bluuebunny/crossref_metadata_2025 huggingface dataset:
A Highly Versatile Platform for Multiplexed Cell Engineering for Cancer Immunotherapy and Stem Cell Therapy
Authors: Rogers Eleni , Rogers Eleni , Pawlak Mathias , Song Zhihui , Hirsch Sophia , Kreienberg Darby , Conover Rachel , Larocque Andrew , Hanson Jacquelyn , Barclay Alec , Sharei Armon
Published: December 2024

Despite their unprecedented efficacy in the clinic, cell and gene therapies remain inaccessible to many patients due to their immense cost and complex manufacturing. Currently, delivery of cell modulating materials (e.g. CAR) to cell types of interest is done through viral, lipid, or electroporation technologies which are expensive, can only accommodate specific cargos or cells, and lack scalability - creating a bottleneck. Portal is developing a universal delivery platform that is compatible across cell and cargo types using mechanoporation. Portal's technology is based on the principle of rapid mechanical deformation of cells to generate transient disruptions of the lipid bilayer that facilitate delivery to the cytoplasm of cells. We have been able to implement Portal technology for use with several therapeutically valuable cargo molecules across multiple cell types, including various primary immune cells, such as T cells, B cells, NK, and monocytes. For example, we have shown multiplexed delivery of mRNA and CRISPR RNP to naive T cells efficiently engineering more than 85% of total viable cells with both GFP expression and deletion of B2M. In addition, we have demonstrated robust expression of mRNA-based CD19-CAR in primary T cells, while maintaining high viability and functionality. In addition to mRNA, we have successfully delivered circular RNA, siRNAs, and proteins to primary immune cells and hematopoietic stem cells. The use of this silicon membrane-based delivery system simplifies the delivery process and enables scalable integration of Portal technology with existing clinical manufacturing equipment. Using Portal's clinical scale integration module, we have the capacity to deliver cargo to more than 1 billion cells per minute. We show high viability and over 90% mRNA expression in activated T cells when integrated into standard GMP manufacturing equipment. Portal's approach is simple, economical, amenable to many cell and cargo types, and scales from research to clinical applications. Portal technology has the potential to alleviate major bottlenecks enabling broader accessibility of impactful cell therapies.
Mapping Path Forward for Using the Generative AI for Comprehension of Prognostic Genesets Implicated in Hematologic Malignancies
Authors: Rech Andrew , Goltsev Yury , Samusik Nikolay , Li Henri , Nolan Garry P. , June Carl H. , Jhala Amol
Published: December 2024

Recent advancements in generative AI, including models such as GPT-4 and LLAMA2, have been rapidly integrated into cancer research. It is not clear to which extent the AI assisted outputs can be trusted and used to the advancement of biomedical knowledge. We discuss and demonstrate several ways the genAI could be used in hematology and related fields.

We have compared a number of commonly available LLM based tools as well as custom trained AIs to determine their ability to enhance the accuracy of functional and genomic discovery screens by reducing the incidence of false positives and refining the interpretation process.

We demonstrate and discuss how custom training of the off-the-shelf genAI can be used to reduce or eliminate the AI-generated inaccuracies, often referred to as 'hallucinations“ . We further show the capacity of semantic scoring applied to candidates based on three orthogonally-tuned criteria: effectiveness, confidence, and novelty.

We observe that in benchmarking tests, the multi-agent scoring systems can outperform GPT-4 and prove particularly adept at identifying candidate targets that may have been overlooked in previous research.

The versatility of the custom trained genAI pipelines is demonstrated through their application in three distinct areas of cancer research. First - we discuss their applicability for optimization of chimeric antigen receptor (CAR) T-cell therapies. Second, we use them to elucidate the network of chemotactic molecules that orchestrate immune cell infiltration and tissue remodeling in the lungs of patients with COVID-19. Third, we use genAI to spatially define signaling pathways in humanized xenograft murine tumor experiments, for which existing cross-species database knowledge is limited.

These applications underscore the genAI potential to contribute to the understanding and treatment of complex diseases.
Unveiling the Unexpected: Tongue Bleeding As the First Sign of Extranodal NK-T Cell Lymphoma
Authors: Shah Nagma , Hajiabbasi Maryam , Haylock Alberto Busmail , Bhatt Navin , Feliciano Erin Garbes , Shah Vaibhav , Guevara Elizabeth
Published: December 2024

Abstract: Natural Killer/T-cell lymphoma (NKTCL) is a rare and aggressive form of non-Hodgkin lymphoma involving natural killer (NK) cells or T lymphocytes, commonly affecting the nasal cavity and upper aerodigestive tract. However, it can also present in extranasal locations like the skin, lungs, and gastrointestinal tract. Here, we describe a rare case of primary extranodal NK/T-cell lymphoma, nasal type (ENKTCL), with an unusual extranasal presentation in the tongue. This led to significant buccal bleeding and hemorrhagic shock due to a lingual artery pseudoaneurysm, an unprecedented complication of ENKTCL.

Case Presentation: A 25-year-old male from Guatemala, residing in the United States, presented with a week-long history of tongue pain, swelling, and a muffled voice following an accidental tongue bite. Examination revealed a large, foul-smelling puncture wound on the tongue with fibrinous exudate, and initial labs showed anemia with a hemoglobin level of 8.8 g/dl. Flexible laryngoscopy revealed erythematous nasal mucosa without masses, and a CT scan of the head and neck showed submandibular lymphadenopathy. Despite treatment with antibiotics and steroids, the tongue lesion did not improve. A biopsy revealed extranodal NK/T-cell lymphoma, nasal type, with necrosis, confirmed by immunostaining positive for CD2, CD7, CD25, TIA-1, granzyme B, and other markers. Before planned radiation therapy, the patient returned to the emergency department with severe tongue bleeding, initially managed with silver nitrate. However, a subsequent episode of profuse bleeding caused hemorrhagic shock. CT angiography identified a lingual artery pseudoaneurysm, necessitating emergent embolization to achieve hemostasis. Further biopsies confirmed NK/T-cell lymphoma with extensive necrosis, and a liver biopsy revealed chronic hepatitis with mild lobular activity and portal fibrosis. The patient was started on chemotherapy with etoposide, steroid, high dose ara-C and cisplatin (ESHAP), however developed further complications and passed away within the following two months.

Conclusion: This case highlights a rare and aggressive presentation of ENKTCL, nasal type, manifesting unusually in the tongue and complicated by a lingual artery pseudoaneurysm. Prompt recognition and management of such atypical presentations are crucial for improving patient outcomes. This case underscores the importance of considering ENKTCL in the differential diagnosis of unusual oral lesions, especially when significant bleeding complications arise.
Treatment Landscape for TP53 Wild-Type CLL: Venetoclax-Obinutuzumab or Second-Generation Bruton Tyrosine Kinase Inhibitors (BTKi)? a Trinetx Review
Authors: Desai Devashish , Sampat Parth , Goodman Alexandra , Madhira Bhaskara Reddy
Published: December 2024

Background:

Venetoclax plus obinutuzumab (V+Obi) as well as acalabrutinib and zanubrutinib (BTKi) are approved as first line treatment options for TP53 negative CLL. Here we have analyzed the real-world data on comparing these treatments.

Methods:

TrinetX, a global federated research network, provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with CLL excluding ones with TP53 mutation or Li-Fraumeni syndrome. The population was further divided into two groups, those who received V+Obi and those who received the newer second generation BTKi. Further, propensity score matching (PSM) was carried out to match age, sex, and race. Descriptive analysis was used for demographic data and for overall survival. Kaplan Meier analysis using log-rank test, as well as Cox regression for hazard ratio (HR) was used.

Results:

3,849 CLL patients were identified to have no aberration in the TP53 gene and received some form of treatment (2,777 in BTKi group and 1,072 in V+Obi group). Patients who received BTKi were older (71.9±10.4 vs 66.7±10.6, p<0.0001) compared to V+Obi recipients. Males were the predominant gender in both the groups, but more females received BTKi compared to V+Obi (35% vs 29%, p=0.0003). Caucasians were the predominant race in both groups, and was more statistically significant in the BTKi group (79% vs 70%, p<0.0001). Patients with unknown race were significantly less in the BTKi group (12% vs 20%, p<0.00001). Median follow up was 420 days and 544 days in the BTKi and the V+Obi group respectively. More deaths occurred in the BTKi group (328 (11.86%) vs 105 (9.83%), p=0.0732, OR = 1.236 (0.98-1.559). The Kaplan Meier curve was separated in favor of V+Obi, with log-rank test p = 0.0028, and HR = 1.397 (1.121-1.741). After PSM, both groups had about 1,000 patients, with no significant difference in deaths (105 (10.07%) vs 103 (9.86%), p=0.8723, OR = 1.024 (0.769-1.363)). The Kaplan Meier curves were not separated, with log-rank test showing p=0.3366 and HR = 1.143 (0.87-1.5).

Conclusion:

Our analysis shows that using V+Obi is non inferior to BTKi in impacting overall survival. With V+Obi's fixed duration, it is an excellent option for CLL patients, as compared to BTKi's indefinite treatment, especially for younger patients.
Low-Dose Venetoclax with Azacitidine in Adults with Acute Myeloid Leukemia: Impact of Phenotype on Outcomes
Authors: Ugarte Luis , Lopez-Garcia Yadith Karina , De La Garza Fernando , Rubio Francisco , Morcos Michelle , Gonzalez Alexia , Tejada Vasquez Ana Cristina , Vega Mateos Antonio , Garcia-Salas Gerardo , Colunga-Pedraza Perla R. , Gomez-Almaguer David , Gomez-De Leon Andres
Published: December 2024

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease that can express more than one phenotypically distinct clone at diagnosis and during its evolution. Venetoclax, a BCL-2 inhibitor, along with azacitidine has been proposed as a therapeutic option. There are reports suggesting that people with AML and monocytic phenotype may experience resistance to venetoclax, although this has not been confirmed in a population of patients who are candidates for intensive treatment.

Patients and methods: In this retrospective, single-center study, we evaluated responses with low-dose venetoclax with itraconazole and azacitidine (Aza-Ven) in adults with AML according to their immunophenotype and compared them to a historical cohort from the intensive chemotherapy era. The primary outcome was the response at the end of induction. Secondary outcomes were event-free survival and overall survival.

Results: 92 patients were included from January 2017 to April 2024, with a median age of 46 years. Thirty-six patients received first-line Aza-Ven, of whom 27.8% had a monocytic phenotype (n=10) and 72.2% other phenotypes (n=26). In patients who received Aza-Ven , the response at the end of induction was 30% vs. 53.8% in patients with monocytic phenotype vs. others, respectively (p=.18). Median OS for monocytic patients was 6.4 months vs. 10.9 months for other phenotypes (p=.171); median DFS was 2.4 months vs. 5.2 months, respectively (p=.075)

In the historical cohort of 46 patients who started intensive chemotherapy, 20 patients had monocytic phenotype. Complete response was observed in 61.9% of patients with this phenotype vs. 42.9% in other phenotypes (p=0.297). The mean OS for patients with monocytic phenotype was 7.1 vs 9.3 months in other phenotypes (p.803). The median DFS was 4.8 months vs. 2.6 months, respectively (p=.929). OS 9.2 months in patients with monocytic phenotype compared to 6.54 and 12.1 months in patients with other phenotypes.

In the Cox regression model, age for all patients was associated with an increased risk of the event (HR 1.02 95% CI 1-1.04), while use of Aza-Ven decreased the risk of the event (HR 0l.508 95% CI 0.276-0.936). When separated by treatment groups, only age was predictive of OS in the intensive QT group (HR 1.02 (95% CI 1-1.04), but not the phenotype.

Conclusion: Patients with monocytic phenotype experienced higher rates of refractoriness and worse outcomes, although no statistical significance was obtained in this small sample. It´s imperative to analyze prospective trials involving the use of venetoclax-based regimens in patients with this monocytic phenotype, in light of previous reports and the findings in this single-center study, seeking to optimize therapy in this population
Real-World Wutcome of Defibrotide for Treatment of Adult Patients Who Developed Severe Hepatic VOD/SOS after Allogeneic Hematopoietic Cell Transplantation
Authors: Yoon Jae-Ho , Kwag Daehun , Min Gi June , Park Sung-Soo , Park Silvia , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Kim Hee-Je , Min Chang-Ki , Cho Seok-Goo , Lee Seok
Published: December 2024

Background: Hepatic veno-occlusive disease/ sinusoidal obstruction syndrome (VOD/SOS) is a rare but severe complication after hematopoietic cell transplantation (HCT) showing high fatality. Recently reported incidence of VOD/SOS in the Korea was 8.9% (7.8% in adults and 14.0% in pediatrics). Estimated 1-year overall survival (OS) of VOD/SOS was around 41% and the outcome was much dismal when it progressed to severe (36.8%) or very severe grade VOD/SOS (5.7%) based on the revised EBMT severity criteria. Defibrotide (DF) is the only approved agent for the treatment of severe to very severe VOD/SOS, and we tried to analyze the real-world outcome in Korea.

Methods: DF was approved in Korea since 2016, and we tried to retrospectively analyze the outcome of severe to very severe VOD/SOS treated with defibrotide from 2016 to 2023. Totally 73 adult patients were identified. DF was indicated in Korea in patients who satisfied 4 or more out of 6 severity parameters - Time from diagnosis to VOD, total bilirubin, bilirubin doubling time, elevation of aminotransferase, weight gain, and decreased renal function, which was amended to 2 or more out of 5 parameters (excluding weight gain). The diagnosis the severity was assessed by revised EBMT criteria.

Results: Median time from HCT to VOD/SOS diagnosis was 21 days (range D-1 to D+414), and the median time from diagnosis to defibrotide was 1 day (range 0 to 40). There were 40 severe and 33 very severe VOD/SOS at DF start, and they progressed to 20 severe and 53 very severe at worst period (WP). Overall response was observed in 34 (46.5%), and complete resolution (CR) was in 29 (39.7%) - 52.5% in severe and 24.2% in very severe. OS at 100-day was 34.2% (40.3% for severe-DF and 26.4% for very severe-DF, while 62.4% for severe-WP and 23.2% for very severe-WP, p<0.001). When only based on the total bilirubin level (<3, 3-5, 5-8, >8mg/dL), the CR rate (71.4%, 50%, 42.9%, and 25%) and 3-year OS (100%, 25%, 16.7%, and 13.2%) were well distinguished to predict prognosis. We also identified that early DF application within 2 days showed higher CR (55.6% vs. 30.4%) and better OS (37.0% vs. 26.1%).

Conclusion: Real-world outcome of defibrotide demonstrated early administration according to current indications showed good therapeutic effects.
Factors Associated with in-Hospital Mortality from Gastrointestinal Bleeding in Patients with Sickle Cell Disease
Authors: Uche Ifeanyi Nnamdi , Hehr Rohan , Becerra Henry , Gold-Olufadi Shakirat , Oluwadeyi Esther Yemisi , Wasifuddin Mustafa , Saparov Dosbai
Published: December 2024

Introduction

Gastrointestinal bleeding (GIB) is a common complication and potential cause of mortality in hospitalized patients. Previous studies have shown that patients with SCD have an increased risk of developing GIB. There is a paucity of literature addressing factors that could predict GIB mortality in patients with SCD. Our study aims to identify these factors and other clinical characteristics of GIB in patients with SCD.

Methods

Data for this study were obtained from the National Inpatient Sample (NIS) database. We identified patients with SCD aged 18 years and older who had GIB between 2016 and 2020. The primary outcome was in-hospital mortality. Patient demographics, clinical and hospital characteristics were compared using x2 test. The association between SCD and in-hospital mortality was assessed using logistic regression controlling for other covariate. A two-sided p≤0.05 was considered statistically significant.

Results

We identified 1284 patients with SCD who had GIB during the study period. 51.25% (n=658) were aged ≥40 years old 48.75% (n=626) were <40 years. 42.21% (n=542) of patients had lower GIB compared to 38.01% (n=488) with upper GIB. 5.61% (n=72) of patients died from GIB. Patients with cerebrovascular disease (CVD) (aOR= 3.62 [95% CI: 1.23-10.67] p-value: 0.019), sepsis(aOR= 14.48 [95% CI:7.70-27.21] p-value: <0.001) and acute kidney injury (AKI) (aOR= 3.54 [95%CI:1.87-6.70]p-value:0.0001) had a increased risk of inpatient mortality from GIB compared to other patients. Vaso-occlusive crisis and acute chest syndrome did not show a significant risk for mortality from GIB. There was no significant association between race, gender, income, or insurance with inpatient mortality.

Conclusion

Our study demonstrates a relationship between AKI, Sepsis and CVD and in-hospital mortality of GIB in patients with SCD. Understanding these factors will assist clinicians in anticipating potential mortality in patients with SCD who develop GIB. Our study was limited by a small sample size. More research is needed to identify factors that could improve survival of GIB in patients with SCD.
Outcomes of Acute Myeloid Leukemia Patients Aged 60 Years and Above: An Analysis of SEER Data
Authors: Gopishetty Swathi , Jaiyesimi Ishmael A. , Ezekwudo Daniel
Published: December 2024

Background: Acute Myeloid Leukemia (AML) is an aggressive and most common hematologic malignancy in adults with a higher incidence in older adults with a median age of diagnosis of 68 years. It accounts for the largest number of annual deaths from leukemias in the United States. Several new therapies have been approved after many years and are expected to impact patient outcomes, especially in patients aged 60 and above.

Design/Methods: We conducted a retrospective analysis of AML patients aged 60 years and above, diagnosed between 2000 and 2021, using the SEER database. Variables such age, gender, race, chemotherapy, and survival outcomes in the last 5 years were extracted and analyzed. Kaplan-Meier survival analysis was performed to evaluate overall survival (OS).

Results: The study included 51,778 AML patients aged 60 years and above. 55.9% were male, and 44.1% were female. The racial distribution was 85.3% white, 6.8% black, 7.2% Asian/Pacific Islander, and 0.6% from other racial backgrounds. Among these only 58.4% of patients received chemotherapy in patients aged 60 and above. Patients who received chemotherapy had median OS of 7 months compared to 1 month in patients who did not receive chemotherapy. Patients who received chemotherapy has significantly reduced risk of death, with hazard ratio of 0.53 (95% CI: 0.42-0.68) and a p-value < 0.01, indicating a 47% reduction in risk of death. The median overall survival (OS) in older patients including patients with and without chemotherapy was 2 months, and 5-year survival rate is 8.3% for Age ≥ 60 years. The results from the multivariate Cox proportional hazards model indicate that, compared to the reference group aged 60-64 years, the hazard ratios (HR) for the age groups 65-69, 70-74, 75-79, 80-84, and 85+ are 1.23 (95% CI: 1.19-1.28), 1.48 (95% CI: 1.43-1.53), 1.79 (95% CI: 1.73-1.85), 2.00 (95% CI: 1.93-2.07), and 2.40 (95% CI: 2.32-2.50) respectively, with all p-values < 0.01. This indicates a statistically significant increase in risk with advancing age, with the 85+ age group having a 140% higher risk compared to the reference group.

Conclusion: This analysis of SEER data highlights that despite advances in treatment, survival outcomes remain poor, in older patients aged 60 and above with AML. A significant percentage was unable to get chemotherapy, and it determines significant challenges in managing this population. These findings emphasize the need for novel therapeutic approaches and strategies to improve outcomes in older AML patients.
Uncovering MHC-1 Racially Defined Leukemogenic Pathways in Adults Patient Diagnosed with Myeloid Hemopoietic Malignancies
Authors: Thalberg Alexandra , Williams Lacey Scott , Sackstein Paul , Renteria Anne S. , Bhatty Hafsa , Rivero Gustavo A.
Published: December 2024

Background: Outcome in African Ancestry (AA) Acute Myelogenous Leukemia and Myelodysplastic Syndrome patients (pt) is inferior. In particular, AML data suggests differential enrichment of genomic abnormalities [i.e., lower incidence of Core binding factor AML, worse outcome among NPM1 mutated cases etc.). The immune system plays a crucial role in recognizing and eliminating cancer cells. HLA class I molecules present endogenous antigens to CD8+ T cells. HLA gene diversity possibly reflects differences in antigen presentation and immune response. Therefore, mapping HLA-I alleles used by “pathogenic variants in hematopoietic cells” during leukemogenesis may inform “prioritized MHC restricted pathways” susceptible to T cell targeting. In this study, we hypothesized that Class I alleles may be classified as disadvantageous when they do not present mutated neoantigens, promoting immune escape, and that such alleles will be differentially found in African Ancestry (AA) pt at higher frequencies compared non-AA population.

Methods: After IRB approval, 31 patients with available Class I HLA typing and clinical data were included in analysis. The mutational profile obtained by NGS was analyzed for each patient to determine mutated protein sequences for the downstream analysis of neopeptides. MHCNetPan software was used to predict MHC-neopeptide binding. To compare HLA frequencies between AA vs non-AA pt, allele frequencies were analyzed using Fisher's exact test.

Results: Median age of studied patients was 63 years (range 28-89). Fifty-one percent were males. AML and MDS were observed in 74% and 26% patients respectively. By ethnicity, 58% were non-AA and 42% were AA. The median number of mutations was 4. Studied patients had mutations in driver genes. Most mutant driver genes in our cohort were methylation genes (TET2 and DNMT3A), chromatin regulation genes (ASXL1, EZH2), transcription factors (TP53 and RUNX1). Alleles that approached “disadvantageous” significance for AA were A*11:01 (p=0.01), A*25:01 (p=0.01), B*13:02 (p=0.001), B*14:02 (p=0.0006), C*02:02 (p=<0.0001), and C*08:02 (p=0.01). Alleles approaching “advantageous” significance for AA cases: A*33:03 (p=<0.0001) and A*02:02 (p=<0.0001).

Conclusion: In conclusion, some HLA alleles, including A*11:01, A*25:01, B*13:02, B*14:02, C*02:02 and C*08:02 are more common in AA pt, suggesting that these alleles may predispose individuals to develop leukemias. On average, these alleles present “lower” number of bindings [i.e., proportion of 1, 2, 3, 5, and 6 bindings in AA vs non-AA, 26% v 72%, 23% v 77%, 0% v 100%, and 31% vs 69%, <p=0.0001]. Differential MHC frequencies in AML/MDS AA vs non-AA pt implicate the involvement of neoantigen presentation in leukemic cells. While our data requires adjustment for local “normal” allele frequencies, they could potentially be used for patient risk stratification and treatments.
Bruton's Tyrosine Kinase (BTK) Inhibitors Plus RM (rituximab and methotrexate) for the First-Line Treatment of Primary Central Nervous System Lymphoma (PCNSL)
Authors: Guan Fangshu , Guo Xing , Li Yi , Chen Jing , He Jingsong , Wu Wenjun , Cai Zhen , Zhao Yi
Published: December 2024

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare invasive non Hodgkin's lymphoma (NHL), with the vast majority being diffuse large B-cell lymphoma. Due to its invasive biological behavior, the median survival time is only 2-3 months without therapy. Currently, the standard regimen for newly diagnosed (ND) PCNSL was high dose methotrexate (HD-MTX) combined with rituximab (R), and more effective regimens also have been explored since its poor prognosis. Genomic studies in PCNSL demonstrated that recurrent and CDKN2A deletions, MYD88 and CD79B mutations, and mutations that activate BCR signaling. BTK mediates downstream signaling of MYD88 and, and is an important regulator of the BCR signaling pathway. To date, three BTKs, Ibrutinib (I), Zebutinib (Z), and Obutinib (O) are approved for clinical using in China and have shown promising anti-tumor activity in NHL, and PCNSL in particular. So we analyze the efficacy and safety of BTKs combined with RM for ND PCNSL.

Methods: ND PCNSL patients who received BTKi-RM (I 420mg po qd (1 patient) , Z 160mg po bid (4 patients) or O 150mg po qd (17 patients), rituximab 375 mg/m2 iv day 0, MTX 3.5 g/m2 iv day1, 21 days per cycle) regimens in our center between March 2021 and February 2024 were included.Tumor evaluation was performed usually every two cycles during the induction therapy, at end of treatment and every 3 to 6 months after that by MRI or PET/CT, PET/MR.The overall remission rate (ORR), complete remission (CR) rate, progression-free survival (PFS), and overall survival (OS) were described.

Results:Twenty patients (11 males), with a median age of 61 (rang, 44-74) years were included, the median number of treatment was 6 (rang, 3-8). Eleven and six patients were considered moderate and high risk respectively according IELSG scores. Eleven patients were non-GCB subtype, and 14 were double-expression. Twelve samples were performed genetic analysis and classified by LymphGen algorithm, 9 (75%) were MCD genetic subtype, 2 were non-subtyped and the other was assigned to BN2.Ten patients underwent ASCT and 15 patients received maintenance therapy (BTKi or Lenalidomide) after induction therapy. After median follow-up of 16.3 months, a CR rate of 60% (12/20 patients) and a ORR of 95% (19/20 patients) was achieved, and 1-year PFS and OS were 71.5% (95% CI 53.1%-96.3%) and 94.7% (95% CI 85.2%-100%), respectively. All patients had response to O-RM (ORR 100%, CR rate 66.7%) in the O-RM cohort, and 8 patients (88.9%) achieved CR in MCD subgroup. There were no treatment-related deaths occurred.Conclusion: This real-word analysis demonstrates that BTKi-RM regimen is effective and safe for the treatment of patients with ND PCNSL.
Comparing Loop Diuretic Efficacy and Safety in Patients with Acute Myeloid Leukemia and Differentiation Syndrome
Authors: Nethagani Sanjana , Fudacz Paul , Furner Mark , Rizwan Umer
Published: December 2024

Background: Differentiation syndrome (DS) is a group of life-threatening complications associated with acute myeloid leukemia (AML) treatment. Loop diuretics are used to manage fluid overload and electrolyte imbalances in DS. The optimal choice of loop diuretics is unclear. Previous studies showed bumetanide and furosemide have similar efficacy and safety in patients with congestive heart failure. Recent research suggest torsemide may be non-inferior to furosemide in critically ill patients with acute kidney injury.

Methods: We performed a retrospective analysis of 5,670 patients diagnosed with AML and differentiation syndrome from a large federated network database. Patients were treated with furosemide (n=2,431), bumetanide (n=466), or torsemide (n=206), alongside glucocorticoids and allopurinol. Propensity score matching was utilized to control for confounding variables, including age, sex, and comorbidities such as chronic kidney disease, diabetes mellitus (types 1 and 2) and hypertension. Patients were matched by AML subtype, including acute myeloid leukemia and acute promyelocytic leukemia.

Results: No significant differences were seen in overall mortality or the incidence of acute renal failure among the three cohorts. Mean glomerular filtration rate, serum creatinine, blood urea nitrogen, serum uric acid, and serum potassium, did not differ significantly between the loop diuretic groups. However, a lower risk of hemodialysis utilization was observed in patients receiving furosemide compared to bumetanide (risk ratio 0.584, 95% CI 0.414-0.825).

Conclusion: Our findings suggest that furosemide, bumetanide, and torsemide have comparable efficacy and safety profiles in patients with AML and differentiation syndrome. Notably, furosemide was associated with a lower rate of hemodialysis utilization compared to bumetanide, with no significant difference in renal function or mortality. This may be due to bumetanide's higher potency, rapid absorption, and shorter half-life, potentially increasing the risk of electrolyte imbalances and acute kidney injury. Conversely, furosemide may facilitate greater cumulative sodium excretion in patients with chronic renal insufficiency.
Development of a PMGDNI model to predict the probability of three-month unfavorable outcome acute ischemic stroke after endovascular treatment: a cohort study
Authors: Yang Chao , Wang Jingying , Zhang Ruihai , Lu Yiyao , Hu Wei , Yang Peng , Jiang Yiqing , Hong Weijun , Shan Renfei , Xu Yinghe , Jiang Yongpo
Published: December 2024

Background

Patients with acute large vessel occlusion stroke (ALVOS) may exhibit considerable variability in clinical outcomes following mechanical thrombectomy (MT). This study aimed to develop a novel statistical model predicting functional independence three months post-endovascular treatment for acute stroke and validate its performance within the cohort.

Method

Consecutive patients undergoing endovascular treatment for acute stroke with large vessel occlusion were randomly divided into a modeling group and a validation group in a 7:3 ratio. Independent risk factors were identified through LASSO regression and multivariate logistic regression analyses, leading to the development of a prognostic model whose performance was rigorously validated.

Results

A total of 913 patients were screened, with 893 cases included. The modeling group comprised 625 cases, and the validation group included 268 cases. Identified independent factors for adverse outcomes after endovascular treatment of acute ischemic stroke (AIS) were pneumonia (OR = 4.517, 95% CI = 2.916–7.101, P < 0.001), mechanical ventilation (OR = 2.449, 95% CI = 1.475–5.148, P = 0.001), admission GCS ≥ 8 (OR = 0.365, 95% CI = 0.167–0.745, P = 0.008), dysphagia (OR = 2.074, 95% CI = 1.375–3.126, P < 0.001), and 72-hour highest Na ≥ 145 (OR = 2.794, 95% CI = 1.508–5.439, P = 0.002), along with intracranial hemorrhage (OR = 2.453, 95% CI = 1.408–4.396, P = 0.002). These factors were illustrated in a PMGDNI column chart. The area under the ROC curve for the modeling group was 82.5% (95% CI = 0.793–0.857), and for the validation group, it was 83.7% (95% CI = 0.789–0.885). The Hosmer-Lemeshow test indicates that there is no statistically significant difference (P > 0.05) between the predicted and actual probabilities of adverse outcomes. The clinical decision curve demonstrated optimal net benefits at thresholds of 0.30-1.00 and 0.25-1.00 for both training and validation sets, indicating effective clinical efficacy within these probability ranges.

Conclusion

We have successfully developed a new predictive model enhancing the accuracy of prognostic assessments for acute ischemic stroke following EVT. It provides an individual, visual, and precise prediction of the risk probability of a 90-day unfavorable outcome.
Lessons learned for pandemic preparedness in the neurodegenerative research and clinical fields: an advice report based on Parkinson’s disease as an example
Authors: Splinter Marije J. , Henderson Emily J. , Ben-Shlomo Yoav , Darweesh Sirwan K. L. , Sowa Pawel , Wolters Frank J. , Velek Premysl , Meijerink Hannie J. E. M. , Bakx Paulus , Ikram M. Arfan , de Schepper Evelien I. T. , Ikram M. Kamran , Licher Silvan
Published: December 2024

Background

A sustainable pandemic preparedness strategy is essential to ensure equitable access to healthcare for individuals with neurodegenerative diseases. Moreover, it is vital to provide clinicians and researchers in the neurodegenerative disease fields with resources and infrastructure to ensure continuity of their work during a (health) crisis.

Methods

We established an international collaboration between researchers, clinicians, and patient representatives from the Netherlands, Poland, and the United Kingdom. We co-created a pandemic preparedness plan primarily informed by examples from those affected by or working in the field of Parkinson’s disease, with potential application to other neurodegenerative diseases or the general population. This plan builds upon insights and experiences from four population-based studies during the COVID-19 pandemic. Between March and November 2023, we organised two hybrid meetings in Bristol (United Kingdom) and Rotterdam (the Netherlands), and two online meetings.

Results

Research recommendations included three core factors in questionnaire design during health crises: 1) using existing, validated questions, 2) questionnaire adaptability and flexibility, and 3) testing within and outside the research group. Additionally, we addressed burden of participation, and we advocated for robust data sharing practices, underlining the importance of regulatory measures extending beyond the COVID-19 pandemic. We also shared clinical perspectives, including strategies to mitigate social isolation; challenges in virtual versus in-person consultations; and systemic changes to recognise and prevent moral injury in healthcare professionals.

Conclusion

In this pandemic preparedness plan, we provide research and clinical recommendations tailored to the field of Parkinson’s disease, with broader relevance to other neurodegenerative diseases and the general population. This establishes an essential framework for setting up new studies and safeguarding research and clinical practices when a new pandemic or other (health) crisis emerges.

Graphical Abstract
Investigation of awareness, sanitation, and customer education practices among employees of pet and animal feed stores that sell live animals in the United States
Authors: Lord Jennifer , Pugh Sheri , Thompson Sharon R.
Published: December 2024

Background

Numerous zoonotic disease outbreaks have been associated with companion animals and poultry purchased at pet and animal feed stores. Employees are often the initial source of information for customers purchasing a new pet. Therefore, the objectives of this study were to: (1) investigate awareness, sanitation, and customer education practices related to zoonotic disease risk, and (2) identify predictors of providing customer education among employees of pet and animal feed stores that sell live animals.

Methods

A survey of pet and animal feed store employees was conducted to evaluate sanitation practices, training, and awareness of zoonotic disease risk. Differences in proportions of categorical variables were assessed using Chi-square tests. Wilcoxon rank-sum and Kruskal–Wallis tests were used to assess for differences in the values of ordinal variables based on the values of categorical variables. A partial proportional odds model was used to identify predictors of providing customer education.

Results

Surveys were completed by 206 respondents from the Southeast, Midwest, Southwest, and Western US, 146 of whom reported that their workplace sold live animals. Handwashing was more frequent among employees whose workplace had handwashing policies related to handling animals and their habitats (p < 0.001). Perceived zoonotic disease risk was higher among those who had received workplace training (p = 0.007). Higher odds of providing customer education related to zoonotic disease risk were associated with serving in a supervisory role (p = 0.005), higher perceived zoonotic disease risk (p = 0.001), and more frequent sanitation practices (handwashing, p = 0.031; surface disinfection, p < 0.001; and glove use, p < 0.001).

Conclusions

Pet and animal feed stores play an important role in minimizing occupational health hazards for employees and providing education for customers. These retailers should implement clear biosecurity protocols and provide training about zoonotic disease risk associated with handling live animals.
Arthroscopic anterior cruciate ligament reconstruction with and without tourniquet use: an updated systematic review and meta-analysis on clinical outcomes
Authors: Samei Mahdieh , Daliri Mahla , Sadeghi Masoumeh , Ganji Reza , Parsa Ali , Ebrahimzadeh Mohammad H.
Published: December 2024

Background

The use of a tourniquet is common during anterior cruciate ligament (ACL) reconstruction, offering convenience for the surgical procedure. However, the potential adverse effects of tourniquet use have gained increasing attention from clinical researchers. We conducted this systematic review and meta-analysis to compare the clinical outcomes of tourniquet application versus non-tourniquet approach during arthroscopic ACL reconstruction.

Methods

A comprehensive search of PubMed, Web of Science, Embase, and Cochrane Library databases, was performed through March 2023 to identify controlled clinical trials. The main outcomes assessed included post-operative drain output, post-operative pain using a visual analogue scale (VAS), operation time, calf girth, and thigh girth. A random-effects meta-analysis was performed to account for heterogeneity, with weighted mean difference (WMD) and 95% confidence intervals (CI) used as pooled estimates for clinical outcomes.

Results

Of the nine potentially related studies, seven eligible studies (sufficient quantitative data) were included in the meta-analysis. Postoperative drain output in the tourniquet group was on average 100 ml higher than in the non-tourniquet group (95% CI: 36 to 168). Pain, measured by the VAS at 24 h postoperatively, was 0.42 points higher in the tourniquet group (95% CI: 0.08 to 0.76), with the increase persisting at 48 h, averaging 0.40 points (95% CI: 0.12 to 0.69). Thigh girth in the tourniquet group was reduced by 1.8 cm (95% CI: -2.7 to -0.94). No significant differences were observed for calf girth and the operation time.

Conclusion

Our meta-analysis indicates that tourniquet use during arthroscopic ACL reconstruction is associated with higher pain levels, increased postoperative drain output, and reduced thigh girth. However, performing the surgery without a tourniquet does not significantly extend the operation time.

Trial registration

The protocol was registered in the International Prospective Register of Systematic Reviews, PROSPERO (CRD42023417604).
A qualitative exploration of the coordinator’s role in an intersectoral childhood overweight prevention programme in the Netherlands: ‘a lot is expected from one person’
Authors: Huiberts Irma , Slot-Heijs Jorien , Singh Amika , Collard Dorine
Published: December 2024

Background

Intersectoral collaboration and its coordination are vital for community health promotion. Given the diverse organisational contexts in which local coordinators build intersectoral collaboration, training and support needs of coordinators may vary widely. To date, there is limited insight into how coordinators tasked with building intersectoral collaboration apply their role given their specific organisational context. A more detailed understanding of this process will provide valuable guidance for training and supporting local coordinators. In the current study we focussed on coordinators involved in building intersectoral collaboration within the ‘Healthy Youth, Healthy Future’ (JOGG) approach in the Netherlands. The organisational contexts in which these local coordinators operate vary considerably. The aim of this study was to explore how local coordinators of the JOGG approach apply their role in building intersectoral collaboration and the competencies they require, taking into account their organisational context.

Methods

We conducted interviews with twelve local JOGG coordinators and two focus groups with eight community advisors from the national JOGG organisation. Data was analysed both inductively and deductively.

Results

JOGG coordinators appeared to take on seven different roles over time: implementer, project manager, networker, matchmaker, linchpin, politician and programme manager. These roles required different competencies and varied according to the organisational context, including: available resources, the position of the employing organisation in existing local stakeholder networks, the coordinators’ responsibilities in their employing organisation and professional background. In addition, the coordinators role depended on the implementation phase of the JOGG approach. During the first phase, roles at the operational level were more prominent, since they were important for engaging stakeholders and facilitating collaboration. In later phases, coordinators took on roles at a tactical and strategic level in order to mobilise their network.

Conclusions

This study highlights the diversity in how JOGG coordinators apply their role. Our findings highlight the importance of carefully selecting the organisation where coordinators are employed, as this influences their possibilities. In addition, our study provides directions for recruiting coordinators for an intersectoral health promotion approach and supporting them, taking into account the phase of the approach and organisational context.
Tailored culture strategies to promote antimicrobial secondary metabolite production in Diaporthe caliensis: a metabolomic approach
Authors: Hoyos Laura V. , Vasquez-Muñoz Luis E. , Osorio Yuliana , Valencia-Revelo Daniela , Devia-Cometa Daiana , Große Miriam , Charria-Girón Esteban , Caicedo-Ortega Nelson H.
Published: December 2024

Background

In the search for new antimicrobial secondary metabolites of fungi, optimizing culture conditions remains a critical challenge, as standard laboratory approaches often result in low yields. While non-selective methods, such as modifying culture media, have been effective in expanding the chemical diversity of fungal metabolites, they have not yet established a direct link to key process parameters crucial for further optimization. This study investigates the capacity of Diaporthe caliensis as a biofactory for biologically active secondary metabolites, employing tailored culture media to explore the relationship between chemical diversity and critical process variables.

Results

The metabolomic profiles, antibacterial activities, and production yields of the extracts were analyzed to progressively adjust the culture conditions. This study was conducted in five steps, evaluating carbon and nitrogen source concentration, nitrogen source type, salt supplementation, and pH adjustment. Altering the rice starch concentration affected biomass yield per unit of oxygen consumed, while modifications to the nitrogen source concentration influenced both the bioactivity and chemical space by Diaporthe caliensis. Despite changes at the metabolome level, the extracts consistently exhibited potent antibacterial activities, influenced by the nitrogen source, added salts and pH adjustments. For instance, when using corn steep liquor and rice starch, supplemented with micronutrients, different metabolites were produced depending on whether buffer or water was used, though both conditions showed similar antibacterial activities (IC50 ≈ 0.10 mg mL− 1 against Staphylococcus aureus and ≈ 0.14 mg mL− 1 against Escherichia coli). In the treatment where buffer was used to stabilize pH change, there was an increase in the production of phomol-like compounds which are associated with known antibiotic properties. In contrast, in the treatments using water, the drop in pH stimulated the production of previously unidentified metabolites with potential antimicrobial activity.

Conclusions

This study proposes a strategic methodology for the tailored formulation of culture media aiming to promote the biosynthesis of diverse secondary metabolites. This approach revealed the critical role of nutrient limitation and pH regulation in stimulating the production of polyketide-lactone derivatives, including the antibiotic phomol. Ultimately, the systematic, custom-designed culture conditions developed in this work offer a promising strategy for expanding the chemical diversity of Diaporthe caliensis, while providing valuable insights into the key parameters needed for optimizing this fungal biofactory.

Graphical Abstract
Exploring the innovative application of cerium oxide nanoparticles for addressing oxidative stress in ovarian tissue regeneration
Authors: Lakshmanan Maya , Saini Monika , Nune Manasa
Published: December 2024

The female reproductive system dysfunction considerably affects the overall health of women and children on a global scale. Over the decade, the incidence of reproductive disorders has become a significant source of suffering for women. Infertility in women may be caused by a range of acquired and congenital abnormalities. Ovaries play a central role in the female reproductive function. Any defect in the normal functioning of these endocrine organs causes health issues and reproductive challenges extending beyond infertility, as the hormones interact with other tissues and biological processes in the body. The complex pathophysiology of ovarian disorders makes it a multifactorial disease. The key etiological factors associated with the diseases include genetic factors, hormonal imbalance, environmental and lifestyle factors, inflammatory conditions, oxidative stress, autoimmune diseases, metabolic factors, and age. Oxidative stress is a major contributor to disease development and progression affecting the oocyte quality, fertilization, embryo development, and implantation. The choice of treatment for ovarian disorders varies among individuals and has associated complications. Reproductive tissue engineering holds great promise for overcoming the challenges associated with the current therapeutic approach to tissue regeneration. Furthermore, incorporating nanotechnology into tissue engineering could offer an efficient treatment strategy. This review provides an overview of incorporating antioxidant nanomaterials for engineering ovarian tissue to address the disease recurrence and associated pathophysiology. Cerium oxide nanoparticles (CeO2 NPs) are prioritized for evaluation primarily due to their antioxidant properties. In conclusion, the review explores the potential applications of CeO2 NPs for effective and clinically significant ovarian tissue regeneration.

Graphical Abstract