bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B016: Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach
Authors: Kuusela Sara , Martikainen Enni , Eloranta Katja , Wang Wenyu , Kumari Romika , Potdar Swapnil , Dashi Giovanna , Lohi Jouko , Mutka Aino , Tynninen Olli , Kanerva Jukka , Pentikäinen Virve , Koskenvuo Minna , Pietiäinen Vilja M.
Published: September 2024

Many pediatric cancer patients with high-risk primary, refractory, or relapsed tumors still lack effective treatment strategies and frequently suffer from both acute and delayed adverse drug effects, including secondary cancers. These tumors are generally characterized by very few druggable molecular alterations, diminishing the advantage of genetics in defining patient-specific treatments. The purpose of this study is to utilize the functional precision medicine approach to provide improved diagnostics and better therapy options for pediatric solid tumors through deep molecular and functional profiling in a patient-specific manner. Here, we describe the results of our current study, which includes exome sequencing for germline and somatic mutations, and transcriptomics analysis for fusion genes, as well as ex vivo drug testing of patient-derived cancer cells (PDCs) in real-time clinical set-up. Our current clinical data and sample collection, currently from 40 patients, include different types of pediatric solid tumors, such as central nervous system (CNS) tumors, sarcomas, and neuroblastomas. We have prepared PDC cultures and screened them using a 3D-drug sensitivity and resistance testing (DSRT) platform with an internationally defined pediatric solid tumor drug panel. Our results include the drug testing results of control cell lines and primary healthy cells to assess the general cytotoxicity of the drugs and patient-specific responses. We present our "fast-track" functional precision medicine concept, incorporated as part of biobank operations to return clinically relevant findings back to the treating clinicians, and exemplify the data returned to the clinics as well as its potential clinical impact. In conclusion, our findings demonstrate that the functional precision medicine approach can i) help to discover clinically relevant molecular events important for diagnosis and treatment, and ii) increase our biological understanding of drug vulnerabilities in pediatric cancers.

Citation Format: Sara Kuusela, Enni Martikainen, Katja Eloranta, Wenyu Wang, Romika Kumari, Swapnil Potdar, Giovanna Dashi, Jouko Lohi, Aino Mutka, Olli Tynninen, Jukka Kanerva, Virve Pentikäinen, Minna Koskenvuo, Vilja M. Pietiäinen. Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B016.
Abstract B017: Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma
Authors: Prensner John , Bandopadhayay Pratiti , Saha Soumik , Lupien Leslie , Choi Seung H.
Published: September 2024

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation.Dysregulation of ribosome activity not only influences known protein-coding genes, but also unannotated small open reading frames (sORFs) as well.We have recently shown that sORFs may produce functional microproteins in medulloblastoma.Here, we performed an integrative analysis of medulloblastoma patient samples and cell lines.We used ribosome profiling, RNAseq, and mass spectrometry to delineate dysregulation of microprotein production.We employed cell models of MYC overexpression to determine the role of MYC in selective translation of microproteins in medulloblastoma, finding specific associations with upstream open reading frames (uORFs) located in gene leader sequences.We then designed a step-wise approach to define functional microproteins in medulloblastoma through the use of CRISPR/Cas9 screens, saturation mutagenesis, and base editing.We observed distinctive signatures of microprotein bioactivity based on the molecular drivers of medulloblastoma according to disease subtypes.In the Group 3 subtype, we observed an enrichment for bioactive uORFs relative to other disease settings.We then characterized several key microprotein dependencies resulting from uORFs including a molecular mechanism for one candidate, ASNSD1-uORF, in mediating protein-RNA dyssynchrony in Group 3 medulloblastoma.Protein-RNA dyssynchrony is the divergent regulation of protein abundance from RNA abundance, and is a hallmark of Group 3 medulloblastoma.We probed the clinical and therapeutic implications of protein-RNA dyssynchrony and determined that this process may be associated with patterns of drug sensitivity and resistance in medulloblastoma.With this insight, we have now used ASNSD1-uORF to stratify medulloblastoma resistance patterns to inhibitors of RNA transcription.We determine that an interplay between RNA translational control and RNA transcriptional control, while driving resistance in some settings, may also reveal additional drug targets, such as cyclin-dependent kinases.Our findings underscore the fundamental importance of sORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets and therapeutic insights.

Citation Format: John Prensner, Pratiti Bandopadhayay, Soumik Saha, Leslie Lupien, Seung H. Choi. Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B017.
Abstract B048: Galectin-3 regulation of immunosuppression in Ewing sarcoma
Authors: Maharjan Yunash , Tufino Adriana C. , Dey Sreya , Mukherjee Elina , Bailey Kelly M.
Published: September 2024

Objective: Ewing sarcoma is a fusion oncoprotein-driven cancer most commonly diagnosed in adolescents. Utilizing single-cell RNAseq of human Ewing tumors, we have previously demonstrated that Galectin-3, an immunosuppressive lectin family member protein, is expressed in both Ewing tumor cells and in CD8 T cells in the Ewing tumor microenvironment, a finding not noted in CD8 T cells infiltrating osteosarcomas. Galectin-3 serves to modulate tumor immunobiology through multiple mechanisms, including interactions with the immune checkpoint protein LAG3. In addition to Galectin-3, Galectin-3BP (binding protein) is also expressed in Ewing sarcoma and can bind to and modulate Galectin-3 function. Here, we aim to determine the role of Galectin-3 and Galectin-3BP on Ewing tumor immunosuppression. Methods: CHLA10 and TC32 human Ewing sarcoma tumor cells -/+ LGALS3 (gene encoding galectin-3) expression were generated using CRISPR/Cas 9 technology. T cells primed again human Ewing tumor cells were generated. The galectin-3 inhibitor TD-139 was also utilized. In vitro IncuCyte live cell monitoring assays, ELISA, and co-culture apoptosis assays were conducted. In vivo analyses of tumor growth, metastasis, and immune cell infiltration were conducted on Ewing tumors developed in immunocompetent, humanized mice and immunodeficient NSG mice. Peripheral blood and spleen controls were also analyzed. Results: CRISPR/Cas 9 knock-out of LGALS3 in both CHAL10 and TC32 cell lines was successful. GSEA of RNAseq data demonstrate distinct developmental signatures and flow cytometry analyses demonstrate altered immune cell signatures in LGALS3 KO Ewing tumors versus controls developed in humanized mice. ELISA demonstrates Galectin-3 is secreted by some Ewing tumors, the functional implications of which are under ongoing investigation. Expression of Galectin-3 and Galectin-3BP alone versus co-expression impacts the net effect of on Ewing tumor behavior. Conclusion: This work contributes to the understanding of galectin-3 on inflammatory responses and tumor progression in Ewing sarcoma. Understanding the complex relationship of Galectin-3 and Galectin-3BP on immunobiology provides valuable clues to best disrupt Galectin-3 mediated immunosuppression and promote enhanced tumor control.

Citation Format: Yunash Maharjan, Adriana C. Tufino, Sreya Dey, Elina Mukherjee, Kelly M. Bailey. Galectin-3 regulation of immunosuppression in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B048.
Abstract B080: Survivorship care models for childhood cancer survivors in low- and middle-income countries: A scoping review
Authors: Lecce Celine , Denburg Avram E. , Gupta Sumit , Martiniuk Alexandra , Qi Ariel
Published: September 2024

Childhood cancer survivors require specific care that includes monitoring for late effects of cancer therapy. Current knowledge on how to deliver survivorship care is based on experience in high-income countries, which may not be applicable to other settings. We thus conducted a scoping review to characterize and describe the models of survivorship care available to childhood cancer survivors in low- and middle-income countries (LMICs). Fifty-one studies were selected from a comprehensive literature search of 8 electronic and 2 grey-literature databases followed by title, abstract, and full-text screening. Elements of survivorship care were categorized within the domains of the Quality of Cancer Survivorship Care Framework using representative Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers guidelines for childhood cancer survivors. The Quality of Cancer Survivorship Care Framework is comprised of 5 domains related to survivorship care services, and 4 domains related to health care delivery. From the 51 studies chosen for data extraction, 61 LMICs were identified. Of these 61 LMICs, only 11 countries reported having active survivorship care services. The most reported services in the included papers from LMICs are related to the surveillance and management of chronic medical conditions and psychosocial effects. Of the countries that that reported survivorship services, literature from India reported on the four fundamental health care delivery domains identified by the Quality Cancer Survivorship Care Framework, which include clinical structure, communication and decision-making, care coordination, and patient/caregiver experience. Additionally, 8 of the 11 countries publishing about their survivorship care documented access to specialty medical care and healthcare professionals for childhood cancer survivors, such as onco-endocrinologists and psychologists. There are patient, clinician, and health system-related barriers to developing and implementing survivorship care in LMICs. Efforts to optimize the delivery of survivorship care include increased patient and family education about treatment late effects, optimized healthcare provider staffing, staff education, and training, and implementation of standardized practice guidelines that are resource-stratified and therefore applicable in multiple settings.

Citation Format: Celine Lecce, Avram E. Denburg, Sumit Gupta, Alexandra Martiniuk, Ariel Qi. Survivorship care models for childhood cancer survivors in low- and middle-income countries: A scoping review [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B080.
Abstract B081: EWS::FLI1 alters DNA damage induced protein dynamics at the RNAPII CTD
Authors: Stoja Aiola , Xu Xiaoping , Libich David S , Bishop Alexander J. R.
Published: September 2024

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer with limited treatment options, highlighting a drastic need for novel therapeutics. EwS is driven by translocation of the EWSR1 low complexity domain and most often the DNA binding domain of FLI1, making up the oncogenic fusion protein EWS::FLI1. Accumulating evidence suggests that EWS::FLI1 alters the biophysical properties of EWS and EWS::FLI1 phase separated condensates. We have previously shown that EWS::FLI1 prevents the release of the double strand break (DSB) repair protein BRCA1 from RNA Polymerase II (RNAPII) complexes, inhibiting BRCA1 mediated DSB repair. However, how EWS::FLI1 alters protein dynamics at the RNAPII complexes is not understood. In this work we show that EWS::FLI1 co-localization to RNAPII C-Terminal Domain (CTD) protein hubs causes enhanced phase separation, imitating a hardening of RNAPII CTD condensates. Additionally, we find that treatment with DNA damaging agents decreases BRCA1 occupancy at RNAPII CTD protein hubs. Expression of EWS::FLI1 in this in cellulo system suggests inhibition of BRCA1 release from RNAPII phase separated entities upon DNA damage. Overall, this data indicates that EWS::FLI1 mediated changes in phase state alters heterotypic protein-protein interactions at the RNAPII complexes. Furthermore, we find that RNAPII CTD phase separated entities are refractory to THZ1 drug treatment. This underscores the physiological significance condensate biology plays in drug efficacy and drug resistance. In conclusion, our results prompt further investigation into EWS::FLI1 affects on protein-protein interactions at RNAPII condensates. Our findings are novel as we look at heterotypic phase condensate biology in cellulo, whereas most phase studies are conducted in vitro and focus on homotypic interactions. Moreover, though much work was conducted on BRCA1 and RNAPII interaction and damage-induced release in the 1990s and early 2000s, little is understood about the relationship of BRCA1 and RNAPII and certainly not in the context of EWS::FLI1. Importantly, this work provides a basis for the physiological role of condensate biology in EWS::FLI1 mediated BRCA1 and RNAPII protein-protein dynamics.

Citation Format: Aiola Stoja, Xiaoping Xu, David S Libich, Alexander J. R. Bishop. EWS::FLI1 alters DNA damage induced protein dynamics at the RNAPII CTD [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B081.
Abstract IA021: Neogenes induced by oncogenic chimeric transcription factors as potential targets for therapy
Authors: Petit Floriane , Lalanne Ana , Collin Céline , Waterfall Joshua , Lantz Olivier , Delattre Olivier
Published: September 2024

We recently showed that oncogenic chiemeric transcription factors (OCTF) of various pediatric cancers induce the expression of highly tumor-specific long intergenic non coding RNAs which are not expressed in normal tissues and which we called neogenes. Since recent reports indicate that such LincRNA may not be as non-coding as initially thought we sought for potential peptides encoded by these neogenes. Using the EWSR1::FLI1 chimera of Ewing sarcoma as a paradigm of such chimeras and through Riboseq profiling and whole cell proteomics we indeed show that some of these neogenes encode peptides. Immunopeptidomic experiments were performed on a series of Ewing sarcoma cell lines and PDX and further showed that peptides encoded by Ewing-specific neogenes are associated with MHC-Class I molecules at the surface of Ewing cells. Ewing peptide-specific CD8 T-cells were isolated from healthy donors. We show that these cytotoxic T-cells can be activated by Ewing cells to secrete cytokins, They can also kill Ewing cells. This killing is specific for the MHC-Class I types, specific for Ewing sarcoma cells as compared to other tumor types and is strictly deendent upon the expression of EWSR1::FLI1 that regulates the neogenes and of the expression of the neogene encoding the peptide. These data support the idea that OCTF-specific neogenes may constitute an interesting resource for various immunotherapy approaches including vaccination, BiTE or TCR-T-cell therapy.

Citation Format: Floriane Petit, Ana Lalanne, Céline Collin, Joshua Waterfall, Olivier Lantz, Olivier Delattre. Neogenes induced by oncogenic chimeric transcription factors as potential targets for therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA021.
Supplementary Table 1 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Table 1
Supplementary Figure 7 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 7
Supplementary Figure 4 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 4
Supplementary Figure 3 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 3
Supplementary Figure 2 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 2
Supplementary Figure 12 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 12
Liddle Syndrome with a SCNN1A Mutation: A Case Report and Literature Review
Authors: Tian Jiajia , Xiang Fei , Wang Liandi , Wu Xueyi , Shao Lijuan , Ma Li , Fang Chuwen
Published: September 2024

Introduction: Liddle syndrome is an autosomal dominant monogenic disease that mainly manifests as early-onset hypertension, hypokalaemia and metabolic alkalosis, as well as hyporeninaemia and hypoaldosteronism. The aetiology of Liddle syndrome is missense or frameshift mutations in the SCNN1A, SCNN1B, or SCNN1G genes, which encode for the epithelial sodium channel subunits. Among these, mutations in the SCNN1A gene are very rare. Case Presentation: A Liddle syndrome case caused by a SCNN1A mutation was reported from China. A 59-year-old proband had a 21-year history of chronic hypertension. His blood pressure was poorly controlled with various antihypertensive drugs, and hypokalaemia was found 8 years ago with no definite cause. At this visit, the patient presented with excessive renal potassium excretion and decreased renin activity in the postural stimulation test; however, his aldosterone level was normal. Subsequent genetic testing identified a missense mutation in SCNN1A (c.1475G>A), which encodes for a protein with an altered amino acid at position 492 (p.Arg492Gln). The pedigree investigation found that the older brother and son of the proband also have the same mutation. The patient’s serum potassium returned to normal, and blood pressure control was significantly improved after being treated with triamterene. Conclusion: A middle-aged patient with Liddle syndrome was diagnosed. A new point mutation in the SCNN1A gene was detected in this patient, and the pathogenicity of this mutation was predicted using AlphaFold software, expanding the genetic mutation spectrum of Liddle syndrome. Genetic testing should be improved to exclude monogenic hypertension in patients with hypertension complicated with hypokalaemia.
Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism
Authors: Polizio Ariel H. , Marino Lucila , Min Kyung-Duk , Yura Yoshimitsu , Rolauer Luca , Cochran Jesse D. , Evans Megan A. , Park Eunbee , Doviak Heather , Miura-Yura Emiri , Good Miranda E. , Wolpe Abigail G. , Grandoch Maria , Isakson Brant E. , Walsh Kenneth
Published: September 2024

BACKGROUND:

Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in the hematopoietic system resulting from somatic mutations in driver genes are prevalent in elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), and it is a newly recognized risk factor for cardiovascular disease. It is not known whether CH and hypertension in the elderly are causally related and, if so, what are the mechanistic features.

METHODS:

A murine model of adoptive bone marrow transplantation was employed to examine the interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) clonal hematopoiesis and hypertension.

RESULTS:

In this model, a subpressor dose of Ang II (angiotensin II) resulted in elevated systolic and diastolic blood pressure as early as 1 day after challenge. These conditions led to the expansion of Tet2-deficient proinflammatory monocytes and bone marrow progenitor populations. Tet2 deficiency promoted renal CCL5 (C-C motif ligand 5) chemokine expression and macrophage infiltration into the kidney. Consistent with macrophage involvement, Tet2 deficiency in myeloid cells promoted hypertension when mice were treated with a subpressor dose of Ang II. The hematopoietic Tet2
−/−
condition led to sodium retention, renal inflammasome activation, and elevated levels of IL (interleukin)-1β and IL-18. Analysis of the sodium transporters indicated NCC (sodium-chloride symporter) and NKCC2 (Na
+
-K
+
-Cl
−
cotransporter 2) activation at residues Thr53 and Ser105, respectively. Administration of the NLRP3 (NLR family pyrin domain containing 3) inflammasome inhibitor MCC950 reversed the hypertensive state, sodium retention, and renal transporter activation.

CONCLUSIONS:

Tet2-mediated CH sensitizes mice to a hypertensive stimulus. Mechanistically, the expansion of hematopoietic Tet2-deficient cells promotes hypertension due to elevated renal immune cell infiltration and activation of the NLRP3 inflammasome, with consequences on sodium retention. These data indicate that carriers of TET2 CH could be at elevated risk for the development of hypertension and that immune modulators could be useful in treating hypertension in this patient population.
The Imaging-Neuropathological Gap in Acute Large Vessel Occlusive Stroke
Authors: Ballout Ahmad A. , Liebeskind David S. , Jovin Tudor G. , Najjar Souhel
Published: September 2024

While imaging has traditionally played a fundamental role in the selection of patients undergoing endovascular thrombectomy, recent thrombectomy trials involving patients with large ischemic strokes demonstrated a consistent benefit of endovascular thrombectomy across all imaging strata, suggesting that reperfusion benefit may exist independent of current imaging constructs. Although these findings attest to the uniformly beneficial effects of reperfusion, they also shed doubt on the accuracy and utility of our imaging modalities in defining reversible versus irreversible ischemia and challenge the premise of imaging-based selection. We aimed to review the histopathologic studies and clinical trials that have shaped our understanding of current imaging constructs aiming to outline the existing imaging-neuropathological gap that may be far wider than previously perceived.
CADA-PRO: A Patient Questionnaire Measuring Key Cognitive, Motor, Emotional, and Behavioral Outcomes in CADASIL
Authors: Di Folco Cécile , Jabouley Aude , Reyes Sonia , Machado Carla , Guey Stéphanie , Hervé Dominique , Fernandes Fanny , Agossa Joseph , Chabriat Hugues , Tezenas du Montcel Sophie
Published: September 2024

BACKGROUND:

Cerebral small vessel disease (cSVD) of ischemic type, either sporadic or genetic, as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), can impact the quality of daily life on various cognitive, motor, emotional, or behavioral aspects. No instrument has been developed to measure these outcomes from the patient’s perspective. We thus aimed to develop and validate a patient-reported questionnaire.

METHODS:

In a development study, 79 items were generated by consensus between patients, family representatives, and cSVD experts. A first sample of patients allowed assessing the feasibility (missing data, floor and ceiling effect, and acceptability), internal consistency, and dimensionality of a first set of items. Thereafter, in a validation study, we tested a reduced version of the item set in a larger sample to assess the feasibility, internal consistency, dimensionality, test-retest reliability, concurrent validity, and sensitivity to change.

RESULTS:

The scale was developed in 44 patients with cSVD and validated in a second sample of 89 individuals (including 43 patients with CADASIL and 46 with another cSVD). The final CADASIL Patient-Reported Outcome scale comprised 18 items covering 4 categories of consequences (depression/anxiety, attention/executive functions, motor, and daily activities) of the disease. The proportion of missing data was low, and no item displayed a major floor or ceiling effect. Both the internal consistency and test-retest reliability were good (Cronbach alpha=0.95, intraclass correlation coefficient=0.88). In patients with CADASIL, CADASIL Patient-Reported Outcome scores correlated with the modified Rankin Scale, Starkstein Apathy Scale, Hospital Anxiety and Depression scale, Working Memory Index, and trail making test times. In patients with other cSVDs, CADASIL Patient-Reported Outcome correlated only with Hospital Anxiety and Depression scale and Starkstein Apathy Scale.

CONCLUSIONS:

The CADASIL Patient-Reported Outcome may be an innovative instrument for measuring patient-reported outcomes in future cSVD trials. Full validation was obtained for its use in patients with CADASIL, but further improvement is needed for its application in other cSVDs.
Polemics on Perfection: Maimonides’ Last Law on Slaves Resolves the Debate
Authors: Navon Mois
Published: September 2024

“What is the summum bonum?” This question is, without exaggeration, the ultimate existential question. Of no less import is its corollary: how is one to achieve this summum bonum? Maimonides’ Guide for the Perplexed endeavors to provide the answers. That said, the precise intent of Maimonides answers has generated no less perplexity than the original questions. Indeed, modern Jewish philosophers have spared no ink in trying to ascertain Maimonides’ intentions on human perfection. In this essay, I seek not to add yet another perspective on Maimonides’ intentions but to provide compelling support for existing positions; support found – worlds apart from the ivory towers where philosophers spill their ink – in the private quarters of a Canaanite slave. It is my thesis that Maimonides, in his last Law on Slaves, provides us with the answers to the ultimate existential questions and, accordingly, with a resolution to the perennial polemics on perfection.
Two new species of the genus Eucypris (Crustacea: Ostracoda) from Northern Cyprus
Authors: KÜLKÖYLÜOĞLU OKAN , ÖZDİLEK AHMET
Published: September 2024

We propose two new species (Eucypris denktasi sp. nov., and Eucypris lefkosaensis sp. nov.) of the genus Eucypris collected from Northern Cyprus. The new species are established based on the similarities and differences in soft body parts (i.e., absence of d2 in the second thoracic leg and absence of aesthetasc y2 in the A2 of the E. denktasi sp. nov. and absence of d1 and d2 and presence of aesthetasc y2 in the A2 of the E. lefkosaensis sp. nov.), carapace shape, presence of a protrusion in the posterior end of left valve, and absence of wart-like elevations (porenwarzen) in the anterior part in two new species. Along with the new species, the genus itself is also described from the island for the first time in the literature. Hence, E. denktasi sp. nov. and E. lefkosaensis sp. nov. are also the sixth and seventh species of the genus reported from Mediterranean islands. Comparisons of the species distributions are provided and discussed.
Study on the Chinese Anostostomatidae (Orthoptera: Ensifera) X: New descriptions of Anabropsis (Pseudapteranabropsis) Pang, Lu & Bian, 2023 from Guangxi
Authors: PANG SIYU , YANG RUIGANG , BIAN XUN
Published: September 2024

The paper reports the male sex of Anabropsis (Pseudapteranabropsis) flavimaculata Pang, Lu & Bian, 2023 and one new species Anabropsis (Pseudapteranabropsis) bifurcata sp. nov. from Guangxi, China. All the specimens are deposited in Guangxi Normal University.
Linking Boundary Organizations to Coproduce Actionable Knowledge: A Case Study of Ice Forecasting for Great Lakes Navigation
Authors: Gill Devin , Jagannathan Kripa , Fujisaki-Manome Ayumi , Field Victoria , Channell Kimberly , Lemos Maria Carmen
Published: September 2024

Navigating the Great Lakes during icy conditions poses significant safety challenges for the shipping sector. Available ice information is uncertain and fragmented, and navigators must seek out multiple sources for information at the spatial and temporal scales they require, if the information is available at all. Navigators have expressed that they require more highly localized and easily usable information for current and predicted ice conditions to support decision-making. In this study, we seek to meet this information need by applying a boundary organization chain (BOC) approach to facilitate the coproduction of an actionable short-term Great Lakes ice forecast. We focus on two main aspects of this research: 1) producing an actionable decision-support product that meets the needs of Great Lakes ice navigators and 2) contributing to the knowledge coproduction scholarship on BOCs by providing a detailed account of our methods to create a BOC and coproduce an actionable ice forecast. Our results support incorporating existing communities of practice (COPs) into BOCs to enhance the coproduction of actionable knowledge, specifically through increasing their complementarity and embeddedness. COPs are informal networks of users that meet voluntarily to share knowledge and develop professional skills, which we found naturally builds the coproduction capacities of participants (e.g., embeddedness and complementarity). We also find that COP members are well positioned to disseminate coproduced knowledge across wider user groups.

Significance Statement

In this study, we identified critical gaps in available ice information to support Great Lakes winter navigation, including predictions of current ice concentration and thickness at localized spatial scales and predicted ice movement. We coproduced an ice forecast with a format that is accessible and usable for navigators, while increasing crew and vessel safety by enabling more informed decisions regarding where and when to travel. We also contributed to theoretical understanding of how boundary organization chains work in context to coproduce actionable knowledge. This is a burgeoning area of research with a small number of empirical studies. By expanding both its thematic breadth (e.g., ice forecasting) and methodological approach (an in-depth account of our engagement efforts), we believe we critically contribute to the existing literature.
Raman Spectroscopy for Temporally Resolved Combustion Gas Diagnostics
Authors: Dal Moro Riccardo , Melison Fabio , Cocola Lorenzo , Poletto Luca
Published: September 2024

A novel approach for cost-effective and temporally resolved in-line combustion gas diagnostics based on spontaneous Stokes Raman spectroscopy is presented in this paper. The proposed instrument uses a multipass configuration designed to increase the scattering generation, giving information about gas species concentrations, including H2 and N2 that are not commonly available from analysis with absorption spectroscopy techniques. The system performs calibrated analysis providing both qualitative and quantitative information about the gas composition. Depending on the application, the device can work with spectra integration time from 0.15 s up to 10 s, with a Raman spectrum ranging from the H2 rotational peak at Raman shift of 587 cm−1 up to the H2 vibrational peak at 4156 cm−1, covering all the Raman emissions of major combustion species. The device response was characterized by a working pressure from 0.7 to 7.5 bar. The instrument prototype has been made completely transportable, designed to operate using a gas sampling system, and ready to be operated in relevant industrial in-line environments.
‘Constant pressures from all angles’: Understanding the mental health of UK police officers
Authors: Porter Cody Normitta , Gavin Paul
Published: September 2024

Policing in the United Kingdom can be challenging. The organisational (i.e., within the police force) and operational (i.e., when working in the field) stressors that police officers encounter can negatively impact their mental health. To investigate this 54 currently serving police officers completed an online survey. Most participants typically felt organisational and operational pressures led to a decline in their mental health, regardless of their years in service. This means that participants in their first year and those with over 25 years in service typically reported similar work-related stressors. This paper provides a qualitative overview of work-related stressors.
Speech and language therapists’ perceptions of contextual factors associated with communicative participation in children with developmental language disorders
Authors: Singer Ingrid , Gerrits Ellen , Gorter Jan Willem , Luinge Margreet
Published: September 2024

Children with developmental language disorders (DLDs) may experience barriers to communicative participation. Communicative participation is defined as ‘participation in life situations in which knowledge, information, ideas or feelings are exchanged’. Barriers experienced in communicative participation cannot be explained by language competence alone and are thought to be influenced by contextual factors. A better understanding of these factors will contribute to tailored speech and language therapy services for children with DLD. We conducted a focus group study with 13 speech and language therapists’ (SLTs) to explore their perspectives on contextual (environmental and personal) factors in early childhood that are associated with communicative participation in children with DLD. The personal factor of child well-being, and the environmental factors of familial support and SLT service provision were developed through thematic analysis. The potential mediating role of these factors on communicative participation implies that it is important to address contextual barriers and facilitators in speech and language therapy services.
Taipan envenoming … south of the border
Authors: Heap Rachel , Kennedy Aaron , Davies William , Tasoulis Theo , Isbister Geoffrey K
Published: September 2024

We present a case of severe taipan envenoming in northern New South Wales in a 68-year-old man. He developed severe neurotoxicity requiring intubation and ventilation, venom-induced consumption coagulopathy, myotoxicity and thrombotic microangiopathy with acute kidney injury requiring dialysis. He was administered brown and tiger snake antivenom consistent with guidelines and snake occurrence in the region. Taipan venom was detected in serum (72 ng/ml) following concern about the severity of neurotoxicity, clinical toxicology consultation and a concurrent report of a taipan in the area. Based on this it would be prudent to stock and consider treating with polyvalent antivenom in north-eastern New South Wales and south-eastern Queensland.
Xylazine Adulteration in Illicit Fentanyl: A Threat to Public Health
Authors: Marshall Samuel A. , Nelson Leigh Anne
Published: September 2024

Background: Xylazine-adulterated fentanyl (FAAX) is a critical public health concern in the United States (US), and the White House Office of National Drug Control Policy designated FAAX as an emerging drug threat in April 2023. Between 2020-2021, fatal xylazine-positive overdoses increased by 100-1127% depending on geographic region in the US. Objectives: This narrative review informs pharmacists about the clinical concerns, potential treatment strategies, and harm reduction approaches directed at FAAX. The objective is to provide pharmacists with the knowledge necessary to contribute to public health efforts in addressing this crisis. Results: Xylazine is commonly found as an adulterant in illicit drug combinations with fentanyl. Significant hypotension, and respiratory and CNS depression are associated with xylazine toxicity, and these effects may be synergistic with opioids. Standard naloxone doses are ineffective for xylazine toxicity, and there is no FDA-approved antidote for xylazine overdose in humans. Chronic use may lead to physiological dependence, withdrawal symptoms, and severe skin ulcerations. Pharmacists are crucial in addressing this crisis through patient education, advocating for testing and treatment, and promoting harm reduction measures. Conclusion: Xylazine and FAAX pose a substantial threat to public health. The synergistic effects of opioids increase the risk of fatal overdoses, highlighting the need for effective harm-reduction strategies. A comprehensive approach involving healthcare professionals, law enforcement, policymakers, and community organizations is required to address this public health issue, and pharmacists have an active role in mitigating the drug threat of FAAX.
Rituximab in IgG4 Related Disease: A Retrospective Study from a Single Tertiary Care Centre
Authors: Somashekar Meghana , Duggal Lalit , Jain Neeraj
Published: September 2024

Background:

IgG4-related disease (IgG4-RD) is a multi-organ, fibro-inflammatory disorder characterised by tumefactive lesions. Corticosteroids are the first line of treatment. Rituximab (RTX) has been reported to be effective in IgG4-RD. It is reserved as a second-line agent and is a useful treatment option for those with intolerance to corticosteroids or have steroid and immunomodulator refractory disease.

Objectives:

To assess the response to treatment with RTX in patients with IgG4-related disease at the end of 6 months.

Methods:

A total of 27 patients diagnosed with IgG4-RD and treated with at least 1g of RTX were included. Patient demographics, clinical data and investigations were noted. Response to RTX was noted at the end of 6 months in terms of clinical improvement, decrease in or normalisation of serum IgG4 levels, withdrawal of steroids or disease-modifying antirheumatic drugs (DMARDs) and the calculation of the IgG4RD responder index (RI).

Results:

Out of the 27 patients treated with RTX, one patient expired and two were lost to follow-up. Of the remaining 24 patients, nine are off steroids; four patients are off treatment. Among the nine who are off steroids, eight patients had orbital and periorbital involvement. Fourteen patients had elevated IgG4 levels. Post RTX, normalisation of IgG4 levels was achieved in six patients. The average RI before and after RTX was 4.79 (2–10) and 1.33 (0–4), respectively.

Conclusions:

Patients with IgG4-RD who were intolerant or refractory to steroids and other DMARDs showed significant improvement after RTX infusion, especially in orbital and periorbital involvement. It suggests that RTX may be beneficial in the management of IgG4-RD.
Effect of health conditions and community program participation on physical activity and exercise motivation in older adults
Authors: Gust Anita
Published: September 2024

Physical activity (PA) declines with age, with chronic health conditions a contributing factor. Exercise motivation (EM), a factor of PA adherence, may be promoted through community program participation. The purpose was to investigate the effect of health conditions and community program participation on PA and EM. Surveys comprising of demographics, physical activity (PASE), and exercise motivation (BREQ-2), were distributed. Significant differences were found for PA between community program participants with and without a health condition. A significant main effect for health condition existed on several subscales of EM: identified regulation and intrinsic regulation, and for obesity on amotivation, identified regulation, and intrinsic regulation. Significant differences existed between community exercise program participants ( N = 77) and non-participants ( N = 145) for amotivation ( p < 0.001), identified regulation ( p < 0.001), and intrinsic regulation ( p < 0.001). The presence of a health condition appears to impact EM. Community program participation positively influenced EM, potentially negating the effect of health condition.
The effect of a self-management programme on blood pressure levels among people with hypertension: a randomised controlled trial
Authors: Polsook Rapin , Aungsuroch Yupin
Published: September 2024

Background:

Hypertension (HT) progression and complications depend on blood pressure levels. Managing blood pressure can reduce complications, increase well-being and improve quality of life.

Purpose:

The study examined how an app-based self-management programme affected HT patients’ blood pressure.

Methods:

The Police General Hospital in Thailand employed a randomised controlled trial design between June 2022 and June 2023. Forty-eight people were randomly split into two groups using permuted blocks: the control group ( n = 24) and the experimental group ( n = 24). The experimental group monitored their blood pressure for 4 weeks using a combination of apps and the phone, whereas the control group received standard care. The information was gathered by measuring blood pressure. Descriptive statistics and t-tests for independence were employed to analyse the data.

Results:

The independent t-test results revealed a statistically significant reduction in the systolic blood pressure levels of the experimental group after the intervention ( t = 2.945, df = 46, p = 0.005). However, no significant decrease was observed in the diastolic blood pressure levels of the experimental group after the intervention ( t = 0.877, df = 46, p = 0.385).

Conclusion:

This study provides evidence for the effectiveness of a self-management programme utilising a mobile application in reducing blood pressure levels.
Outcomes of patients with blastomycosis-associated respiratory failure requiring veno-venous ECMO: a case series
Authors: Melamed Roman , Tierney David M. , Martins Summer , Zamorano Clara , Hahn Madison , Saavedra Ramiro
Published: September 2024

Blastomycosis can result in lung injury with high mortality rates. The literature on veno-venous extracorporeal membrane oxygenation (VV-ECMO) used as a rescue therapy is limited to case reports and small case series collected over extended time periods. This report describes the clinical course and post-hospitalization outcomes among patients with blastomycosis-induced respiratory failure requiring VV-ECMO in the most recent time frame. The data were collected retrospectively from the health records of eight patients with blastomycosis-induced respiratory failure admitted to a tertiary care center between 2019 and 2023. The mean time from the start of mechanical ventilation to ECMO initiation was 57 h. All patients survived to ECMO decannulation, and seven of them survived to hospital discharge. All six patients whose post-discharge follow-up information was available were weaned from mechanical ventilation and lived at home while two required supplemental oxygen. This includes a case where the provision of adequate ECMO support was challenging due to the patient’s morbid obesity. The most common residual imaging abnormalities included pulmonary infiltrates and pneumatoceles. The study demonstrates the feasibility of VV-ECMO as a rescue therapy in patients with blastomycosis-related refractory respiratory failure. Rapid initiation of ECMO support in eligible patients may have contributed to the good outcomes.
Intelligent course recommendation approach based on modified felder-silverman learning style model
Authors: Ashraf Erum , Laghari Shams ul Arfeen , Manickam Selvakumar , Mahmood Khurrum , Abrejo Sehrish , Karuppayah Shankar
Published: September 2024

The popularity of E-learning has encouraged learners to benefit from Massive Open Online Courses (MOOC) platforms however information overload is a common challenge in order to select the appropriate courses. Recommendation systems aid learners to select relevant courses and content based on their preferences, interest and learning goals from MOOC. Various factors are considered in course recommendation systems however little research has been done in recommending courses based on learning styles despite its significance laid down by various studies. Most studies have focused on content filtering matching with learners learning style instead from a course. This research study is oriented towards learning style-based course categorization using course content delivery information data from a MOOC platform. The Felder-Silverman learning style model (FSLSM) has been used to develop a course learning style support identification model. The effectiveness of the model developed is analyzed through an experimental study performed on real-time data due to absence of a standard data set for course contents and learning style relationships. The model threshold values are finetuned through the results obtained from the experimental. The application of the course learning style identification model is demonstrated by conducting test case studies consisting of users with different learning styles and recommending courses from a MOOC platform with matching learning style.
Mind the context! The role of theoretical concepts for analyzing legislative text data
Authors: Schwalbach Jan
Published: September 2024

With the progressing advances in text analysis methods and the increasing accessibility of parliamentary documents, the range of available tools for legislative scholars has increased massively over the past years. While the potential for comparative studies is huge, researchers can easily overlook the pitfalls associated with analyzing these documents. Against this background, I asses which theoretical considerations need to be carefully thought through preceding any (legislative) text analysis: I show that a clear definition and conceptualization of the unit of analysis such as speech or bill can vary substantially depending on the research interest. Furthermore, I discuss how the nested structure of legislative behavior and the data generating process influence our theoretic assumptions about parliamentary behavior. Based on these concepts, I derive some recommendations for the theoretical approach to quantitative textual analyses of parliamentary documents.