bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment of Bruton Tyrosine Kinase Inhibitor-Resistance Related Gene Signature to Predict Prognosis and Identification of TRIP13 As a Chemotherapeutic Target in Diffuse Large B-Cell Lymphoma
Authors: Ding Yangyang , Huang Keke , Sun Cheng , Liu Zelin , Zhu Jinli , Jiao Xunyi , Liao Ya , Feng Xiangjiang , Guo Jinjin , Zhu Chunhua , Zhai Zhimin , Xiong Shudao
Published: December 2024

Background: Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is a major cause of relapse and death in DLBCL. This study aims to explore the relationship between BTKi-resistance related genes (BRRGs) and DLBCL prognosis, and to clarify the function and mechanism of key resistance genes.

Results: In this study, we analyzed transcriptome data from parental and ibrutinib-resistant clone cell lines (GSE138126) and identified 1186 differentially expressed genes (DEGs), with 552 upregulated and 634 downregulated in the ibrutinib-resistant group. The GSE31312 dataset was used as the training cohort, while GSE87371 and GSE10846 served as external validation cohorts. Univariate Cox regression analysis identified 247 BRRGs associated with overall survival (OS). LASSO regression and tenfold cross-validation further identified 10 key BRRGs (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) to construct a prognostic signature. The resistance score formula based on 10-BRRGs is: Resistance Score=(0.2242×CARD16)+(0.0064×TRIP13)+(0.0174×PSRC1)+(0.0276×CASP1)+(0.0118×PLBD1)+(0.0627×CARD6)+(−0.0394×CAPG)+(−0.0661×CACNA1A)+(−0.3578×CDH15)+(0.6447×NDUFA4). Patients were divided into high- and low-resistance score groups based on the median resistance score. Kaplan-Meier survival analysis showed that patients with high-resistance scores had worse OS compared to those with low-resistance scores in both the training and validation cohorts. Additionally, the BRRGs signature exhibited good predictive efficacy for 1-year, 3-year, and 5-year OS, with AUC values of 0.731, 0.761, and 0.777, respectively. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Furthermore, we identified TRIP13 as a key resistance gene in this signature and found that TRIP13 was overexpressed in DLBCL and BTKi-resistant DLBCL cell lines. Knockdown of TRIP13 inhibited cell proliferation, promoted apoptosis, and enhanced the apoptotic effect of BTKi in vivo and in vitro. Mechanistically, these effects were mediated through the Wnt/β-catenin signaling pathway.

Conclusion: Our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL. Additionally, TRIP13 might be a potential therapeutic target for resistant DLBCL.
KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study
Authors: Ghimire Krishna , Goodman Alexandra , Sampat Parth , Srivastava Nimisha , Nam Myungwoo , Ross Jeffrey
Published: December 2024

Background: KMT2A (MLL1) gene is altered in a variety of hematolymphoid neoplasms and solid tumors. In acute myelocytic leukemia, the interactions between KMT2A gene fusion proteins and menin have been linked to leukemogenesis and represent new potential targets for anti-tumor therapies.

Methods: 4,190 cases of AML underwent comprehensive genomic profiling using the Foundation One Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of genomic alterations (GA) were evaluated. The tumor mutation burden (TMB) and microsatellite stability (MSS) status were determined from the sequencing data.

Results: Of the 4,190 AML cases, there were 43.1% female and 56.9% male patients with a median age of 62 years. 520 (12.4%) of the AML cases featured a GA in the KMT2A gene 99.1% of which were large rearrangements (KMT2Ara). The KMT2Ara AML cases had a median age of 62 years and were 41.7% female and 58.3% male gender. In contrast, the KMT2A not rearranged (KMT2Anra) cases had a similar mean age and gender distribution. Of the KMT2Ara cases there were 43.1% KMT2A duplications, 52.7% fusions and 4.2% not otherwise specified rearrangements. 0.9% of the KMT2A altered AML cases were short variant mutations. There were no KMT2A (0%) amplifications or deletions. GA enriched in the KMT2Ara vs the KMT2Anra AML cases included significantly increased frequencies of GA in FLT3 (27.3% vs 19.9%; p=.0001), KRAS (16.0% vs 8.0%; P<.0001) (overall; 1.1% KRAS G12C) and IDH2 (16.0% vs 7.2%; p<.0001) and significantly decreased frequencies in GA in RUNX1 (15.8% vs 19.6%; p=.05), ASXL1 (10.5% vs 16.1%; p=.0008) and TET2 (10.1% vs 16.3%; p=.0002). Similar GA frequencies in NRAS (17.2% vs 17.7%) DNMT3A (16.0% vs 16.4%) and WT1 (10.7% vs 10.1%) were not significant. The median TMB in the KMT2Ara and KMT2Anra cases was identical at 0.8 mutations/Mb with only 0.2% of both groups having a TMB of > 10 mutations/Mb. All (100%) of KMT2Ara and KMT2Anra AML cases were MS stable.

Conclusions: Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.
Timing of Peripheral Leukemic Blast Clearance in Patients with Acute Myeloid Leukemia Undergoing Induction Therapy at an Urban University Cancer Center
Authors: Quan Walter JR , Miatech Jennifer , Quan Austin , Rogers Christy , Quan Francine M
Published: December 2024

Background. Gajjar noted that patients with Acute Lymphoblastic Leukemia who had early peripheral leukemic blast clearance during induction chemotherapy experienced improved relapse-free survival (1995). Elliot described that for individuals with Acute Myeloid Leukemia (AML) treated with Cytosine Arabinoside (100 mg/m2/day by continuous infusion for 7 days) and Daunorubicin 45 mg/m2 IV or Idarubicin 12 mg/m2 IV daily for 3 days, time to clearance of peripheral leukemic blast clearance correlated with relapse-free survival (2007). Methods. In this retrospective study of our patients seen/treated between November, 2019 and July 2024, seventeen patients with Acute Myeloid Leukemia with evidence of leukemic blasts detected by automated hematology analyzer and confirmed by visual examination on peripheral smear, were treated with curative intent with Cytosine Arabinoside 100 mg/m2/day by continuous intravenous infusion for 7 days and Daunorubicin 90 mg/m2 IV (one patient over concern about potential cardiomyopathy received Mitoxantrone 12 mg/m2 IV) daily for 3 days or for the two patients with myelodysplasia-related AML, liposomal Daunorubicin 44 mg/m2 and liposomal Cytosine Arabinoside 100 mg/m2 intravenously on days 1, 3, and 5. Results. Patient characteristics: 9 males/8 females, median age-62 (range: 21-76), African-American (8), Caucasian/Latin American (7), Asian (2); median circulating absolute peripheral blast count-6107/mm3, median white blood count-11.8/mm3, and median LDH-473 IU/L. ELN risk categories: favorable-3 (18%), intermediate-7 (41%), adverse-7 (41%). On post-induction bone marrow examination on day 28, nine patients achieved morphologic complete response (CR). Patients experiencing CR had median peripheral leukemic blast clearance on day 3 (2-6) compared to those experiencing other than CR who had median blast clearance on day 6 (3-9); p=0.049 (Mann Whitney test). Conclusion. Early clearance of blasts from peripheral blood during induction therapy of patients with AML treated with high-dose Daunorubicin (90 mg//m2) may serve as a predictor of complete response.
Circulating Peripheral Blood Mononuclear Cells from Adults with Sickle Cell Disease (SCD)- Associated Pulmonary Hypertension (PH) Patients Have Increased Iron Content and a Unique Multi-Omic Signature
Authors: Lisk Christina , Cendali Francesca I , Swindle Delany , George Gemlyn , Nuss Rachelle , Hassell Kathryn Louise , Buehler Paul , D'Alessandro Angelo , Irwin David
Published: December 2024

Introduction: The prevalence of PH in the SCD adult population is 6-10%, compared to approximately 3 in one million in the general population. However, the molecular mechanisms are not clearly defined, particularly as they relate to the onset and progression of SCD-PH. Previously, we have shown an accumulation of pulmonary vascular macrophages (Mϕ), iron, and hemoglobin (Hb) in SCD-PH, suggesting that hemolysis-mediated iron-overloading is a pathological contributor to progressive pulmonary vascular disease with SCD patients. Hypothesis: Here we hypothesized that PBMCs in SCD-PH patients will have a higher iron content and express a different proteomic and metabolomic landscapes than PBMCs collected from adults with other etiologies of PH and SCD without PH. Methods: PBMCs were analyzed for iron content and multi-omics analysis from six (n=6) SCD-PH (PHSCD), ten (n=10) PH without SCD (PH), and twenty two (n=22) SCD no PH patients (SCD). Results: ICP analysis revealed that PBMCs from PHSCD and SCD patients had greater iron concentration then PH patients. Proteomics captured a total 6,487 proteins from PBMCs isolated from PHSCD, PH, and SCD patients. Remarkably, 2,251proteins were significantly altered between PHSCD and PH patients (p-value £ 0.05), including 209 proteins associated with completement, 38 proteins coupled with inflammation, 163 proteins linked from idiopathic PH, and 48 proteins correlating to iron. Using the top 100 differentiated proteins, network analysis showed a significant increase in cellular macromolecule catabolic processes. Metabolic analysis depicted a decrease in alpha linolenic acid (ALA) metabolism and an increase in purine metabolism, but not purine recycling. ALA metabolism has been shown to be antioxidant and anti-inflammatory. In contrast, comparing PHSCD to SCD just 204 proteins (9%) were significantly altered; 90% less than in PH (p<.05). Importantly, this includes SAMD14, a protein known to be involved in stressed-dependent erythropoiesis. The top 100 differentiated proteins were used for network analysis and were shown to highly correlate with positive regulation of transcription. Metabolomic differences were not as well clustered as the proteomic differences. Most metabolites were decreased and were highly correlated with the Warburg Effect and glycolysis. Conclusion: The results support the hypothesis that PBMCs from adults with SCD-associated PH differ from those with other etiology-associated PH and even the greater SCD population. Further, the relative similar PBMC phenotype observed between SCD-PH and SCD patients (as compared to PH patients) may suggest why SCD patients are at such a high risk of developing PH.
Differential Effects of GPVI Deletion and SYK Inhibition on Thrombus Organization and Platelet Adhesion in a Murine Jugular Puncture Wound Model
Authors: Storrie Brian , Pokrovskaya Irina D , Ball Kelly K. , Webb Michael W.
Published: December 2024

Essential Points GPVI is the major collagen receptor in platelets as well as a receptor for fibrinogen/fibrin and signals intracellularly by activating SYK kinase.Deletion of GPVI in contrast to SYK inhibitor treatment has a mild but significant effect on jugular vein puncture wound bleeding cessation in the murine model. The SYK inhibitor was used at a concentration sufficient to inhibit ferric chloride induced occlusive clotting.Deletion of either GPVI or SYK inhibition inhibits the induction of a high platelet activation state at the collagen/thrombus interface and results in a thinning of the extravascular cap that leads to bleeding cessation in the jugular puncture wound model.The GPVI knockout has a profound effect on the tightness of platelet packing in a 5-min post puncture wound and affects thrombus structure in general through the formation of a very loose intravascular thrombus crown. In contrast, SYK inhibition has little effect on thrombus structure in general.The substantial effect of GPVI knockout on platelet adhesion and intravascular crowning of the puncture wound thrombus indicates a significant late role of GPVI in thrombus formation that is presumably mediated by GPVI-fibrinogen/fibrin interactions.These findings have clinical implications in terms of targeting GPVI to inhibit thrombosis. Is targeting the intracellular SYK pathway versus extracellular domains of GPVI safer? The SYK inhibitor Bi 1002494 is known to preferentially affect thrombosis versus hemostasis (van Eeuwijk et al, 2016; present work)

Literature Cited

Van Eeuwjk JM, Steger D, Lamb DJ, Kraft P, Beck S, Thielmann I, Keifer F, Walzog B, Stoll G, and Nieswandt B. 2916. The novel oral Syk Inhibitor, Bi 1002494, protects mice from arterial thrombosis and thromboinflammatory brain infarction. Arterscler Throm Vasc Biol 36:1247-1253.
BCL-2 Inhibitor Venetoclax Shows Synergistic Effects on CD8 T Cell Proliferation and Blast Death in Vitro When Combined with Anti PD-1 Checkpoint Inhibitor
Authors: Cho Hyun , Lind Evan F. , Pandita Ravina , Kosaka Yoko
Published: December 2024

Background

Acute myeloid leukemia (AML) is a hematologic malignancy with significant heterogeneity characterized by various genetic mutations and translocations, rendering its treatment highly complicated. Of the numerous factors predicting prognosis, age plays a big role in determining the course of treatment (Juliusson et al. Blood 2009). Median age of 68 (NIH, 2024) poses a challenge to successful treatment induction with exponentially higher mortality rate in elderly patients (Walter et al. Journal of Clinical Oncology 2011) . Median survival rate 4.6 months and 1-year survival rate of 28% in patients age over 70 treated with cytarabine-based chemotherapy. BCL-2 inhibitors, such as venetoclax, have been recently approved for treating newly diagnosed and relapsed AML, improving outcomes for patients over 60 (Pollyea et al. Bone Marrow Transplant 2021). Although BCL-2 inhibition and its effects on T cell proliferation has been demonstrated in the past (Cheng et al. Oncogene 2004), the effects on CD 8 T cell proliferation when combined with checkpoint inhibitors, such as anti PD-1, are yet to be explored.

Methods

Splenocytes from a mouse model of AML with FLT3-ITD, TET2 mutations and wild type mice were collected for T cell proliferation assays. Treatment groups included: venetoclax alone and with azacitidine. On Day 3, the cells were harvested and stained for flow cytometry. CD 8 T cells were defined as CD3+CD8+CD4- and proliferation was quantified with Cell Trace Violet staining. AML blasts were defined as CD3-CD11b+.

Results

Flow cytometry analysis showed significantly increased CD8 T cell proliferation in venetoclax-treated murine AML groups in vitro, and more AML blast deaths when combined with anti PD-1 compared to the standard combination with azacitidine.

Conclusion

We found a higher population of proliferated CD 8 T cells and more blast deaths in venetoclax-treated groups when combined with anti PD-1, than azacitidine-combined groups. However, same analysis showed less T reg cell survival in azacitidine, warranting further investigation on the mechanism of the higher CD 8 T cell proliferation and increased blast deaths when Venetoclax is used with anti PD-1.
Sickle Cell Disease (SCD)-Related Stigma Among Indian SCD Patients - Findings of a Multicentric Study
Authors: Babu Bontha V , Jena Rabindra Kumar
Published: December 2024

Background: Sickle Cell Disease (SCD) is the most prevalent hemoglobinopathy, affecting approximately 5% of the global population. Within India, the tribal population has been a primary focus of the national SCD program. Due to increased SCD-related awareness, SCD patients and their caregivers in these communities often face health-related stigma due to the multifaceted impact of the disease.

Methodology: This study was implemented in five tribal-dominated districts of India and initiated with exploratory qualitative data, followed by the development of an SCD-related stigma scale and measuring the stigma using the developed scale. In addition, the impact of stigma on Health-Related Quality of Life (HRQoL) and health care utilization. Initially, the study's framework for developing the stigma tool was rooted in Bronfenbrenner's Ecology of Human Development. Subsequently, quantitative surveys were conducted to measure the SCD-related stigma, HRQoL, which was measured through the Medical Outcome Study (MOS) 36-item short-form health survey (SF-36) for adult patients, SCD module and Family Impact Module (FIM) of Pediatric Quality of Life Inventory (PedsQL) for SCD pediatric patients and healthcare-seeking behavior of these patients and caregivers.

Results: The study identified four themes and several subthemes explaining the nature of stigma, its sources, and contributing factors. These themes - (i) perceived stigma, encompassing elements such as disclosure, self-isolation, and self-judgment; (ii) internalization of stigma; (iii) experienced stigma, specifically the impact of the disease on daily life; and the support systems required by patients. The framework underscored the varying degrees of stigma in different aspects of patients' lives and environments. The study also found a considerable negative impact of stigma on HRQoL. Healthcare-seeking behavior is also impacted due to stigma as well as health system-related factors. Poor treatment-seeking behavior is reported, and many patients have not sought appropriate SCD-related treatment, and a considerable number of patients did not report regular hydroxyureas therapy.

Conclusion: Our study, for the first time from India, measured the SCD-related stigma among SCD patients and their caregivers. As the national SCD program has been initiated and implemented in the primary health care system, these findings have considerable implications. Awareness generation activities and preventive measures are to be implemented by taking the stigma and its impact into consideration.
Space Disinfection Using TiO2 Photocatalyst Reduces the Incidence of Febrile Neutropenia in Cancer Patients
Authors: Iizuka Kazuhide , Ochiai Heihachiro , Iizuka Yoshikazu , Somei Junichi , Miura Katsuhiro , Nakamura Hideki , Nakayama Tomohiro , Hatta Yoshihiro , Takei Masami
Published: December 2024

Background/Purpose

Febrile neutropenia (FN) is life-threatening condition, and airborne microorganisms have been identified as one of the potential transmission routes. Therefore, air disinfection using laminar air flow (LAF) unit with high-efficiency particulate air (HEPA) filter is recommended to prevent infection in patients undergoing intense chemotherapy. However, HEPA filters are expensive and not available in sufficient numbers. Recently, TiO2-photocatalyzed reactions have garnered attention because of their strong oxidative degradation ability against various bacteria, fungi, and viruses. In this study, we investigated the effect of spatial sterilization using a photocatalyst device, which is inexpensive and easy to install and maintain, on the incidence of FN and the causative microorganisms in patients undergoing cancer treatment.

Methods

The space disinfection device which equipped a mechanism that irradiates photocatalytic platinum-added titanium dioxide with 405 nm wavelength LED (LED-TiO2 device) is exhibits a strong oxidative degradation effect. In a previous study, the LED-TiO2 device inactivated aerosolized SARS-Cov-2 viruses in a 120-L acrylic box in 20 minutes. LED-TiO2 device was installed per 21.5-35 m³ in hospital rooms to investigate changes in the incidence of FN and the number of airborne microorganisms.

Results

Airborne microorganisms in the hospital rooms matched those responsible for nosocomial infections. The incidence of nosocomial infections showed a decreasing trend in the After group compared with that in the before group, but the difference was not significant (Figure 1c; 13/32 versus 5/23, P = 0.160). However, the incidence of FN was significantly reduced after installation of the LED-TiO2 device (9/13 vs 2/12, P=0.015). Among the FN cases, pneumonia occurred in 4/13 patients before group and 0/12 patients after group (P = 0.096). In addition, When G-CSF was not administered due to AML/MDS or induction of remission therapy, there was a significant decrease between the Before and After groups (7/8 versus 2/8, P = 0.041). The LED-TiO2 device decreased the number of airborne microorganisms in patient-free rooms by approximately 75% after 2 hours (P<0.001). When patient was in the room, the number of airborne microorganisms increased with medical procedure. However, after 20 minutes after procedure, the number of airborne microorganisms was approximately 50% lower than without the device room (p=0.019).

Conclusions

The LED-TiO2 device successfully achieved spatial disinfection in hospital rooms, and reduced the incidence of FN. Spatial disinfection using photocatalysts is considered an effective new infection prevention measure in patients with severe neutropenia undergoing cancer treatment.
TIFAB modulates metabolic pathways in KMT2A::MLLT3−induced AML through HNF4A
Authors: Wang Yang , Xiu Yan , Dong Qianze , Zhao Jinming , Neumbo Kelao , Miyagi Masaru , Borcherding Nicholas , Fu Lin , De Celis Havana , Pintozzi Nicolas , Starczynowski Daniel T. , Zhao Chen
Published: December 2024

Tumor necrosis factor (TNF) receptor–associated factor (TRAF)–interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-κB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3–driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15–mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3–induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene set enrichment analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation. By comparing genes upregulated in TIFAB-overexpressing LSPCs with those downregulated upon Tifab deletion, we identify hepatocyte nuclear factor 4 alpha (Hnf4a) as a key TIFAB target, regulated through the inhibition of NF-κB component RelB, which suppresses Hnf4a in leukemia cells. HNF4A, a nuclear receptor involved in organ development, metabolism, and tumorigenesis, rescues the metabolic defects caused by Tifab deletion and enhances leukemia cell engraftment. Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3–induced AML and uncover a novel regulator in leukemia biology.
Peripheral neuropathy in the phase 3 ASPEN study of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia
Authors: Heyman Benjamin M. , Opat Stephen S. , Wahlin Björn E. , Dimopoulos Meletios-Athanasios C. , Castillo Jorge J. , Tedeschi Alessandra , Tam Constantine S. , Buske Christian , Owen Roger G. , Leblond Véronique , Trotman Judith , Barnes Gisoo , Chan Wai Y. , Schneider Jingjing , Allewelt Heather , Cohen Aileen , Matous Jeffrey V.
Published: December 2024

Peripheral neuropathy (PN) is a significant cause of morbidity associated with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. This ad hoc analysis examined treatment outcomes with zanubrutinib or ibrutinib on PN symptoms associated with WM in patients enrolled in ASPEN. Logistic regression was performed between PN symptom resolution and several predictors. Health-related quality of life (HRQOL) was assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Forty-nine patients with PN symptoms were included (zanubrutinib treated, n = 27; ibrutinib treated, n = 22). Overall, 35 patients (71.4%) experienced resolution of PN symptoms, with a median time to resolution of 10.1 months (range, 1-46.8). In cohort 1 (MYD88 mutation), the median time to PN symptom resolution was 4.6 months (range, 1.1-46.8) with zanubrutinib and 14.1 months (range, 1-44) with ibrutinib. Logistic regression demonstrated a significant relationship between PN symptom resolution and both major response and lower baseline anti–myelin-associated glycoprotein antibody levels. Patients with PN symptom resolution had greater improvement in HRQOL. Physical functioning improved in patients with PN symptom resolution and was unchanged in patients without resolution. Improvements observed in PN symptoms may be in response to a reduction in immunoglobulin M. Although further investigation is required, this analysis supports the potential use and further exploration of Bruton tyrosine kinase inhibitors to treat PN symptoms in patients with WM. This trial was registered at www.clinicaltrials.gov as #NCT03053440.
Nailfold videocapillaroscopy – a novel method for the assessment of hemodynamic incoherence on the ICU
Authors: Kintrup Sebastian , Listkiewicz Lukasz , Arnemann Philip-Helge , Wagner Nana-Maria
Published: December 2024

Background

Loss of hemodynamic coherence is a phenomenon in critically ill patients. Due to inflammatory events and endothelial remodeling, macro- and microhemodynamics are decoupled from each other, resulting in microcirculatory disturbances and end organ ischemia despite adequate vital parameters. So far, quantification of perfusion of vessels with < 100 μm diameter on the intensive care unit (ICU) was regularly performed with incident darkfield (IDF) microscopy. Nailfold videocapillaroscopy (NVC), however, is an established and easy method for visualization of the microcirculation in chronic diseases. We here evaluated NVC in critically ill patients and compared its use with consensus microcirculatory assessment of IDF-microscopy.

Methods

A new score, the capillary microcirculation (CapMic) score summarizing the microcirculation of the nail fold at four regions of digitus III, IV and V in a number between 0 (= no microcirculation) and 1 (= completely preserved microcirculation) was first established in 10 healthy volunteers and compared to the Microangiopathy Evolution Score (MES) standardized for NVC in chronic diseases. Then, n = 60 critically ill patients were recruited from a surgical ICU. Consensus-defined IDF scores and NCV data were compared at a single time point.

Results

Evaluation of the CapMic score in 10 healthy volunteers at rest and under iatrogenic limb ischemia showed robust changes (0.80 ± 0.03 vs. 0.51 ± 0.12, p < 0.001). In critically ill patients, the IDF microscopy parameters “proportion of perfused vessels” (PPV) and “microvascular flow index” (MFI) inversely correlated with the MES (Spearman’s R = -0.590, p < 0.001; Spearman’s R = −0.585, p < 0.001). There was a positive correlation between PPV and the CapMic score (Spearman’s R = 0.714, p < 0.001) and between MFI and the CapMic score (Spearman’s R = 0.711, p < 0.001) and an inverse correlation between MES and the CapMic score (Spearman’s R = −0.610, p < 0.001). Both sublingual and nailfold microcirculation deteriorated under rising norepinephrine- and crystalloid volume-requirements.

Conclusion

NVC-imaging provides comparable information on the microcirculation in critically ill patients compared to sublingual IDF microscopy. NCV could represent a new, additional method for diagnosing microcirculatory parameters on the ICU.
Analysis of Huanglongbing transmission model with vector preferences and heterogeneous environments
Authors: Luo Youquan , Tang Shuimei , Zhang Fumin , Liu Yujiang , Gao Shujing
Published: December 2024

The world citrus industry is confronting an unprecedented challenge from citrus Huanglongbing (HLB). With no resistant commercial citrus varieties or curable chemicals currently available, HLB remains the top threat to the world citrus industry. In this paper, two dynamic models of citrus HLB are proposed based on the preference and diffusion of citrus psyllids. The first model is a single-patch model of HLB with vector preference. The basic reproduction number of the model is calculated, and dynamic properties of the single-patch model, including the existence and local stability of the disease-free equilibrium, are analyzed. By sensitivity analysis, the parameters that have a significant impact on the basic reproduction number are identified. Numerical simulations are conducted to demonstrate that the preference of citrus psyllids is not conducive to disease prevention. Considering the diffusion of citrus psyllids between two patches, a two-patch diffusion model of HLB with preference is formulated. The global basic reproduction number of the diffusion model is determined, and the global stability of the disease-free equilibrium is established under certain conditions. Finally, numerical simulation results explore how the preference behavior of the vector and the coupling strength between two patches affect the HLB transmission.
Innovative sterile male release strategies for Aedes mosquito control: progress and challenges in integrating evidence of mosquito population suppression with epidemiological impact
Authors: Rahul Arya , Reegan Appadurai Daniel , Shriram A. N. , Fouque Florence , Rahi Manju
Published: December 2024

Background

Aedes mosquitoes pose a significant global threat as vectors for several debilitating arboviruses, including dengue, Zika, yellow fever, and chikungunya. Their unique breeding habits, behavior, and daytime activity complicate control efforts, prompting the search for innovative solutions. The sterile insect technique (SIT) and incompatible insect technique (IIT) are promising new techniques under investigation. This review synthesizes findings from field trials on SIT and/or IIT for Aedes mosquito control.

Methods

A scoping review was conducted through comprehensive searches on Scopus, Web of Science, MEDLINE, PubMed, and preprint repositories up to April 25, 2024. Studies were initially screened for relevance based on their titles and abstracts, followed by a full-text review conducted by two independent extractors. Only field trials with control groups were included, with the final assessment focusing on trials reporting epidemiological outcomes. Data were abstracted into templates, emphasizing study design, intervention details, and outcomes. The review adhered to the PRISMA-ScR guidelines.

Results

The search identified 21 field trials in various countries against Aedes mosquitoes. These trials employed diverse methodologies and mosquito release strategies, achieving varying levels of mosquito population suppression. Notably, two SIT and two Wolbachia-based IIT trials reported epidemiological outcomes, including reductions in dengue incidence and associated risk ratios. However, the reliance on national surveillance data for assessing dengue incidence suggests caution due to the potential underreporting of subclinical cases.

Conclusions

The review underscores the promise of SIT and IIT for controlling Aedes mosquito populations, citing successful reductions in mosquito densities and dengue transmission. However, it calls for more rigorous study designs and standardized methodologies, as well as the adoption of comprehensive frameworks to accurately assess the effectiveness of these interventions. Future research should focus on bridging gaps in real-world effectiveness by addressing factors such as feasibility, acceptability, scalability, and cost, which are crucial for guiding their successful large-scale deployment in any country.
The interplay of forgiveness by God and self-forgiveness: a longitudinal study of moderating effects on stress overload in a religious Canadian sample
Authors: Skalski-Bednarz Sebastian Binyamin
Published: December 2024

Background

A consistent link between self-forgiveness and well-being has been established, yet a full understanding of self-forgiveness and its correlates, particularly in relation to forgiveness by God, remains limited, especially given that most existing data are cross-sectional. This study sought to address this gap by investigating the interplay between self-forgiveness and perceived forgiveness by God in reducing stress overload among religious individuals over time.

Methods

This study involved 211 religious individuals in Canada, 55% of whom were female. Through multilevel analyses, the research examined the between-person, within-person, and cross-level effects of these forms of forgiveness on stress across three waves conducted over a total 12-month period.

Results

The findings suggested that the effectiveness of self-forgiveness in mitigating stress may be significantly influenced by the perception of forgiveness by God, with the greatest stress reduction occurring when forgiveness by God was perceived at higher levels.

Conclusions

These findings highlight the potential value of incorporating spiritual dimensions into psychological approaches to stress management, offering insights into the complex relationships between different forms of forgiveness and their impact on mental health of religious individuals. Future research is encouraged to further explore these dynamics across diverse cultural and religious contexts.
Portraying heritage corridor dynamics and cultivating conservation strategies based on environment spatial model: an integration of multi-source data and image semantic segmentation
Authors: Chen Jinliu , Zhao Xiaoxin , Wang Haoqi , Yan Jianxiong , Yang Di , Xie Kong
Published: December 2024

Under the background of the transformation of resource-based cities, heritage as the symbolic cultural representation plays a synergistic role in revitalizing urban vibrancy. A majority of contemporary research focuses on specific heritage restoration and renovation. However, scant literature has been concerned with an integrated heritage corridor upgrading framework from the spatial quality perspective, which has limited effects on promoting urban socio-cultural development. This research aims to evaluate the heritage corridor through the GIS-based environmental spatial model (ESM) with multi-source data and verification through AI-based image semantic segmentation analysis, cultivating suggestions for heritage restoration and management to revitalize the holistic urban–rural areas. The research takes a resource-based city, Fengfeng Mining District (FMD) in Handan, China, as a research case. The research found heterogeneity of the heritage evaluation results and their geographical distribution, and image-based spatial quality verification evidenced the suitability and reliability of ESM for heritage assessment. This research proposes a quantitative and holistic evaluation framework for assessing and improving heritage corridors. The restoration and optimization of heritage corridors should combine a comprehensive, precise, and people-oriented spatial quality assessment, and the GIS-based ESM analysis method could be an effective decision-making support system.
Human liver stem cells and derived extracellular vesicles protect from sepsis-induced acute lung injury and restore bone marrow myelopoiesis in a murine model of sepsis
Authors: Costamagna Andrea , Pasquino Chiara , Lamorte Sara , Navarro-Tableros Victor , Delsedime Luisa , Fanelli Vito , Camussi Giovanni , Del Sorbo Lorenzo
Published: December 2024

Background

Sepsis is a condition with high mortality and morbidity, characterized by deregulation of the immune response against the pathogen. Current treatment strategies rely mainly on antibiotics and supportive care. However, there is growing interest in exploring cell-based therapies as complementary approaches. Human liver stem cells (HLSCs) are pluripotent cells of mesenchymal origin, showing some advantages compared to mesenchymal stem cells in terms of immunomodulatory properties. HSLC-derived extracellular vesicles (EVs) exhibited a superior efficacy profile compared to cells due to their potential to get through biological barriers and possibly to avoid tumorigenicity and showed to be effective in vivo and ex vivo models of liver and kidney disease. The potential of HLSCs and their EVs in recovering damage to distal organs due to sepsis other than the kidney remains unknown. This study aimed to investigate the therapeutic potential of the intravenous administration of HSLCs or HSLCs-derived EVs in a murine model of sepsis.

Results

Sepsis was induced by caecal ligation and puncture (CLP) on C57/BL6 mice. After CLP, mice were assigned to receive either normal saline, HLSCs or their EVs and compared to a sham group which underwent only laparotomy. Survival, persistence of bacteraemia, lung function evaluation, histology and bone marrow analysis were performed. Administration of HLSCs or HLSC-EVs resulted in improved bacterial clearance and lung function in terms of lung elastance and oedema. Naïve murine hematopoietic progenitors in bone marrow were enhanced after treatment as well. Administration of HLSCs and HLSC-EVs after CLP to significantly improved survival.

Conclusions

Treatment with HLSCs or HLSC-derived EVs was effective in improving acute lung injury, dysmyelopoiesis and ultimately survival in this experimental murine model of lethal sepsis.
Bilateral occlusive retinal vasculitis secondary to intravitreal faricimab injection: a case report and review of literature
Authors: Lee Yong Min , Gurung Rajya , Gilhotra Jagjit Singh , Simon Sumu , Cugati Sudha
Published: December 2024

Background

This article describes a rare occurrence of bilateral retinal occlusive vasculitis secondary to intravitreal faricimab injection.

Case presentation

A 72-year-old female with age-related macular degeneration presented with bilateral retinal occlusive vasculitis following intravitreal faricimab injections. The patient was treated with 3 days of intravenous methylprednisolone followed by oral prednisolone taper and topical steroid therapy. Resolution of retinal occlusive vasculitis was observed 2 months post treatment.

Conclusions

Retinal occlusive vasculitis is a rare complication of intravitreal anti-vascular endothelial growth factor (anti-VEGF), particularly with faricimab injections. We also present a review of literature regarding retinal occlusive vasculitis following intravitreal anti-VEGF injections and propose further information regarding its pathophysiology.
Design and implementation of O-PAS user-defined function blocks
Authors: Pantoni Rodrigo Palucci , Mossin Eduardo André , Halfeld Victor Teixeira C. , Donaires Omar Sacilotto , da Silva Afonso Eduardo , da Silveira Guilherme Santos , Marcelino Mariana Ferraz , do Carmo Sampaio Pedro , De Oliveira Spagiari Victoria
Published: December 2024

In recent decades, standardisation has become crucial in Industrial Automation Systems, promoting interoperability among devices from different manufacturers. Nonetheless, the portability of manufacturing engineering tools continues to present a significant challenge. AutomationML (IEC 62714 -5) has played a role in formulating strategies that leverage O-PAS Standard Function Blocks. The O-PAS specification includes several standards, such as IEC 62443, IEC 61499, IEC 61131–3, OPC-UA (Open platform communications unified architecture), DCS (Distributed control system), and PLC (Programmable logic controller). This highlights the necessity of integrating new technologies with legacy systems to achieve enhanced interoperability. In this context, this work proposes the development of User-Defined Function Blocks (UDFB) that adhere to O-PAS standards and can be implemented across any compliant system. The proposed methodology is aligned with O-PAS standards, leading to the inclusion of UDFB information in XML format within the Function Block Library and AutomationML.
Management of clozapine-associated neutropenia
Authors: Gupta Sumeet , Bannon Angela , Nodiyal Sunil , Sinha Baxi
Published: December 2024

Clozapine is the only evidence-based intervention for treatment-resistant schizophrenia. One of the drug's most well-known and potentially fatal adverse effects is agranulocytosis (severe neutropenia). Hence, regular blood tests are an essential component of clozapine treatment. This article presents a narrative review of the history, incidence, potential aetiology and management of clozapine-associated neutropenia. It gives an overview of clozapine monitoring requirements, including those for benign ethnic neutropenia. We point to the growing body of evidence that the risk of clozapine-induced agranulocytosis is mostly confined to the first year of treatment and that the risk of fatality is considerably lower than previously assumed. Given the absence of alternative evidence-based interventions for treatment-resistant schizophrenia, we suggest that rechallenging with clozapine should be considered in most patients with clozapine-associated mild to moderate neutropenia who do not respond to other treatments. A more careful risk–benefit analysis is needed in cases of severe neutropenia (agranulocytosis).
Multicenter External Validation of the Accuracy of Computed Tomography Criteria for Detecting Thoracolumbar Posterior Ligamentous Complex Injury
Authors: Aly Mohamed M. , Abdelaziz Mohamed , Alfaisal Faisal A. , Alrumian Rumian Abdulkarem , Espinoza Xavier A. Santander , Gutiérrez-González Raquel , García Teresa Kalantari , Al Fattani Areej , Almohamady Waleed , Al-Shoaibi Abdulbaset M.
Published: December 2024

BACKGROUND AND OBJECTIVE:

Recent studies have proposed computed tomography (CT) criteria for posterior ligamentous complex (PLC) injury: disrupted if ≥2 CT findings, indeterminate if single finding, and intact if 0 CT findings. The study aims to validate the CT criteria for PLC injury externally.

METHODS:

Three level 1 trauma centers enrolled 614 consecutive patients with acute thoracolumbar fractures (T1-L5) who received CT and MRI. Three reviewers from each center assessed CT for facet joint malalignment, horizontal laminar fracture, spinous process fracture, and interspinous widening and MRI for disrupted PLC, defined as black stripe discontinuity. The primary outcome is the diagnostic accuracy of CT criteria (0, 1, ≥2 findings) in detecting disrupted PLC on MRI using all CT readings. A subgroup analysis was performed for each participating center and reviewer. The inter-reader agreement on PLC status on MRI and CT criteria was assessed using Fleiss Kappa (k).

RESULTS:

The positive predictive value for PLC injury was 0 findings 3%, single positive CT 43%, and ≥2 CT findings in 94%. The accuracy measures were consistent across various centers and reviewers. The area under the curve for ≥1 CT finding in detecting PLC injury ranged from 90% to 97%, indicating excellent discrimination for all centers. The inter-reader k on PLC status by MRI and overall CT findings was substantial (k > 0.60).

CONCLUSION:

This study externally validates the previously proposed CT criteria for PLC injury. A total of ≥2 positive CT findings or 0 CT findings can be used as criteria for a disrupted PLC (B-type injury) or intact PLC (A-type injuries), respectively, without added MRI. A single CT finding implies indeterminate PLC status and the need for further MRI assessment. The CT criteria will potentially guide MRI indications and treatment decisions for neurologically intact thoracolumbar burst fractures.
Understanding Permeability Changes in Vestibular Schwannomas as Part of the Dynamic Response to Radiosurgery Using Golden-Angle Radial Sparse Parallel Imaging: A Retrospective Study
Authors: Meng Ying , Lee Matthew D. , Berger Assaf , Wiggins Roy , O'Callaghan James , Bernstein Kenneth , Santhumayor Brandon , Block Kai Tobias , Fatterpekar Girish , Kondziolka Douglas
Published: December 2024

BACKGROUND AND OBJECTIVES:

Vestibular schwannomas demonstrate different responses after stereotactic radiosurgery (SRS), commonly including a transient loss of internal enhancement on postcontrast T1-weighted MRI thought to be due to an early reduction in tumor vascularity. We used dynamic contrast-enhanced based golden-angle radial sparse parallel (GRASP) MRI to characterize the vascular permeability changes underlying this phenomenon, with correlations to long-term tumor regression.

METHODS:

Consecutive patients with vestibular schwannoma who underwent SRS between 2017 and 2019, had a transient loss of enhancement after SRS, and had long-term longitudinal GRASP studies (6, 18, and 30 months) were included in this retrospective cohort analysis (n = 19). Using GRAVIS (https://gravis-imaging.org/gravis/), an analysis pipeline for GRASP studies, we extracted the key parameters normalized to the venous sinus from a region of interest within the tumor.

RESULTS:

The peak, area under the curve (AUC), and wash-in phase slope were significantly reduced at 6, 18, and 30 months after SRS (corrected P < .05), even while the internal enhancement returned in the tumors. Larger pre-SRS tumors were more likely to have a greater reduction in peak (P = .013) and AUC (P = .029) at 6 months. In a subset of patients (N = 13) with long-term follow-up, the median percentage reduction in tumor volume was 58% at a median of 62 months. These patients showed a strong correlation between peak, AUC, and wash-in phase slope changes at 6 months and tumor volume at the last follow-up.

CONCLUSION:

After SRS and loss of internal contrast uptake within vestibular schwannomas, a slow vascular permeability dynamic persisted, suggesting the presence of postradiation processes such as fibrosis. We show for the first time, using GRASP, a quantitative assessment of the vascular radiobiological effect.
Intraoperative Real-Time Near-Infrared Image-Guided Surgery to Identify Necrotic Tissues
Authors: Fujiwara Eiji , Muto Jun , Murayama Kazuhiro , Yamada Seiji , Hirose Yuichi
Published: December 2024

BACKGROUND AND IMPORTANCE:

The usefulness of intraoperative real-time fluorescence navigation using indocyanine green (ICG) for metastatic brain tumors, schwannomas, and meningiomas is well established. However, its application in cases of radiation-induced brain necrosis remains unexplored. Surgical intervention is performed in symptomatic and medically refractory cases; however, radiation-necrotic lesions often exhibit a diffuse pattern with unclear surgical boundaries, making it challenging for surgeons to identify the lesion during the surgery.

METHODS:

Four patients with intracranial necrotic tissues received 1.5 mg/kg ICG 1 hour before observation during the surgery. We used near-infrared fluorescence to identify the necrotic location.

CLINICAL PRESENTATION:

Case 1: A 61-year-old man with lung cancer and metastatic brain tumor history exhibited left-sided weakness a year after craniotomy and radiotherapy. A new lesion required surgery, where ICG fluorescence imaging highlighted a significant contrast in the resection cavity, aiding in successful lesion removal without complications. Case 2: A 51-year-old man with resected glioblastoma developed paralysis. ICG fluorescence during surgery confirmed necrosis and enabled the lesion's removal despite potential inaccuracies due to brain shift, without ICG-related complications. Near-infrared fluorescence could visualize necrotic tissues in all 4 cases. The mean signal-to-background ratio of the necrotic tissues in delayed window ICG was 3.5 ± 0.7. The ratio of the gadolinium-enhanced T1 tumor signal to the brain (T1-weighted background ratio) was 2.3 ± 0.4.

CONCLUSION:

This report is the first to demonstrate the efficacy of ICG intraoperative fluorescence imaging in identifying radiation-induced necrotic brain tissues.