bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Platelet Transfusion and Bleeding Risk Stratification in Patients with Immune Thrombocytopenia before Procedures: A Nationwide Population-Based Cohort Study
Authors: Kang Ka-Won , Choi Yumin , Lim Hyung-Jun , Kwak Kunye , Choi Yoon Seok , Park Yong , Kim Byung Soo , Lee Kwang-Sig , Ahn Ki Hoon
Published: December 2024

Background: The main treatment goal for immune thrombocytopenia (ITP) is to reduce bleeding risk, requiring extra precautions during procedures. Adjusting platelet thresholds with ITP treatments is usually recommended, but platelet transfusions are commonly used despite their controversial benefits. This study aims to evaluate the effectiveness of platelet transfusion in reducing post-procedure bleeding risk and to identify predictive indicators of post-procedure bleeding.

Methods: This study used a nationally representative database to develop a model to predict the risk of post-procedure bleeding in patients with ITP. Machine learning analyses, including random forest feature importance and Shapley additive explanations (SHAP) values, were employed. This contained a total of 34 post-procedural bleeding risk factors, including the amount of platelet transfusion.

Results: The random forest model had an area under the receiver-operating characteristic curve of 93.6%. The analysis identified the following variables as most important: amount of platelet transfusion, high-risk procedure, use of anticoagulant drugs, no use of antiplatelet or anticoagulant drugs, anemia, age, low-risk procedure, moderate-risk procedure, ITP treatment, and newly diagnosed ITP. Amount of platelet transfusion, high-risk procedures, use of anticoagulant drugs, anemia, ITP treatment, and newly diagnosed ITP positively correlated with post-procedure bleeding risk. In contrast, no use of antiplatelet or anticoagulant drugs and moderate- or low-risk procedures were negatively associated with post-procedure bleeding risk. In the SHAP dependence plot, the amount of platelet transfusion was associated with high-risk procedures. Additionally, among patients undergoing high-risk procedures, the likelihood of post-procedure bleeding increased with age.

Conclusions: Platelet transfusion does not significantly reduce the risk of post-procedural bleeding in patients with ITP. The risk of post-procedural bleeding is more closely related to the bleeding risk of the procedure and the patient's medical condition. Minimizing inappropriate platelet transfusions and addressing factors that can increase bleeding risk before procedures are crucial.

Keywords: Immune thrombocytopenia, Procedure, Platelet transfusion, Bleeding risk, Machine learning analysis
Improving Thrombotic Thrombocytopenic Purpura Outcomes with a TMA Team and TTP Pathway
Authors: Yu Stephen , Webber Sylvia E , Gotses John , Platt Emma , Arays Ruta , Shmookler Aaron Daniel , Merrill Sam A
Published: December 2024

Background: Providing optimal care for patients with thrombotic thrombocytopenic purpura (TTP) is challenging but using a multidisciplinary team to develop a systematic process could improve TTP care by reducing morbidity and mortality.

Objectives: To develop a thrombotic microangiopathy (TMA) Team and implement a TTP Pathway to improve TTP care by reducing TTP relapse or TTP-related death (TTP-RRD) at a rural, Appalachian, tertiary medical center.

Methods: Prospective quality improvement project using the DMAIC (Define, Measure, Analyze, Improve, Control) methodology to develop a multi-disciplinary TMA team and a TTP Pathway. The TMA team comprised Hematology, Nephrology, Laboratory Medicine, and Pharmacy members who guided the Hematology/Oncology consult service. Pathway care included standardized plasma exchange (PEX), rituximab, caplacizumab, improved coordination between medical services, and regular outpatient biochemical TTP surveillance. TMA outcomes were determined by retrospective chart review for patients with acute TTP treated with usual care (N=16) and the TTP Pathway (N=16) between 2016 and 2023.

Results and conclusions: Patients were predominantly women (63.2%), Caucasian (88.5%), located far (85%) from the medical center and low-income (46.2%) based on insurance. All patients had acquired TTP. TTP-RRD at 90 days was reduced from 56% with usual care to 6% with Pathway care (95% CI 0.23 to 0.77, P=0.022); TTP relapse alone at 90 days was reduced from 50% to 0% (95% CI 0.26 to 0.74, P= 0.0011) with TTP Pathway care. On Kaplan Meier analysis, TTP-RRD was significantly lower throughout the intervention with TTP Pathway care (P=0.018). With TTP Pathway, the duration of PEX increased (median 6 vs 12 sessions, P<0.05), as did the usage of rituximab (31.3% vs 93.8%, 95% CI -0.36 to -0.88, P=0.003) and caplacizumab (6.3% vs 62.5%, 95% CI -.027 to -0.81, P=0.001). All TTP Pathway patients underwent biochemical surveillance in remission, and 31% of patients had pre-emptive rituximab to reduce the possibility of clinical relapse.

This study shows that a TMA team utilizing a protocol-based TTP Pathway can reduce TTP morbidity and improve care for this rare hematologic disease. This approach can improve the care of other multisystem hematologic diseases.
Prophylactic Administration of Glucocorticoids and Tacrolimus in AAV8-F8 Gene Therapy of Severe Haemophilia-a Achieved a Significant Long-Term Efficacy
Authors: Liu Wei , Pei Xiaolei , Xu Bingqi , Dai Xinyue , Xue Feng , Chen Linging , Wang Yuhua , Chen Yunfei , Liu Xiaofan , Fu Rongfeng , Wang Wentian , Chi Ying , Li Huiyuan , Yang Renchi , Zhang Lei
Published: December 2024

Following adeno-associated virus (AAV) gene therapy, administering immunosuppressants can enhance therapeutic efficacy by suppressing induced immune responses. GS001, a novel vector constructed with AAV8 and a liver-specific expression cassette for B domain-deleted factor VIII (FVIII), was evaluated in an open-label, phase 1 dose-escalation pilot study (NCT04728841) with 12 adult severe haemophilia A (HA) patients. Patients received either 2×10¹² or 4×10¹² vector genomes (vg)/kg of GS001 following one-week prophylactic treatment with prednisone alone or with tacrolimus. Median follow-up was 123.5/58.5 weeks (2×10¹²/4×10¹² vg/kg). Transgene expression peaked at 5-7 weeks post-infusion. At week 52, mean (±SD) FVIII activity (FVIII:C) levels were 14.6 ± 20.2 IU/dL (2×10¹² vg/kg) and 71.0 ± 24.0 IU/dL (4×10¹² vg/kg). Both groups showed significant reductions in annualized bleeding rate and FVIII consumption with grade 1-2 adverse events. Prophylactic prednisone and tacrolimus increased FVIII expression in the 2×10¹² vg/kg group. Immune responses, including AAV8-specific interferon-secreting T cells and antibodies, did not differ between dose groups. Single-cell RNA sequencing of peripheral blood immune cells before and after infusion revealed major inflammatory pathways not activated in CD8+ T cells in either dose group, while interferon-α-related genes exhibited a slight increase. Tacrolimus effectively inhibited patient-derived activated CD8+ T cell proliferation in vitro. Overall, GS001 infusion was safe, well-tolerated, achieving a significant and durable increase in FVIII. Pre-treatment with glucocorticoids and tacrolimus may benefit by suppressing induced immune responses, thereby enhancing sustained transgene expression.
Final Results of a Phase II Study of Brentuximab Vedotin and Lenalidomide in Relapsed and Refractory T-Cell Lymphomas
Authors: Reneau John C. , Huang Ying , Hanel Walter , Brammer Jonathan E. , Chung Catherine , William Basem
Published: December 2024

Brentuximab vedotin (BV) and lenalidomide (Len) demonstrate independent activity in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL). This study evaluated the efficacy and safety of this combination at reduced doses.

This phase II trial enrolled 26 patients (table 1) with relapsed/refractory PTCL/CTCL. CD30 positivity was not required, and prior BV treatment was not exclusionary. Patients were treated with BV 1.2 mg/kg IV q3weeks and Len 20 mg PO daily. Len was reduced to 10 mg due to tolerability. The primary endpoint was overall response rate (ORR).

Enrolled patients had a median age of 60 (37-90), 18 were male (69%), and had a median of 4.5 prior lines of therapy (1-9). Thirteen patients (50%) were diagnosed with mycosis fungoides, 8 with PTCL (31%), 3 with Sezary syndrome (12%), and 2 with CD30+ lymphoproliferative disorder (8%). The mean CD30 percent positivity was 7.5% (1-75%); CD30 was negative in 4 patients (18%).

Five patients achieved complete response (2 CTCL, 3 PTCL), four achieved partial response (3 CTCL, 1 PTCL), and ten had stable disease (all CTCL). The ORR was 27.8% (5/18) for CTCL and 50% (4/8) for PTCL. Nineteen patients experienced grade 3 or higher adverse events, the most common of which were neutropenia (19.2%), lymphopenia, rash, fatigue, and abdominal pain (11.5% each) Patients came off treatment most commonly for progression (54%) and adverse events (23%).

This combination demonstrated efficacy that was comparable to each agent when used as monotherapy. After reducing the Len dose to 10 mg, the combination had toxicity similar when compared to monotherapy at FDA approved dosing, although hematologic toxicity may be slightly higher. Including patients who were CD30 negative (4 patients, 18%) and having a relatively low median CD30 positivity at 7.5% may explain the lack of substantial improvement in efficacy over monotherapy with either agent. The trial was terminated early because of poor accrual.
Automated Rapid CAR-T Cell Manufacturing Process, Starting from Whole Blood, on a Novel Closed Platform
Authors: Sa Silin , Yu Liping
Published: December 2024

Background: Autologous CAR-T (Chimeric Antigen Receptor T) cell therapy has been a great success in treating hematological cancers and making progress in treating autoimmune diseases as well as solid tumors. However, the high manufacturing cost and complicated logistics have prevented the therapy from being accessible by general patients. Recently, there are discoveries and developments in the manufacturing process to reduce cost, including reduction of manufacturing time from 7-14 days to one day by elimination of in vitro cell expansion. Researchers have learned that the “rapid” manufacturing process maintains stemness of the CAR-T cells that achieved a higher potency after infusion. Additionally, changing the cell source from leukapheresis products to peripheral whole blood also helps reduce processing time and overall cost. Finally, having CAR-T cells manufactured at “point-of-care” facilities that are closer to patients will greatly reduce logistical overhead. An automated closed platform that achieves: (1) “point-of-care” manufacturing, (2) starting from whole blood, and (3) completes CAR-T cell manufacturing within 1~2 days would be ideal to reduce the CAR-T therapy cost to 10% of its current cost, and potentially further to 1% when becoming a generally practiced method with volume.

Method: We have developed a novel cell manufacturing platform (MARS Atlas), which integrates T cell isolation, viral transduction and cell washing/formulation processes on one platform. We demonstrated the CAR-T manufacturing process starting from whole blood can be completed within 24 hours. Using healthy donor's peripheral blood, we isolated T cells with CD4 and CD8 directly conjugated magnetic beads. The T cells were then activated and transduced with lentiviral vector containing CAR-19 gene. After overnight incubation, product cells were washed and harvested in either the medium that is suitable for injection or medium for cryopreservation. As a comparison, we also performed a standard 7-day expansion of transduced T cells in culture.

Results: CAR-T cell count, CAR-T cell phenotype, and CAR-T cell cytotoxic activity were monitored and compared of the 24-hour process and 7-day process. In the rapid process we harvested an average of 20million T cells after 24 hours from 30mL of blood with purity >94%. The product T cells have twice more naïve population (CD45RA+CCR7+) than the T cells harvested after 7- day process. Transduction efficiency was 60%-70% (CAR expression was stable after day 2). The function of CAR-T cells manufactured in 24 hours were verified by in vitro killing assay. By repeated stimulation with target cells CAR-T cells was observed to kill target cells in day 7.

Conclusion: In this study, we demonstrated an automated 24-hour LV-based CAR-T cell manufacturing workflow produced functioning CAR-T cells and this process has great potential for high potency and extreme low-cost CAR-T therapy.
Impact of Kidney Transplantation on Hospitalization Outcomes in Patients with Multiple Myeloma
Authors: Iqbal Rabia , Bajwa Ahmad Taimoor , Bazaz Aemen Shafqat , Gaddam Mrunanjali , Khan Fiqe , Htet Nyan Linn , Mumtaz Aqsa , Anwer Faiz
Published: December 2024

Introduction:

Despite the advancement in the treatment of Multiple Myeloma, most of the patients still develop end-stage renal disease, requiring hemodialysis. Kidney transplant is rarely performed due to risks of graft rejection and other complications, and data is limited to only a few case reports.

Objective:

In this study, we aimed to determine the impact of kidney transplants' impact on all-cause mortality and other outcomes in multiple myeloma patients who were hospitalized.

Methods:

We conducted a retrospective analysis using the National Inpatient Sample Database (NIS) from 2016 to 2020. We used ICD-10 codes to diagnose patients with a primary diagnosis of Multiple Myeloma (MM). The database was further used to classify the MM patients who underwent kidney transplants due to irreversible kidney damage. We calculated the multivariate regression analysis after adjusting for confounding variables.

Results:

A total of 580,544 patients were detected with a primary diagnosis of multiple myeloma between 2016 and 2020. Out of them, 1741 patients had a history of kidney transplant. The mean age of the patients was 64 years (P-value <0.001). Out of them, 62% (n=359,937) of the patients were male, while 38% (n=220,606) of them were female (p-value 0.03). The majority of the patients who underwent kidney transplants were white (62%, n=1079), while the black population constituted 23% (n=400), and Hispanics were almost 7% (n=122) of the patients. Most patients (78%) had medicare insurance, 18% had private insurance, and 3% had Medicaid (p-value 0.2). Our analysis showed that multiple myeloma patients who underwent kidney transplants had a decrease in mortality (aOR 0.9, p-value 0.09). However, it revealed that kidney transplant was associated with an increased risk of organ rejection (2%, aOR 49 [95% CI: 10- 235], p-value <0.01), organ infection (0.2%, aOR 11 [95% CI: 1.5-84], p-value 0.01), organ failure (4%, aOR 23 [95% CI: 6-82], p-value <0.001) and sepsis (11.6%, AOR 1.2 [95% CI: 0.6-2.3], p-value 0.5).

Conclusion:

Our study concludes that for renal damage caused by multiple myeloma, kidney transplants if performed, are associated with a decrease in all-cause mortality. However, it is also found to be associated with an increase in worse outcomes, including organ infection, rejection, and failure. Hence, although it has mortality benefits, kidney transplant comes with substantial risks leading to rejection and wasting of the organ. More research is needed to understand these associations better and improve patient selection for possible transplants.
Deep Learning the Cis-Regulatory Code of Epigenomic Rewiring By Fusion Transcription Factors in Pediatric Leukemia
Authors: Mani Shouvik , Grubert Fabian , Gratzinger Dita , Kundaje Anshul , Kasowski Maya
Published: December 2024

Pediatric leukemias are commonly driven by chromosomal translocations which create gene fusions involving hematopoietic transcription factors (TFs) in progenitor lymphoid and myeloid cell populations. Although driver gene fusions and altered signaling pathways across leukemia subtypes have been extensively cataloged, the regulatory mechanisms enabling TF fusions to reprogram the epigenome and arrest hematopoietic differentiation remain unclear.

In this study, we generated a single nucleus multiomic atlas from pediatric leukemia patient samples and leveraged deep learning models of regulatory DNA sequence to decipher the regulatory logic linking mutant TFs and regulatory elements to downstream genes and pathways in a sample and cell type-specific manner.

We profiled 22 bone marrow specimens from major diagnostic categories (T-ALL, B-ALL, AML) and including recurrent gene fusions such as ETV6-RUNX1 and RUNX1-RUNX1T1. Using whole genome sequencing (WGS) and multiplexed 10X multiome profiling (single-nucleus RNA+ATAC-seq), we simultaneously profiled gene expression and chromatin accessibility for over 70,000 cells. Unsupervised clustering and cell type annotation revealed 21 distinct clusters, including leukemic and healthy cell populations. Demultiplexing using SNPs from WGS allowed us to recover sample identities and distinguish between malignant and healthy cell populations.

To determine the sequence basis and downstream functional effects of TF rewiring in leukemia, we trained and interpreted ChromBPNet, a fully convolutional neural network, on ATAC-seq data from healthy and malignant B cell clusters. The model discovered enriched motifs for hematopoietic transcription factors, including RUNX1, ETV6, PAX5, and ERG, in ATAC peak regions of ETV6-RUNX1 B-ALL samples.

This integrative approach provides new insights into how oncogenic fusions confer blocked differentiation, survival, and proliferation to leukemia cells. Future work will leverage these models to identify novel motifs for TF fusions and fine-map germline variants to identify functional mutations that perturb TF binding and accessibility through motif disruption.
Platelet RIG-I Promotes Flu-Induced Severe Lung Injury in Sickle Cell Disease
Authors: Kaminski Tomasz , Swendrowski Nicholas , Katoch Omika , Sundd Prithu
Published: December 2024

Background: Sickle cell disease (SCD) affects over ~8 million people world-wide. Acute chest syndrome, a type of acute lung injury (ALI) is a major cause of mortality among SCD patients. Flu typically causes a self-resolving upper airway inflammation, however, it may progress for unknown reasons into a highly morbid ALI. Epidemiological evidence suggests that flu results in severe outcomes in SCD patients and associates with a 50-fold higher risk of hospitalization among SCD compared to non-SCD humans. However, the mechanisms underlying the flu severity and subsequent severe lung injury in SCD remains largely unknown.

Methods: We have developed a new model of A/PR/8/34 (H1N1) influenza A virus (IAV) induced respiratory infection in knock-in, humanized Townes SCD (SS) mice. SCD or control (Townes AS) mice were inoculated intranasally with a mild dose of IAV, and severity of lung injury was evaluated 14 days post infection using histological scoring, oxygen saturation was measured every other day and body weight was assessed every day. Real-time intravital (in vivo) multi-photon-excitation fluorescence microscopy (MPE) was used to assess thrombo-inflammation and vascular leakage in the lung of mice at 10 days post IAV-infection. Platelets were isolated for western blotting and co-immunoprecipitation to assess the activation of anti-viral pathways in platelets.

Results: SCD+Flu mice manifested significant drop in oxygen saturation (<90%), body weight (³ 20%) and developed severe lung injury indicated by the presence of hemorrhage, vascular congestion and edema in the lung histopathological analysis. Severe ALI in SCD+Flu mice at day 10 post infection was associated with pulmonary thrombo-inflammation leading to microvasculature occlusion by platelet-rich neutrophil-platelets aggregates (NPAs), resulting in pulmonary ischemia and loss of blood-air barrier. In contrast to SCD mice, control mice inoculated with mild dose of flu did not develop ALI and neutrophil-platelet aggregates were absent in the lung microcirculation of Control+Flu mice at day 10th post infection. Co-immunoprecipitation showed assembly of viral-RNA sensing RIG-I-MAVS complex in SCD+Flu but not Control+Flu mice platelets, suggestive of the activation of anti-viral response in SCD+Flu but not Control+Flu mice platelets 10-days post infection.

Conclusions: These findings suggest for the first time a potential role for platelet-dependent anti-viral RIG-I signaling in promoting thrombo-inflammation and severe lung injury following flu infection in SCD. Currently, studies are in progress to identify the innate immune signaling downstream to platelet RIG-I-MAVS complex formation, and how it can be therapeutically manipulated to reduce the flu morbidity in SCD.
Interim Results of a New Examination Protocol for Women and Girls with Inherited Bleeding Disorders (WGBD)
Authors: Halimeh Susan , Daoud Mohamad Ayman , Schmitz Derya , Habermann Bjoern
Published: December 2024

Women and girls with haemophilia (WGBD), including those who are symptomatic carriers (F VIII/IX plasma levels ≥ 40 IU/ml1), experience joint haemarthrosis similar in nature to that experienced by men with mild haemophilia.2 However, WGBD are often overlooked in both clinical and research settings.3,4 Current ultrasound techniques are primarily able to detect synovitis, which is a later stage of haemarthrosis.5 Inflammatory processes may lead to joint dysfunction even in the absence of structural damage.6 Early detection of subclinical joint bleeding is of paramount importance.7

We are therefore developing a new assessment protocol for WGBD that combines biomechanical analysis and our new psychometric quality of life questionnaire with the existing diagnostic toolset of the Pictorial Blood Loss Assessment Chart (PBAC), Haemophilia Joint Health Score, ISTH Bleeding Score, Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US).

In collecting the interim results described in this second abstract, we aimed to determine whether the Noraxon system, using validated inertial measurement units (IMUs) and electromyography (EMG), can facilitate the early detection of joint damage in WGBD using non-invasive gait analysis. A comparison was made between the results of the Noraxon biomechanical analysis and those obtained from PBAC, ISTH bleeding scores, HEAD-US and HJHS measurements in a group of 26 WGWH. Symptomatic participants were asked about any joint complaints.

The mean age of the participants was 38.8 years (range 14-71). Of the participants, 23 had haemophilia A and three had haemophilia B, including seven individuals with combined VWD. As expected, the PBAC score for heavy menstrual bleeding was above 150 (mean 161). There was a positive correlation between HJHS and HEAD-US scores (Pearson correlation coefficient r = 0.595). Interestingly, there is a positive and moderately significant correlation between the ISTH Bleeding Score and HJHS (r = 0.5), but not with HEAD-US.

When patients were asked about joint complaints, a strong correlation was found in bilateral EMG measurements when the gastrocnemius muscle was considered in the stance phase (Pearson correlation coefficient (r = 0.446)). A very high significance was also observed when the recorded ankle complaints were correlated with kinematic measurements of hip abduction (0.002), hip rotation (0.034) and ankle abduction (0.011).

The strong correlations shown in the interim results convinced us that gait and movement analysis is a very powerful tool for early detection of incipient joint and ankle changes in WGBD. Therefore, we are encouraged to a) further develop our new WGBD-Examination-Protocol b) test it on more patients and c) propose to collect and analyze more data nationally and internationally.
Bone biochemical markers, bone mineral density, and the risk of osteonecrosis of the femoral head: a Mendelian randomization study
Authors: Jia Hai-feng , Tian Ze-ming , Liang Xue-zhen , Li Han-zheng , Lu Bo-wen , Zhang Jian , Li Gang
Published: December 2024

Background

Alterations in bone metabolism may play a significant role in the early stages of femoral head necrosis, yet the causal relationship remains unclear. This study utilizes a two-sample Mendelian randomization (MR) approach to explore the genetic causal links between biochemical markers of bone metabolism, bone mineral density, and the risk of femoral head necrosis.

Methods

This study utilizes publicly available genome-wide association study (GWAS) datasets, with exposure factors including biochemical bone markers (25OHD, calcium, and alkaline phosphatase) and bone mineral density (measured at the lumbar spine, heel, femoral neck, and total body). The outcome of interest is osteonecrosis of the femoral head. We selected validated single nucleotide polymorphisms that are strongly associated with the exposure factors as instrumental variables. Mendelian randomization analysis was conducted using inverse variance weighting(IVW), MR-Egger regression, and weighted median estimation. Additionally, we performed analyses for horizontal pleiotropy, heterogeneity, and sensitivity.

Results

A total of 934 SNPs were included in this study. The MR analysis results indicate that the IVW analysis of 25OHD, Ca, and ALP did not reach statistical significance (25OHD OR = 1.006, 95%CI: 0.69–1.47, P = 0.975; Ca OR = 0.856, 95%CI: 0.43–1.70, P = 0.657; ALP OR = 1.022, 95%CI: 0.86–1.21, P = 0.801). However, bone density, including heel, lumbar spine, and total body bone density, showed a protective causal relationship with the onset of ONFH, while the results for femoral neck bone density did not reach statistical significance (lumbar spine BMD OR = 0.662, 95%CI: 0.48–0.91, P = 0.010; heel BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; total body BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; femoral neck BMD OR = 0.748, 95%CI: 0.53–1.05, P = 0.096). Cochran’s Q statistic for IVW and MR-Egger methods indicated no intergenic heterogeneity for all exposure outcomes’ SNPs, and the tests for pleiotropy suggested a low likelihood of pleiotropy in all causal analyses.

Conclusions

The results of this study indicate that there is no genetically mediated causal relationship between serum levels of 25-hydroxyvitamin D, calcium, and alkaline phosphatase and osteonecrosis of the femoral head. However, heel, lumbar spine, and total body bone mineral density can be considered protective factors for the occurrence of ONFH. There is no genetic causality between femoral neck bone mineral density and ONFH development.
The role of the public health service in the implementation of heat health action plans for climate change adaptation in Germany: A qualitative study
Authors: Geffert Karin , Voss Stephan , Rehfuess Eva , Rechel Bernd
Published: December 2024

Background

In response to climate change-induced increases in heat periods, the WHO recommends the implementation of heat health action plans (HHAPs). In Germany, HHAPs are implemented neither comprehensively nor nationwide. Several recommendations have identified the public health service (PHS) at municipal and federal state levels as a key actor regarding to heat and health. Therefore, this study aimed at assessing the role of the PHS in implementing HHAPs at municipal and federal state levels in Germany.

Methods

We conducted a policy document analysis to assess the legal basis for the work of the PHS in the 16 federal states in Germany. Furthermore, we conducted semi-structured interviews with 16 experts from within and outside the PHS to explore their perceptions of the PHS in the implementation of HHAPs. The interviews were analysed using reflective thematic analysis.

Results

The policy document analysis revealed that heat is not mentioned in any of the federal states’ regulatory frameworks for the PHS, while tasks related to environment and health are addressed, but tend to remain vague. The interviews confirmed that there is currently no clearly defined role for the PHS in implementing HHAPs in Germany and that the actual role primarily depends on the local setting. Main barriers and facilitators could be assigned to three levels (individual, organizational and political), and two overarching contextual factors (awareness of the need for adaptation and existence of other public health emergencies) influenced the implementation of HHAPs across all levels. At the individual level, motivation, knowledge and competencies, and previous experience were possible barriers or enablers. At the organizational level, administrative structures, financial and human resources, leadership and networks were barriers or facilitators, while at the political level they included legislation and political decisions.

Conclusions

The PHS could and should be a relevant actor for implementing measures addressing health and climate change locally, in particular because of its focus on vulnerable populations. However, our findings suggest that the legal basis in the federal states of Germany is insufficient. Tailored approaches are needed to overcome barriers such as rigid, non-agile administrative structures and competing priorities, while taking advantage of facilitators such as awareness of relevant actors.
Short- and long-term pathologic responses to quartz are induced by nearly free silanols formed during crystal fracturing
Authors: Pavan Cristina , Leinardi Riccardo , Benhida Anissa , Ibouraadaten Saloua , Yakoub Yousof , Brule Sybille van den , Lison Dominique , Turci Francesco , Huaux François
Published: December 2024

Background

Inhalation of respirable crystalline silica particles, including quartz, is associated with an increased risk of developing pathologies, including persistent lung inflammation, fibrosis, cancer, and systemic autoimmunity. We demonstrated that the nearly free silanols (NFS) generated upon quartz fracturing trigger the early molecular events determining quartz toxicity. Here, we address the involvement of NFS in driving short- and long-term pathogenic responses, including lung inflammation, fibrosis, cancer, and autoimmunity in multiple mouse models.

Results

In vivo pulmonary responses to as-grown NFS-poor quartz (gQ) and fractured NFS-rich quartz (gQ-f) of synthetic origin were compared to two NFS-rich reference quartz dusts (Min-U-Sil 5, mQ-f). Acute and persistent inflammation, as well as fibrosis, were assessed 3 and 60 days, respectively, after administering one dose of particles (2 mg) via oropharyngeal aspiration (o.p.a.) to C57BL/6 mice. The carcinogenic potential was assessed in a co-carcinogenicity study using A/J mice, which were pre-treated with 3-methylcholanthrene (3-MC) and administered four doses of quartz particles (4 × 1 mg, o.p.a.), then sacrificed after 10 months. Autoimmunity was evaluated in autoimmune-prone 129/Sv mice 4 months after particle administration (2 × 1.25 mg, o.p.a). Mice exposed to NFS-rich quartz exhibited a strong acute lung inflammatory response, characterized by pro-inflammatory cytokine release and leukocyte accumulation, which persisted for up to 60 days. No inflammatory effect was observed in mice treated with NFS-poor gQ. Fibrosis onset (i.e., increased levels of pro-fibrotic factors, hydroxyproline, and collagen) was prominent in mice exposed to NFS-rich but not to NFS-poor quartz. Additionally, lung cancer development (tumour numbers) and autoimmune responses (elevated IgG and anti-dsDNA autoantibody levels) were only observed after exposure to NFS-rich quartz.

Conclusions

Collectively, the results indicate that NFS, which occur upon fracturing of quartz particles, play a crucial role in the short- and long-term local and systemic responses to quartz. The assessment of NFS on amorphous or crystalline silica particles may help create a predictive model of silica pathogenicity.
Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models
Authors: Horn Lucas A. , Lind Hanne , Fousek Kristen , Qin Haiyan , Rajabian Nika , Angstadt Shantel , Hsiao-Sanchez Nicole , Medina-Enriquez Miriam M. , Kelly Marcus D. , Allen Clint T. , Hammoudeh Sarah M. , Weigert Roberto , Maeda Dean Y. , Zebala John A. , Palena Claudia
Published: December 2024

Background

Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC.

Methods

Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.

Results

High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8+ T cells in the combination therapy treated tumors compared to controls.

Conclusions

This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.
Acceptability of midazolam and melatonin as premedications for anxious children undergoing general anaesthesia: a qualitative interview study with children, caregivers and health professionals participating in the MAGIC trial
Authors: Kettle Jennifer , Bolt Robert , Deery Chris , Papaioannou Diana , Rodd Helen , Hyslop Marie C. , Totton Nikki , Marshman Zoe
Published: December 2024

Background

The acceptability of a children’s premedication, prior to general anaesthesia (GA), is fundamental to ensuring positive clinical- and patient-reported outcomes. Midazolam, the current standard premedication, is known to have an unfavourable side-effects profile and presents a degree of risk which is accepted due to a need for compliance. Melatonin is a functionally diverse hormone with anxiolytic properties that offer potential benefits over midazolam. Little is currently known about how patients and health professionals view these two different premedications. This research aimed to explore the acceptability of midazolam and melatonin as premedications for anxious children undergoing GA, from the perspective of children, caregivers and health professionals involved in the Melatonin for Anxiety prior to General Anaesthesia In Children (MAGIC) trial.

Methods

Participants were children recruited to the MAGIC trial, their caregivers and health professionals involved in recruitment to the trial. In total, 37 participants (23 health professionals, 10 caregivers and 4 children) took part in semi-structured interviews relating to the MAGIC trial and acceptability of premedications. Interviews were carried out face-to-face, by telephone or online by a trained qualitative researcher. Interviews were transcribed verbatim and analysed using a framework approach.

Results

The acceptability of midazolam and melatonin is related to six main factors: effectiveness as premedication prior to GA; administration of premedication; experience of recovery; prior experiences of premedication; associations and evidence; and range of options for managing anxiety. Interviews highlighted the trade-offs involved and the relevance of the wider context in which premedications are provided. Barriers and facilitators were identified on the acceptability of premedications more generally.

Conclusions

Future clinical trials evaluating the effectiveness of premedications in children prior to general anaesthesia need to consider that premedication choice is multifactorial. The MAGIC study found that melatonin was less effective at reducing anxiety (pre-operative distress) when compared with the standard of care, midazolam. However, there remains a need for a premedication with a better side effects profile to midazolam. While children, caregivers and health professionals are open to alternatives to midazolam, this is likely to vary by subgroup and will involve trade-offs in terms of benefits.

Trial registration

ISCRCTN ISRCTN18296119. Registered on 10/01/2019.
Monitoring alpha-cypermethrin susceptibility of Phlebotomus argentipes, the vector of visceral leishmaniasis in India, using the CDC bottle bioassay
Authors: Chaubey Rahul , Shukla Ashish , Kushwaha Anurag Kumar , Singh Shakti Kumar , Singh Om Prakash , Kumar Rajiv , Lawyer Phillip , Rowton Edgar , Petersen Christine A. , Bernhardt Scott A. , Sundar Shyam
Published: December 2024

Background

Visceral leishmaniasis (VL), known as Kala-azar on the Indian subcontinent, is a parasitic disease caused by the flagellated protozoa Leishmania donovani and can be fatal if left untreated. The sand fly Phlebotomus argentipes is the only proven vector of VL in the Southeast Asia region, and VL control in this region has relied on the use of synthetic insecticides for indoor residual spraying (IRS). The use of DDT in VL control programmes has led to the development of resistance to this insecticide in sand flies, resulting in DDT being replaced with the insecticide alpha-cypermethrin. However, alpha-cypermethrin has a similar mode of action as DDT and, therefore, the risk of resistance development in sand flies increases under the pressure of regular exposure to this insecticide. In the present study we assessed the susceptibility status of wild-caught sand flies and F1 progeny using the CDC bottle bioassay.

Methods

Sand flies were collected from 10 villages in Muzaffarpur District, Bihar, India. Eight of these villages are receiving continuous IRS with alpha-cypermethrin, one village had discontinued IRS with alpha-cypermethrin and one village had never received IRS with alpha-cypermethrin. The collected sand flies were exposed to a pre-determined diagnostic dose for a specific time duration (3 µg/ml for 40 min), and knockdown and mortality at 24 h post-exposure were recorded.

Results

Knockdown ranged from 91.19% to 99.47% for wild-caught sand flies and from 91.70% to 98.89% for their F1 progeny. At 24 h post-exposure, mortality ranged from 89.34% to 98.93% for wild-caught sand flies and from 90.16% to 98.33% for F1 progeny.

Conclusions

The results of this study showed that P. argentipes is potentially developing resistance, signalling the need for continuous monitoring and vigilance to sustain the validation of elimination once achieved.

Graphical Abstract
An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy
Authors: Lopes Luis R. , Macken William L. , Preez Seth Du , Kotwal Huafrin , Savvatis Konstantinos , Sekhri Neha , Mohiddin Saidi A. , Kabiljo Renata , Pitceathly Robert D. S.
Published: December 2024

Background

A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particularly in genotype-elusive participants. The homoplasmic MT-TI 4300A>G is unusual in that it typically presents with a cardiac-only phenotype, but MT-TI is currently not part of the genes analysed for non-syndromic cardiomyopathies.

Results

We analysed 1363 cardiomyopathy genomes from the 100KGP project (of which only 172 had been previously solved) to detect disease causing mtDNA variants. MitoHPC was used to call variants. For controls, 1329 random subjects not recruited for a cardiomyopathy diagnosis and not related to any participant in the cardiomyopathy cohort were selected. We have additionally compared the frequency of detected variants with published UK Biobank data. Pathogenicity annotations were assigned based on MitoMap. Four patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM) and without a previously identified genetic cause from the 100KGP clinical-standard analysis, were found to harbour the pathogenic MT-TI m.4300A>G variant (0.6% of HCM cases without a diagnosis).

Conclusion

These data support the inclusion of MT-TI in the initial genetic testing panel for (non-syndromic) HCM.
Performance assessment of interpolation methods for orbits of altimetry satellites
Authors: Zeitlhöfler Julian , Alkahal Riva , Rudenko Sergei , Bloßfeld Mathis , Seitz Florian
Published: December 2024

Global and regional sea level variations are important indicators of climate change and are derived from accurate sea surface height measurements and precisely determined orbits of altimetry satellites. To validate and improve the quality of these orbits, comparisons with external solutions are important. Since orbit solutions of different institutions are not necessarily provided at the same time instants, interpolation is required for comparison. In this study, we investigate the appropriate interpolation method and its degree to reduce interpolation errors to sub-millimetre levels. We also assess the magnitude of errors occurring at transformations when expressing orbit differences not only in the terrestrial reference frame (Cartesian coordinates), but also in local orbital and ellipsoidal coordinates. The analyses conducted in this study provide good results for Hermite interpolation of degrees 7–11 and Newton interpolation of at least degree 9 with a three-dimensional interpolation error of 0.6 mm and a scattering of 0.2 mm on average for satellite coordinates given with an accuracy of 1 mm in the SP3 format. These interpolation settings limit transformation errors between coordinate systems to ±0.01 mm and incorrect mapping of interpolation errors into certain components in the target system to ±0.02 mm. The spectral analysis of orbit differences is affected up to 0.1 mm in magnitude with appropriate interpolation settings. Extending the number of decimal digits of the satellite position and velocity in SP3 files by one digit benefits the orbit comparisons and reduces the interpolation error by 90% from 0.6 to 0.06 mm. The results are obtained using piece-wise interpolation and a validity interval inside the interpolation interval to minimise the effects of the Runge phenomenon.

Graphical Abstract
Does septic arthritis after anterior cruciate ligament reconstruction lead to poor outcomes? A systematic review and meta-analysis of observational studies
Authors: Lin Ashleigh Peng , Nguyen Bao Tu Thai , Tran Son Quang , Kuo Yi-Jie , Huang Shu-Wei , Chen Yu-Pin
Published: December 2024

Background

Septic arthritis is a rare but devastating complication after anterior cruciate ligament reconstruction (ACLR). While early treatment can prevent significant graft complications, outcomes are often inferior to those in uncomplicated ACLR. Furthermore, whether to retain or remove the graft after infection remains debatable. Therefore, we sought to compare the outcomes of septic arthritis post ACLR with uncomplicated ACLR and evaluate graft retention versus removal in infected patients.

Methods

We conducted a systematic review and meta-analysis in which PubMed, Embase, and Cochrane Library databases were searched. Clinical studies were included if they compared patient-reported, clinician-reported, or radiographic outcomes (minimum follow-up of 12 months) between patients with post-ACLR septic arthritis and those with uncomplicated ACLR or that compared graft retention and removal in patients with post-ACLR septic arthritis.

Results

Thirteen studies were retrieved. Patients with post-ACLR septic arthritis reported inferior Lysholm Knee Scoring Scale scores (mean difference (MD) 7.53; 95% confidence interval (CI) 3.20–11.86; P = 0.0006), Tegner Activity Scale scores (MD, 1.42; 95% CI 1.07–1.76; P < .00001), and return to sports rates (53% versus 76%, respectively) to those of patients with uncomplicated ACLR. Patients with post-ACLR septic arthritis and those with uncomplicated ACLR did not differ in terms of the pooled estimate of various clinician-reported outcomes, such as the objective International Knee Documentation Committee score, anterior–posterior laxity, pivot shift, and Lachman test results. Furthermore, no significant difference was noted between the aforementioned patient groups regarding osteoarthritis (detected radiographically). Graft retention led to better patient- and clinician-reported outcomes than graft removal.

Conclusions

Despite similar clinician-reported outcomes and osteoarthritis rates, patients with post-ACLR septic arthritis reported worse outcomes than those with uncomplicated ACLR. Graft retention leads to improved patient- and clinician-reported outcomes compared with the outcomes of graft removal. Our findings may help develop realistic expectations and management strategies for this rare complication.
Externally validated clinical prediction models for estimating treatment outcomes for patients with a mood, anxiety or psychotic disorder: systematic review and meta-analysis
Authors: Burghoorn Desi G. , Booij Sanne H. , Schoevers Robert A. , Riese Harriëtte
Published: December 2024

Background

Suboptimal treatment outcomes contribute to the high disease burden of mood, anxiety or psychotic disorders. Clinical prediction models could optimise treatment allocation, which may result in better outcomes. Whereas ample research on prediction models is performed, model performance in other clinical contexts (i.e. external validation) is rarely examined. This gap hampers generalisability and as such implementation in clinical practice.

Aims

Systematically appraise studies on externally validated clinical prediction models for estimated treatment outcomes for mood, anxiety and psychotic disorders by (1) reviewing methodological quality and applicability of studies and (2) investigating how model properties relate to differences in model performance.

Method

The review and meta-analysis protocol was prospectively registered with PROSPERO (registration number CRD42022307987). A search was conducted on 8 November 2021 in the databases PubMED, PsycINFO and EMBASE. Random-effects meta-analysis and meta-regression were conducted to examine between-study heterogeneity in discriminative performance and its relevant influencing factors.

Results

Twenty-eight studies were included. The majority of studies (n = 16) validated models for mood disorders. Clinical predictors (e.g. symptom severity) were most frequently included (n = 25). Low methodological and applicability concerns were found for two studies. The overall discrimination performance of the meta-analysis was fair with wide prediction intervals (0.72 [0.46; 0.89]). The between-study heterogeneity was not explained by number or type of predictors but by disorder diagnosis.

Conclusions

Few models seem ready for further implementation in clinical practice to aid treatment allocation. Besides the need for more external validation studies, we recommend close examination of the clinical setting before model implementation.