 levels and decreased Sdf1 levels. Post-appliance removal, persistent gene expression reveals a true joint stimulation.

The Role of Complement C1qa in Experimental Intracerebral Hemorrhage.

Evidence indicates that the complement system is activated and plays a role in brain injury after intracerebral hemorrhage (ICH). Most studies have focused on the role of C3, C5 and the membrane attack complex. The purpose of this study was to investigate the potential impact of complement C1q, a key upstream component of the classical pathway, on ICH-induced brain injury. Wild-type (WT) and C1qa knock out (KO) mice were compared using an autologous blood injection ICH model. Magnetic resonance imaging (MRI) was performed on days 1, 3 and 7 and brains harvested on days 3 and 7 for immunohistochemistry to examine brain injury mechanisms. WT and C1qa KO mice also received an intracerebral injection of thrombin, a key factor in ICH-induced brain injury. Following MRI scans, brains were harvested for immunohistochemistry on day 1. In comparison to WT mice, C1qa KO mice had reduced hematoma erythrolysis and neutrophil infiltration after ICH. However, they also had delayed hematoma clearance, which was associated with reduced induction of phagocytic multinuclear giant cells, and increased perihematomal neuronal damage. After thrombin injection, C1qa KO mice had smaller lesion volumes, less neuronal loss, reduced neutrophil infiltration, and less BBB damage. C1qa knockout has beneficial and detrimental effects on ICH-induced brain injury mechanisms, but a consistent beneficial effect after thrombin injection. Strategies to balance the roles of C1q after ICH may represent a promising therapeutic direction.

Engaging Indigenous communities in research to inform practice: The multisite implementation evaluation of Tribal home visiting.

Community engagement (CE) is widely acknowledged as a way to enhance the ethics, rigor, and impact of research. Additionally, CE is a demonstrated way to integrate Indigenous and colonial (western) research systems. For these reasons and others, designers of the Multi-site Implementation Evaluation of Tribal Home Visiting (MUSE) used a community-engaged approach to study the implementation of federally funded home-visiting programs across 17 Indigenous communities throughout the United States. This paper describes MUSE's community-engaged approach and its practical applications from the perspective of the MUSE study team. The paper highlights key outcomes attributable to CE, addresses barriers to CE, and details responses to these barriers and their impacts. Adding to the rich evidence base demonstrating the value of community-engaged approaches, MUSE demonstrates that in-depth CE is feasible and valuable in multisite studies done in partnership with Indigenous communities.

La incorporación de la comunidad es reconocida ampliamente como una manera de mejorar la ética, el rigor y el impacto de la investigación. Adicionalmente, la incorporación de la comunidad es una manera que ha demostrado la integración de los sistemas de investigación indígenas y coloniales (occidentales). Por estas y otras razones, quienes diseñaron el programa de Implementación de la Evaluación de Visitas a Casa en Múltiples Lugares Tribales (MUSE) hicieron uso de un acercamiento de participación de la comunidad para estudiar la implementación de programas de visitas a casa subvencionados federalmente a lo largo de 17 comunidades indígenas esparcidas dentro de los Estados Unidos. Este ensayo describe el acercamiento de participación comunitaria de MUSE y sus aplicaciones prácticas desde la perspectiva del equipo de estudio de MUSE. El estudio enfatiza los resultados claves atribuibles a la participación de la comunidad, aborda barreras relacionadas con la participación de la comunidad y detalla las respuestas a esas barreras y al impacto que ellas ejercen. Como un aporte más a la rica base de evidencias que demuestra el valor de los acercamientos de participación comunitaria, MUSE demuestra que una profunda participación de la comunidad es posible y de mucho valor en múltiples estudios realizados en conjunto con las comunidades indígenas.

Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline.

Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated in Multiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.

Lanadelumab in a kidney transplant patient with hereditary angioedema due to C1-inhibitor deficiency and high cardiovascular risk - a case report.

Introduction: Cardiovascular pathologies represent the first cause of death in uremic patients and are among the leading causes of mortality in patients with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). Before 2020, the most common treatment for long-term prophylaxis in HAE-C1INH patients in Italy was attenuated androgen, which may increase cardiovascular risk by multiple mechanisms. Case description: We present a case report of a 56-year-old patient with HAE-C1INH type I affected by IgA nephropathy with severe kidney impairment. The patient experienced a first kidney transplant and, after late rejection, underwent a second kidney transplant. Further comorbidities included obesity, hypertensive cardiomyopathy, HCV liver disease, and dyslipidemia. His prophylactic therapy to prevent angioedema attacks had consisted of attenuated androgens for about 40 years. Since 2020, new modern targeted therapy for LTP, particularly lanadelumab, has shown promising results. The majority of patients with attenuated androgens have been successfully switched to lanadelumab, including our patient. Since introducing lanadelumab (300 mg subcutaneously every two weeks; after a six-month attack-free period, the dosing interval of lanadelumab was extended to four weeks), the patient has not experienced any acute HAE attack and did not report any adverse events. Moreover, we observed decreased total cholesterol, C-LDL, and body mass index, reducing the Matsushita et al. score for ten years of cardiovascular risk from 13.2% to 9.3%. Conclusion: lanadelumab is effective and safe in preventing hereditary angioedema attacks, as well as in reducing cardiovascular risk in an immunosuppressed patient with significant comorbidities. The successful outcomes of this case highlight the potential of lanadelumab as a promising prophylactic therapy.

The Self in the Consulting Room.

The realization of the Self, although the absolute basis of Jungian psychology, has internal inconsistencies, is difficult to understand, and offers a promise of realization that cannot be fulfilled. This has weakened it, and its existence is now one of speculation. If this is the case, what is to be done with it in the consulting room? How should it be introduced and accounted for, if at all? This paper suggests some alternatives but concludes that the myth of the Self has gravitas in other established traditions, and it is those that offer a more coherent framework for the emergence of the Self.

La réalisation du Soi, bien qu'elle soit la base absolue de la psychologie jungienne, présente des incohérences internes, est difficile à comprendre et offre une promesse de réalisation qui ne peut être atteinte. Tout cela a conduit à un affaiblissement, et l'existence du Soi est aujourd'hui une spéculation. S'il en est ainsi, qu'en fait­on dans la salle de consultation? Est­ce pertinent d'en faire cas? Comment devrait­il être introduit et pris en compte? Cet article suggère quelques alternatives, mais conclut que le mythe du Soi a de la valeur dans d'autres traditions établies, et que ce sont ces autres traditions qui, elles, offrent un cadre plus cohérent pour l'émergence du Soi.

La realización del Self, aunque es la base absoluta de la psicología Junguiana, tiene inconsistencias internas, es difícil de entender y ofrece una promesa de realización que no puede cumplirse. Esto la ha debilitado, y su existencia es ahora una especulación. Si esto es así, ¿qué hay que hacer con ella en la consulta? ¿Cómo debe introducirse y ser tenida en cuenta? En este artículo se sugieren algunas alternativas, pero se concluye que el mito del Self tiene un lugar de importancia en otras tradiciones establecidas, y son éstas las que ofrecen un marco más coherente para la emergencia del Self.

Diagnostic accuracy of pleural fluid complement C1q for tuberculous pleural effusion in elderly patients.

BACKGROUND: Previous studies indicated that pleural fluid complement C1q was helpful for diagnosing tuberculous pleural effusion (TPE), but the participants in these studies were young. The diagnostic accuracy of C1q for TPE in elderly patients remains unknown. This study aimed to investigate the diagnostic accuracy of C1q for TPE in elderly patients. METHODS: We prospectively recruited patients with undiagnosed pleural effusion who visited the Affiliated Hospital of Inner Mongolia Medical University between September 2018 and July 2021. Their C1q in pleural fluid was detected, and the diagnostic accuracy of C1q was assessed by the receiver operating characteristic (ROC) curve analysis. RESULTS: The median ages of patients with TPE and non-TPE were 75 and 71 years, respectively. TPE patients had significantly higher C1q than non-TPE. The area under the ROC curve (AUC) of C1q was 0.67 (95 %CI: 0.51-0.82). At the threshold of 100 mg/L, C1q had a sensitivity of 0.44 (95 %CI: 0.19-0.69) and specificity of 0.79 (95 %CI: 0.71-0.86). CONCLUSION: C1q in pleural fluid has low diagnostic accuracy for TPE in elderly patients.

Establishing a Robust Nonlinear Targeted Switch for C1 Electroproduction in Atomic Alloy Cox/Pd Bimetallenes.

Establishing a targeted switch for CO2 conversion under electric drive is essential for achieving carbon-balance by enabling selective chemicals. However, engineering the topological assembly of active sites to precisely regulate the competing pathways for various intermediates has been plagued by unclear structure-function relationships. To tailor the CO/formate pathways, herein we established a robust nonlinear targeted switch with tunable active Cox sites integrated into Pd metallene, which involves Co1/Pd single-atom alloy (favoring CO) and Co2/Pd diatomic alloy (favoring formate). Transitioning from Co1/Pd to Co2/Pd atomic alloy bimetallenes resulted in a nonlinear, high-contrast flip in selectivity, surpassing 94% for CO and formate productions in both H-cell and flow cell. Furthermore, the superior selectivity and current efficiency for CO (> 80 %) and formate (> 88%) were consistently maintained at -150 mA cm-2 over continuous 200 h. Theoretical simulations and in-situ spectroscopy analyses unveiled that appropriate adjacent metal site combinations (Pd-Pd, Pd-Co and Co-Co) lead to tunable dz2 band center and a nonlinear shift in preferred adsorption configurations of intermediates, dictating the C1 pathways. Our finding reveals a desired switch in C1 selectivity and robust stability within Cox/Pd system, providing a new perspective for fine-tuning energy conversion processes through specific topological assembly.

Hereditary Angioedema in Pregnancy Complicated by Upper Extremity Deep Venous Thrombosis: A Case Report.

Hereditary angioedema (HAE) is a rare disorder that causes episodes of angioedema due to a mutation in the C1 esterase inhibitor gene (C1-INH). Complications of HAE include intestinal obstruction, asphyxiation, and venous thromboembolism (VTE). In this case, we report a 34-year-old G4P2011 female with HAE at 24 weeks gestation presenting with acute right upper extremity pain and swelling following a peripherally inserted central catheter (PICC) line for HAE treatment infusion, revealing a right upper extremity VTE. Early treatment with Lovenox, PICC line removal, and continuation of HAE therapy via peripheral IV infusion resolved and prevented further angioedema and subsequent VTEs during this patient's pregnancy. This case serves as an example of effective management of HAE complications during pregnancy and supports peripheral IV line usage over PICC lines for medication infusions in pregnant patients with HAE. The overall purpose of this case report is to improve safety outcomes for pregnant patients with HAE by mitigating the risks of PICC line usage and to highlight the significance of VTE inclusion within the differential diagnosis in this population.

A novel technique for C1-C2 posterior screw insertion using patient-specific guides created by CT-based 3D printing.

C1-C2 fixation has been developed for the rigid fusion of atlantoaxial instability. C1 lateral mass screw (C1 LMS)-C2 pedicle screw fixation is used more frequently due to its rigid fixation and high bone fusion rate. However, C1 screw placement is relatively unsafe even with recently developed image-based navigation systems. Patient-specific screw guide templates (PSGT) were developed to improve the accuracy and safety of C1 screw placement. Herein, we investigated the outcomes of the C1-C2 posterior fixation technique using PSGT. This was a retrospective study of six patients who underwent posterior cervical spinal fusion using the PSGT between January 2022 and April 2023. Operative time, estimated blood loss, intraoperative radiation dose, surgical cost, and screw placement accuracy were evaluated and compared with those achieved with preoperative CT-based navigation (navigation group, n = 15). Screw accuracy was assessed using Neo's classification. PSGT showed good results, although the differences were not statistically significant (operation time: 104.3 ± 9.7 min vs 116.4 ± 20.8 min; estimated blood loss: 56.7 ± 72.4 mL vs 123.2 ± 162.3 mL; and radiation dose: 1.8 ± 1.2 mSv vs 2.6 ± 0.8 mSv, respectively). PSGT was particularly better in terms of the accuracy of C1 LMS (PSGT: 100%, navigation: 83.3%). The deviation at the entry point was minimal, and the difference between the sagittal and transversal angles from the preoperative plan was small. We investigated the clinical efficacy of using the PSGT for C1-C2 posterior fixation. PSGT improved the accuracy of C1 LMS insertion.

Genome-wide association analysis reveals novel candidate loci and a gene regulating tiller number in orchardgrass.

Tillers are specialized lateral shoots arising from axillary buds at basal nodes, and are also an important agronomic trait that determines the aboveground biomass and grain yield of various gramineous crops. So far, few genes have been reported to control tiller formation and most have been in the annual crop rice (Oryza sativa). Orchardgrass (Dactylis glomerata) is an important perennial forage crop with great economic and ecological value, but its genes regulating tillering have remained largely unknown. In the present study, we used a natural population of 264 global orchardgrass germplasms to determine genes associated with quantitative variation in tiller number through genome-wide association study analysis. A total of 19 putative loci and 55 genes associated with tiller number were thus identified. Additionally, 26 putative differentially expressed genes with tiller number, including DgCYC-C1, were identified by RNA-seq and genome-wide association study analysis. DgCYC-C1 which is involved in cell division, was overexpressed, revealing that DgCYC-C1 positively regulates tiller number. These results provide some new candidate genes or loci for the improvement of tiller number in crops, which might advance new sustainable strategies to meet global crop production challenges.

C1orf106 (INAVA) Is a SMAD3-Dependent TGF-ß Target Gene That Promotes Clonogenicity and Correlates with Poor Prognosis in Breast Cancer.

Transforming Growth Factor-ß (TGF-ß) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-ß signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-ß directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-ß target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-ß stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer.

The Endogenous Inhibitor of CETP, apoC1, Remains Ineffective In Vivo after Correction of Hyperglycemia in People with Type 1 Diabetes.

ApolipoproteinC1 (apoC1) is the main physiological inhibitor of the cholesterol ester transfer protein (CETP). Increased CETP activity is associated with macrovascular complications in patients with type 1 diabetes (T1D). ApoC1 has lost its ability to inhibit CETP in patients with T1D, and in vitro glycation of apoC1 increases CETP activity, suggesting that hyperglycemia could be a factor implicated in the loss of the inhibitory effect of apoC1 on CETP. Thus, we aimed to see whether improvement of glycemic control might restore apoC1 inhibitory effect on CETP. We studied 98 patients with T1D and HbA1c > 9% at baseline and 3 months after improvement of glycemic control by a medical intervention (insulin introduction or changes in multi-injection therapy or pump therapy introduction/therapeutic education for all patients). CETP activity was assessed by a radioactive method and plasma apoC1 levels were measured by ELISA. The different isoforms of apoC1 were determined by mass spectrometry. CETP activity was not significantly modified after improvement of glycemic control, despite a significant reduction in mean HbA1c (8.7 ± 1.7 vs. 10.8 ± 2, p < 0.0001). No association between plasma apoC1 and CETP activity was observed in patients with T1D at baseline, nor at 3 months, even in the subgroup of patients with optimal control (3-month HbA1c < 7%). We did not find any glycated form of apoC1 using mass spectrometry in people with T1D. Hyperglycemia in vivo does not seem to be a major factor implicated in the loss of apoC1 ability to inhibit CETP activity observed in T1D. Other factors, such as qualitative abnormalities of lipoproteins, could be involved. Our data emphasize the fact that hyperglycemia is not the only factor involved in lipid abnormalities and macrovascular complications in T1D. Clinical trial reg. no. NCT02816099 ClinicalTrials.gov.

Real-world outcomes of patients with hereditary angioedema with normal C1-inhibitor function and patients with idiopathic angioedema of unknown etiology in Canada.

BACKGROUND: Hereditary angioedema with normal C1-inhibitor function (HAE nC1-INH) and idiopathic angioedema of unknown etiology (AE-UNK) are rare conditions that cause recurrent subcutaneous and submucosal swelling. The characteristics and clinical outcomes of patients with these conditions in Canada have not been studied. METHODS: The aim of this study was to extract real-world evidence from the electronic health records of patients with HAE nC1-INH or AE-UNK who were managed in selected practices of Canadian HAE-treating specialist physicians between 01-Jan-2012 and 01-Jan-2022, to examine case numbers, treatment, clinical outcomes, and healthcare utilization. RESULTS: Of 60 patients (37 with HAE nC1-INH, 23 with AE-UNK), median (range) age at symptom onset was 21.5 (5.0-57.0) and 23.0 (10.0-54.0) years, respectively. Time to diagnosis from onset of symptoms was 7.0 (0.0-43.0) and 2.0 (- 10.0 to 50.0) years. Significant differences were observed in terms of the predominant triggers for angioedema attacks between patients with HAE nC1-INH and AE-UNK: stress (65% vs. 26%, p = 0.007) and estrogen therapy (35% vs. 9%, p = 0.031). Before diagnosis, most patients received antihistamines (50% of HAE nC1-INH and 61% of AE-UNK patients). Post-diagnosis, 73% and 74% of HAE nC1-INH and AE-UNK patients received long-term prophylaxis (LTP), with the most common LTP treatments being subcutaneous pdC1-INH (43% of HAE nC1-INH patients and 39% of AE-UNK patients) and tranexamic acid (41% of HAE nC1-INH patients and 35% of AE-UNK patients). Of patients with HAE nC1-INH, and patients with AE-UNK, 22% and 13%, respectively, were taking more than one LTP treatment concurrently. Before HAE treatment initiation, significantly fewer patients with AE-UNK compared to patients with HAE nC1-INH had angioedema attacks affecting their extremities (13% vs. 38%, p = 0.045) and GI system (22% vs. 57%, p = 0.015). In the three months following treatment initiation, patients with AE-UNK experienced significantly fewer angioedema attacks compared to patients with HAE nC1-INH (median 2.0 attacks [0.0-48.0] vs. 6.0 attacks [0.0-60.0], p = 0.044). Additionally, fewer patients with AE-UNK compared to HAE nC1-INH experienced attacks affecting their GI system (26% vs. 57%, p = 0.032). Attack duration and frequency significantly decreased for patients with HAE nC1-INH from a median of 1.00 day (range: 0.00-7.00) to 0.29 day (range: 0.02-4.00; p = 0.001) and from 10.50 attacks (range: 0.00-90.00) to 6.00 attacks (range: 0.00-60.00; p = 0.004) in the three months following HAE treatment initiation. CONCLUSIONS: Using Canadian real-world evidence, these data demonstrate differing clinical trajectories between patients with HAE nC1-INH and AE-UNK, including diagnostic delays, varied attack characteristics, treatment responses and healthcare utilization. Despite treatment response, many patients still experienced frequent angioedema attacks. These results suggest an unmet need for treatment guidelines and therapies specifically for patients with HAE nC1-INH and AE-UNK and better understanding of the pathophysiology accounting for the reported differences between the two.

Association of Endothelial Cell Activation with Acute Kidney Injury during Coronary Angiography and the Influence of Recombinant Human C1 Inhibitor-A Secondary Analysis of a Randomized, Placebo-Controlled, Double-Blind Trial.

BACKGROUND: Acute kidney injury (AKI) as a result of iodinated contrast media (CM) has been linked to CM-induced renal ischemia and toxic effects on endothelial cells (EC). The recombinant human C1 inhibitor (rhC1INH) has been shown to influence EC activation. METHODS: Secondary analysis of 74/77 (96%) participants of a double-blind, randomized, and placebo-controlled study that assessed the effect of rhC1INH on AKI. E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and CC-chemokin-ligand-5 (CCL5) were determined in frozen blood samples over 48 h and analyzed according to the treatment group and renal outcomes. RESULTS: The mean age was 76.7 years, and 37 patients each received rhC1INH and placebo, respectively. In the entire study population, minor differences in median EC activation markers/CCL5 concentrations during the first 48 h compared to baseline were observed (e.g., E-selectin 27.5 ng/mL at baseline vs. 29.7 ng/mL on day 1, CCL5: 17.7 ng/mL at baseline vs. 32.2 ng/mL on day 2). Absolute changes in ICAM-1/E-selectin concentrations correlated with a higher peak change in urinary NGAL concentrations. However, AKI was not associated with significant changes in EC markers/CCL5. Last, no significant differences in serum concentrations of EC activation markers/CCL5 were evident between the placebo and the rhC1INH group. CONCLUSIONS: CM administration during coronary angiography only mildly activated ECs within the first 48 h, which does not explain subsequent AKI. The administration of rhC1INH was not associated with a reduction of EC activation or CCL5.

Anatomic variation of the vertebral artery: a case involving a persistent first intersegmental artery at C1-C2.

BACKGROUND: We observed a rare anatomical variation of a persistent first intersegmental vertebral artery in the C1-C2 region in an elderly Chinese male cadaver at Changzhi Medical College. In this case, the vertebral artery, rather than passing through the transverse foramen of the atlas, exits the transverse foramen of C2 and enters the spinal canal at the lower portion of the C1 posterior arch. The original transverse foramen of C1 was filled with connective tissue. This report details the anatomical characteristics of this abnormal vertebral artery and discusses its anatomical, surgical, and developmental implications. PURPOSE: We describe the detailed morphological features of a rare VA variant and discuss the anatomical, clinical, and developmental aspects of this case. METHODS: A case of head dissection. The anatomical characteristics of the VA were studied and documented, and anatomical measurements were collected. RESULTS: In this case, the vertebral artery, rather than passing through the transverse foramen of the atlas, exits the transverse foramen of C2 and enters the spinal canal at the lower portion of the C1 posterior arch. The original transverse foramen of C1 was filled with connective tissue. CONCLUSION: The anomalous development of segmental arteries in our case is linked to failures in the embryonic sclerotome reconstruction during development and failure.