bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab
Authors: Kwek Serena S. , Lewis Jera , Zhang Li , Weinberg Vivian , Greaney Samantha K. , Harzstark Andrea L. , Lin Amy M. , Ryan Charles J. , Small Eric J. , Fong Lawrence
Published: March 2024

Abstract
Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration-resistant prostate cancer was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of ≥50% and radiographic responses were observed at doses of ≥3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T-cell phenotype in peripheral blood and overall survival was examined retrospectively. We found that the treatment induced an increase in the levels of CD4+ effector T (Teff) cells, regulatory T cells, PD-1+ CD4 Teff cells, and PD-1+ CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pretreatment baseline levels of PD-1+ CD4 Teff cells were found to correlate with longer overall survival. Furthermore, baseline levels of PD-1+ CD4 Teff cells from patients with shorter overall survival were higher than from cancer-free male control subjects. These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients that may benefit from ipilimumab treatment. Cancer Immunol Res; 3(9); 1008–16. ©2015 AACR.
Data from CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell–Relevant Genes
Authors: Aznar M. Angela , Labiano Sara , Diaz-Lagares Angel , Molina Carmen , Garasa Saray , Azpilikueta Arantza , Etxeberria Iñaki , Sanchez-Paulete Alfonso R. , Korman Alan J. , Esteller Manel , Sandoval Juan , Melero Ignacio
Published: March 2024

Abstract
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naïve versus antigen-experienced CD8+ T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. Cancer Immunol Res; 6(1); 69–78. ©2017 AACR.
Data from Selective Targeting of Glioblastoma with EGFRvIII/EGFR Bitargeted Chimeric Antigen Receptor T Cell
Authors: Jiang Hua , Gao Huiping , Kong Juan , Song Bo , Wang Peng , Shi Bizhi , Wang Huamao , Li Zonghai
Published: March 2024

Abstract
The heterogeneous expression of EGFRvIII [variant III mutant of epidermal growth factor receptor (EGFR)] in glioblastoma has significant impact on the clinical response to the treatment of EGFRvIII-specific chimeric antigen receptor–engineered T (CAR T) cells. We hypothesized that CAR T cells that could target both EGFRvIII and the form of EGFR expressed on tumor cells, but not EGFR on normal cells, would greatly improve efficacy without inducing on-target, off-tumor toxicity. Therefore, we developed a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed. M27-derived CAR T cells effectively lysed EGFRvIII- or EGFR-overexpressing tumor cells, but showed no observable toxicity on normal cells. Inclusion of the CD137 (4-1BB) costimulatory intracellular domain in the M27-28BBZ CAR provided CAR T cells with higher tumor lysis activity than when not included (as in the M27-28Z CAR). The growth of established EGFR- or EGFRvIII-overexpressing glioma xenografts was suppressed by M27-28BBZ CAR T cells as well. The growth of heterogeneic xenograft tumors, created by mixing EGFR- and EGFR-overexpressing glioblastoma cells, was also effectively inhibited by M27-28BBZ CAR T cells. The survival of mice in the orthotopic models was significantly prolonged after M27-28BBZ CAR T-cell infusion. These results suggested that tumor-selective, bitargeted anti-EGFR/EGFRvIII CAR T cells may be a promising modality for the treatment of patients with EGFR/EGFRvIII-overexpressing glioblastoma. Cancer Immunol Res; 6(11); 1314–26. ©2018 AACR.
Data from Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma
Authors: Zhao Fei , Evans Kathy , Xiao Christine , DeVito Nicholas , Theivanthiran Balamayooran , Holtzhausen Alisha , Siska Peter J. , Blobe Gerard C. , Hanks Brent A.
Published: March 2024

Abstract
Although anti–PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti–CTLA-4 immunotherapy but failed to augment anti–PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9–dependent cleavage of PD-L1 surface expression, leading to anti–PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti–PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti–PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti–PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti–PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti–PD-1 resistance.

See related Spotlight on p. 1444
Data from IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties
Authors: Khosravi Nasim , Caetano Mauricio S. , Cumpian Amber M. , Unver Nese , De la Garza Ramos Cynthia , Noble Oscar , Daliri Soudabeh , Hernandez Belinda J. , Gutierrez Berenice A. , Evans Scott E. , Hanash Samir , Alekseev Andrei M. , Yang Yi , Chang Seon Hee , Nurieva Roza , Kadara Humam , Chen Jichao , Ostrin Edwin J. , Moghaddam Seyed Javad
Published: March 2024

Abstract
Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras-mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells. Cancer Immunol Res; 6(7); 788–97. ©2018 AACR.
Data from Circulating Tumor Microparticles Promote Lung Metastasis by Reprogramming Inflammatory and Mechanical Niches via a Macrophage-Dependent Pathway
Authors: Zhang Huafeng , Yu Yuandong , Zhou Li , Ma Jingwei , Tang Ke , Xu Pingwei , Ji Tiantian , Liang Xiaoyu , Lv Jiadi , Dong Wenqian , Zhang Tianzhen , Chen Degao , Xie Jing , Liu Yuying , Huang Bo
Published: March 2024

Abstract
Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell–released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T-MPs remodeled the lung parenchyma via a macrophage-dependent pathway to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma where they are taken up by local macrophages and induce CCL2 production. CCL2 recruits CD11b+Ly6Chigh inflammatory monocytes to the lungs where they mature into F4/80+CD11b+Ly6C− macrophages that not only produce IL6 but also trigger fibrin deposition. IL6 and the deposited fibrin facilitate the survival and growth of tumor-repopulating cells in the lungs by providing chemical and mechanical signals, respectively, thus setting the stage for lung metastasis. These data illustrate that T-MPs reprogram the lung microenvironment promoting metastasis. Cancer Immunol Res; 6(9); 1046–56. ©2018 AACR.
Supplementary Table 1 from Ex Vivo Efficacy of SAR442257 Anti-CD38 Trispecific T-cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA-targeted Therapies
Authors: Keller Alana L. , Reiman Lauren T. , Perez de Acha Olivia , Parzych Sarah E. , Forsberg Peter A. , Kim Peter S. , Bisht Kamlesh , Wang Hongfang , van de Velde Helgi , Sherbenou Daniel W.
Published: March 2024

Treatment History of Patients Donating Samples
Supplementary Figure 5 from Ex Vivo Efficacy of SAR442257 Anti-CD38 Trispecific T-cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA-targeted Therapies
Authors: Keller Alana L. , Reiman Lauren T. , Perez de Acha Olivia , Parzych Sarah E. , Forsberg Peter A. , Kim Peter S. , Bisht Kamlesh , Wang Hongfang , van de Velde Helgi , Sherbenou Daniel W.
Published: March 2024

The percentage of MM cells CD28+ does not appear to affect sensitivity to SAR442257
Data from Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study
Authors: Munster Pamela , Iannotti Nicholas , Cho Daniel C. , Kirkwood John M. , Villaruz Liza C. , Gibney Geoffrey T. , Hodi F. Stephen , Mettu Niharika B. , Jones Mark , Bowman Jill , Smith Michael , Lakshminarayanan Mani , O'Day Steven
Published: March 2024

AbstractPurpose:
This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor].
Experimental Design:
Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks).
Results:
A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR.
Conclusions:
Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors.
Significance:
PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.
Data from Ex Vivo Efficacy of SAR442257 Anti-CD38 Trispecific T-cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA-targeted Therapies
Authors: Keller Alana L. , Reiman Lauren T. , Perez de Acha Olivia , Parzych Sarah E. , Forsberg Peter A. , Kim Peter S. , Bisht Kamlesh , Wang Hongfang , van de Velde Helgi , Sherbenou Daniel W.
Published: March 2024

Abstract
T cell–engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma, even in patients that relapsed after B-cell maturation antigen (BCMA)-targeted therapy. Patients with multiple myeloma may have compromised T-cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-multiple myeloma cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients’ own endogenous T cells to inform clinical development of the compound in multiple myeloma. My-DST incubates primary mononuclear cells in humanized media for 48 hours followed by flow cytometry for multiple myeloma cell viability with or without drug treatment. SAR442257 was tested on 34 samples from patients with multiple myeloma across disease settings. Potential biomarkers, T-cell dependence, and degranulation were assessed. SAR442257 was effective at low dose in My-DST cultures. High ex vivo response rates were observed in primary aspirates taken from patients with multiple myeloma at diagnosis, with modestly reduced response in multiple myeloma recently treated with anti-CD38 mAbs. SAR442257 was highly effective in patients relapsing after BCMA therapy. The CD38/CD28xCD3 trispecific format was substantially more effective than a conventional bispecific CD38/CD3 antibody format and CD38 mAbs. Anti-multiple myeloma cell cytotoxicity was dependent on the presence of endogenous T cells. Surface CD38 expression was the strongest biomarker of TCE response. My-DST is capable of measuring T cell–dependent killing using the multiple myeloma patient's own bone marrow–derived T cells. SAR442257 shows promise for multiple myeloma and may be best suited for patients declared resistant to both CD38 mAbs and BCMA-targeted therapy.
Significance:
This study introduces the use of My-DST to measure and characterize sensitivity to anti-CD38 T-cell engager SAR442257 in primary samples using matched endogenous T cells. Preclinical testing in samples from patients with diverse treatment history supports further testing in post-chimeric antigen receptor T-cell multiple myeloma.
Serum Calcium Normal Range in 1,000 Term Newborns
Authors: Levaillant Lucie , Linglart Agnès , Letamendia Emmanuelle , Boithias Claire , Ouaras-Lounis Samra , Thérond Patrice , Lambert Anne-Sophie , Levaillant Mathieu , Souberbielle Jean-Claude , Benachi Alexandra , Gajdos Vincent
Published: March 2024

Introduction: Serum calcium rapidly declines at birth because of the sudden interruption of the maternal-fetal calcium influx. Several factors are known to influence serum calcium in the first days of life, including circulating concentrations of maternal vitamin D. Objective was to establish the normal range variations of neonatal serum calcium according to the current French vitamin D supplementation during pregnancy, i.e., 100,000 IU of cholecalciferol during the third trimester. Methods: We included in our prospective cohort study 1,002 mother-newborn dyads recruited from April 2012 to July 2014 in two centers located in the neighborhoods of Paris, France. Results: Total serum calcium at 3 days of life in neonates varied from 2.06 mmol/L to 2.73 mmol/L [2.5 and 97.5 percentiles], with a mean of 2.45 mmol/L. Serum calcium was similar between babies born from vitamin D-supplemented mothers and those born from non-supplemented ones. In univariate and multivariable analyses, we demonstrated the importance of maternal and cord blood 25(OH)D concentrations for newborn serum calcium maintenance. Conclusion: We established that the expected serum calcium in neonates ranges between 2.06 mmol/L and 2.73 mmol/L which is significantly wider than the adult range. This finding should help physicians in the diagnosis of hypo- or hypercalcemia. In addition, our study supports the importance of vitamin D supplementation and 25(OH)D status for neonatal serum calcium maintenance.
Pain/Stress, Mitochondrial Dysfunction, and Neurodevelopment in Preterm Infants
Authors: Zhao Tingting , Chang Xiaolin , Biswas Subrata Kumar , Balsbaugh Jeremy L. , Liddle Jennifer , Chen Ming-Hui , Matson Adam P. , Alder Nathan N. , Cong Xiaomei
Published: March 2024

Introduction: Preterm infants experience tremendous early life pain/stress during their neonatal intensive care unit (NICU) hospitalization, which impacts their neurodevelopmental outcomes. Mitochondrial function/dysfunction may interface between perinatal stress events and neurodevelopment. Nevertheless, the specific proteins or pathways linking mitochondrial functions to pain-induced neurodevelopmental outcomes in infants remain unidentified. Our study aims to investigate the associations among pain/stress, proteins associated with mitochondrial function/dysfunction, and neurobehavioral responses in preterm infants. Methods: We conducted a prospective cohort study, enrolling 33 preterm infants between September 2017 and July 2022 at two affiliated NICUs located in Hartford and Farmington, CT. NICU Network Neurobehavioral Scale (NNNS) datasets were evaluated to explore potential association with neurobehavioral outcomes. The daily pain/stress experienced by infant’s during their NICU stay was documented. At 36–38 weeks post-menstrual age (PMA), neurobehavioral outcomes were evaluated using the NNNS and buccal swabs were collected for further analysis. Mass spectrometry-based proteomics was conducted on epithelial cells obtained from buccal swabs to evaluate protein expression level. Lasso statistical methods were conducted to study the association between protein abundance and infants’ NNNS summary scores. Multiple linear regression and Gene Ontology (GO) enrichment analyses were performed to examine how clinical characteristics and neurodevelopmental outcomes may be associated with protein levels and underlying molecular pathways. Results: During NICU hospitalization, preterm premature rupture of membrane (PPROM) was negatively associated with neurobehavioral outcomes. The protein functions including leptin receptor binding activity, glutathione disulfide oxidoreductase activity and response to oxidative stress, lipid metabolism, and phosphate and proton transmembrane transporter activity were negatively associated with neurobehavioral outcomes; in contrast, cytoskeletal regulation, epithelial barrier, and protection function were found to be associated with the optimal neurodevelopmental outcomes. In addition, mitochondrial function-associated proteins including SPRR2A, PAIP1, S100A3, MT-CO2, PiC, GLRX, PHB2, and BNIPL-2 demonstrated positive association with favorable neurodevelopmental outcomes, while proteins of ABLIM1, UNC45A, keratins, MUC1, and CYB5B showed positive association with adverse neurodevelopmental outcomes. Conclusion: Mitochondrial function-related proteins were observed to be associated with early life pain/stress and neurodevelopmental outcomes in infants. Large-scale studies with longitudinal datasets are warranted. Buccal proteins could be used to predict potential neurobehavioral outcomes.
National Service Evaluation of the Quality of Care for Children and Young People with Congenital Adrenal Hyperplasia in the UK: Survey Responses from Patients and Clinicians
Authors: Lawrence Neil R. , Bacila Irina A. , Collins Gary S. , Dawson Jeremy , Lang Zi-Qiang , Ji Xiaochen , Ahmed S. Faisal , Alvi Sabah , Bath Louise Eleanor , Blair Joanne , Cheetham Tim , Crowne Elizabeth Clare , Davies Justin H. , Dattani Mehul , Gevers Evelien F. , Krone Ruth , Patel Leena , Thankamony Ajay , Randell Tabitha , Ryan Fiona , Elford Sue , Blackett Sallyann , Krone Nils P.
Published: March 2024

Introduction: Quantifying differences in service provision for children and young people (CYP) living with congenital adrenal hyperplasia (CAH) across the UK. Methods: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH and via the “Living with CAH” support group mailing list. Results: Total of 195 responses relating to patients aged 0–20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were “completely satisfied” with the service provided, compared to 68% of carers and 76% of patients. While 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further “unsure” responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots and 12% reporting regular urinary steroid metabolites. Conclusion: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes.
Association of Proton Pump Inhibitor Use and Immune Checkpoint Inhibitor-Mediated Acute Kidney Injury: A Meta-Analysis and a Review of Related Outcomes
Authors: Mohan Arjunmohan , Krisanapan Pajaree , Tangpanithandee Supawit , Thongprayoon Charat , Kanduri Swetha Rani , Cheungpasitporn Wisit , Herrmann Sandra M.
Published: March 2024

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they pose the risk of immune-related adverse events, including ICI-mediated acute kidney injury (ICI-AKI). Recent studies have implicated proton pump inhibitors (PPIs) as potential contributors to ICI-AKI development. This meta-analysis examines the association between PPI use and ICI-AKI, exploring a potential modifiable risk factor in ICI therapy while also reviewing the possible outcomes of ICI-AKI. Methods: We conducted a comprehensive systematic review and meta-analysis of observational studies, assessing the risk of ICI-AKI in cancer patients concurrently using PPIs and potential outcomes. Odds ratios (ORs) were pooled using random-effects models. Subgroup analyses and sensitivity analyses were performed to evaluate heterogeneity and potential biases. Results: A total of 14 studies involving 12,694 patients were included. In total, we analyzed 639 patients with all-cause AKI and 779 patients with ICI-AKI. The pooled OR for the overall incidence of AKI from all-causes was 1.57 (95% confidence interval [CI] 1.02–2.40) among patients on PPIs. Specifically, the risk of ICI-AKI associated with PPI use was significantly higher, with a pooled OR of 1.84 (95% CI 1.16–2.90). This indicates approximately 84% higher likelihood of developing ICI-AKI with concurrent use of PPIs. Additionally, among patients with ICI-AKI, 67% had complete or partial recovery of renal function, 32% progressed to chronic kidney disease (CKD), and about 36% died during a follow-up period of at least 3 months. Conclusion: This meta-analysis highlights the importance of cautious PPI prescription in cancer patients undergoing ICI therapy. Clinicians are advised to evaluate the risks and benefits of PPI use and consider alternative therapies when feasible.
Signal Smoothing and Syntactic Choices: A Critical Reflection on the UID Hypothesis
Authors: Juzek Tom S.
Published: March 2024

The Smooth Signal Redundancy Hypothesis explains variations in syllable length as a means to more uniformly distribute information throughout the speech signal. The Uniform Information Density hypothesis seeks to generalize this to choices on all linguistic levels, particularly syntactic choices. While there is some evidence for the Uniform Information Density hypothesis, it faces several challenges, four of which are discussed in this paper. First, it is not clear what exactly counts as uniform. Second, there are syntactic alternations that occur systematically but that can cause notable fluctuations in the information signature. Third, there is an increasing body of negative results. Fourth, there is a lack of large-scale evidence. As to the fourth point, this paper provides a broader array of data—936 sentence pairs for nine syntactic constructions—and analyzes them in a test setup that treats the hypothesis as a classifier. For our data, the Uniform Information Density hypothesis showed little predictive capacity. We explore ways to reconcile our data with theory.
“Shoot Me and Let Me Die”: Cash Scarcity and the Performance of Deviant Nude Protest in Nigeria
Authors: Tade Oludayo
Published: March 2024

Using Erving Goffman’s dramaturgical approach, this paper interrogates how space shapes the nature of nude protests and how human bodies performed as sites of power, contestation and attention. Although nude protests are not new to Africa, and Nigeria in particular, where nudehood is deployed to challenge unpleasant social conditions, mostly by women, I interrogated the performance of nude protest by two bank customers (male and female) inside two Nigerian Banking halls as a reaction to the naira redesign policy of the Central Bank of Nigeria, launched in December 2022, which limited access to physical cash in a cash-based economy. Findings showed that the protesters’ performances included claims-making, refusal, undressing, shouting, crying and embellishing narrative of willingness to die to bring about desired attention and change in their situations. The naked bodies of the protesters are complex composites of verbal and non-verbal communication expressed through facial expressions, body movements, and refusal to yield to persuasions. Indeed, naked protest in the banking hall is a daring, disruptive and problem-solving behaviour which challenged the serenity and formality associated with the banking space and showed the agency of the bodies and presentation of the selves.
International Political Contexts, Digital Technologies, and Political Outcomes in Nigeria’s #EndSARS Movement
Authors: Makinde Ebenezer
Published: March 2024

When do social movements achieve political outcomes? Extant literature has identified two broad factors that can explain the political outcomes of social movements: movements’ infrastructure, and political opportunities. Focusing on the 2020 #EndSARS protest in Nigeria, I build on this literature to understand how and why social movements may achieve policy outcomes when social movements’ infrastructure and domestic political opportunities are relatively absent. I analyzed the Twitter activities of protesters during the 2020 #EndSARS Movement in Nigeria. I argue that the #EndSARS Movement transformed from online campaigns to offline demonstrations against police brutality because of favourable international political contexts (Black Lives Matter or blm protests in the US, covid-19 induced economic hardships). Further analysis shows that the protest achieved significant political outcomes and responses from both federal and state governments in Nigeria because the protesters were able to successfully leverage digital technologies (like social media, blockchain technology), international media and global personalities to their advantage.
The New Shi’a Mahdawi Movements in Iraq: Religious Discontent or Political Protest?
Authors: Kadhem Fouad
Published: March 2024

Mahdawi ‘protest’ movements have played a significant role throughout Islamic history. As salvation movements, they often incorporated religious principles with social and economic demands to protest against authorities in order to bring about political change. Historically, Iraq has always been, and still is, the centre of Mahdawi movements in the Islamic world. Immediately after 2003, a host of new Shi’a Mahdawi movements emerged. These movements nonetheless were active underground since the late 1980s. They demonstrated an evident negative stance towards both Baghdad’s government and Shi’a religious authorities. I will pose the following questions that I intend to answer using primary source data from selected political actors: How did these movements emerge? What are the religious and social factors behind their existence? What are the political ideas and views advocated by these movements? What are the reasons that render these Shi’a movements at conflict with the Iraqi state on the one hand, and the authority of Shi’a ‘ulama in Najaf on the other hand?
Taxonomy, distribution, and conservation status of a rare arboreal lizard, Bronchocela celebensis Gray, 1845 (Reptilia: Agamidae) endemic to Sulawesi, Indonesia
Authors: AMARASINGHE A.A. THASUN , CAMPBELL PATRICK D. , RIYANTO AWAL , HALLERMANN JAKOB , HAMIDY AMIR , ANDAYANI NOVIAR , ABINAWANTO A. , SUPRIATNA JATNA
Published: March 2024

Bronchocela celebensis Gray, 1845 is one of the rarest species of the genus, known only from less than 20 museum specimens collected from northern Sulawesi. It is often confused with its similar congener, B. cristatella, which occurs widely throughout the Indonesian Archipelago and Peninsular Malaysia, except on the Sulawesi mainland. Here, we examine the morphology of B. celebensis based on 46 museum specimens including freshly collected individuals, and redescribe the species based on the holotype (by monotypy). We studied the characters of B. celebensis with morphometric comparison to its allopatric congener B. cristatella from the adjacent islands of southern Sulawesi in Indonesia. Based on the current distribution pattern and the apparent threats, we update the conservation status of B. celebensis using the IUCN Red List Criteria and propose that it be considered as a Vulnerable (VU) species endemic to Sulawesi.
Studies on Neotropical crickets: A new Tusked Cricket genus (Orthoptera: Phalangopsidae) from Colombia
Authors: CADENA-CASTAÑEDA OSCAR J. , QUINTANA-ARIAS RONALD FERNANDO
Published: March 2024

Dentoluzara spatulatus n. gen. et n. sp., from the middle lands of the Colombian Andes, is described. This new phalangopsid cricket is distinguished by its asymmetrical mandibles with a basal prolongation in the left one, which is why it is recorded as the first “Tusked Cricket.” This rare morphological structure has only been observed in some species of anostostomatids and a couple of genera of tettigoniids, but never in crickets. Furthermore, D. spatulatus n. gen. et n. sp., has the ps. p2, from the male genitalia, spatula-shaped, deriving its specific epithet from there. Finally, the new genus’ peculiar mandibular morphology and the subfamily Luzarinae’s taxonomy are commented and discussed.
Predicting the Intensity of Tropical Cyclones over the Western North Pacific Using a Dual-Branch Spatiotemporal Attention Convolutional Network
Authors: Tian Wei , Chen Yuanyuan , Song Ping , Xu Haifeng , Wu Liguang , Lim Kam Sian Kenny Thiam Choy , Zhang Yonghong , Xiang Chunyi
Published: March 2024

This paper proposes a spatiotemporal attention convolutional network (STAC-Pred) that leverages deep learning techniques to model the spatiotemporal features of tropical cyclones (TCs) and enable real-time prediction of their intensity. The proposed model employs dual branches to concurrently extract and integrate features from intensity heatmaps and satellite cloud imagery. Additionally, a residual attention (RA) module is integrated into the three-channel cloud imagery convolution process to automatically respond to high wind speed regions. TC’s longitude, latitude, and radius of winds are injected into the multi-timepoint prediction model to assist in the prediction task. Furthermore, a rolling mechanism (RM) is employed to smooth the fluctuation of losses, achieving accurate prediction of TC intensity. We use several TC records to evaluate and validate the universality and effectiveness of the model. The results indicate that STAC-Pred achieves satisfactory performance. Specifically, the STAC-Pred model improves prediction performance by 47.69% and 28.26% compared to the baseline (official institutions) at 3- and 6-h intervals, respectively.

Significance Statement

Tropical cyclones are one of the most deadly and damaging natural disasters in coastal areas worldwide. Early prediction can significantly reduce casualties and property losses. This study innovatively conducts dimensionality augmentation on one-dimensional intensity numerical sequences and proposes a new network model for rolling forecast of their future intensity. The proposed prototype model (not yet incorporating any atmospheric conditions) shows promising results for 3- and 6-h advance forecasts, providing valuable guidance for forecasters regarding real-time operational predictions of short-term tropical cyclone intensity.
Sowing the Seeds of Recovery: A Qualitative Study of Women in Recovery From Addiction and Victimization
Authors: Edwards Katie M. , Siller Laura , LaChance Abby S. , Murphy Sharon B. , Lim Stephanie
Published: March 2024

The purpose of this study was to understand the lived experiences of women with histories of victimization and addiction who were recently admitted to a sober living home (SLH). From the 17 interviews conducted, five themes (i.e., experiences of violence, challenges leaving an abusive relationship, chaos, using substances to cope, and social support) and one constitutive pattern (i.e., sowing the seeds of recovery) emerged from the data. These results highlight the importance of social support in promoting recovery and that social support may foster positive relationships with safe and trustworthy individuals as well as empower and support others with similar experiences.
“I’m dealing with a health care system that doesn’t get it”: Barriers and facilitators to inclusive healthcare for autistic adults
Authors: McLean Kiley J , Haas Meghan , Koenig Jamie , Horvath Megan , Vigil Mariah , Werner Nicole E , Bishop Lauren
Published: March 2024

Emerging research points to high rates of major psychiatric disorders and chronic medical conditions among autistic adults. However, the unique healthcare needs of autistic adults are often overlooked, perhaps due to limitations in population-level surveillance and widespread public misconceptions about autism in adulthood. Understanding the mechanisms underlying this prevalence of poor health outcomes in autistic adults requires an exploration into the lived experiences of autistic adults across their lifespans. This study uses a qualitative approach to investigate the healthcare experiences of autistic adults. We conducted semi-structured interviews with 23 autistic adults in the United States, ranging in age from 18 to 56 years, seven of whom identified as nonbinary or gender non-conforming. We asked autistic adults about how they manage their health and interact with healthcare systems. Through thematic analysis of the data, barriers to receipt of quality care for autistic adults were identified. Results were then conceptualized through the Systems Engineering Initiative for Patient Safety model of work system and patient safety. Through this model, this study describes the interactions between autistic adults and their healthcare systems, pointing to specific areas for improvement and intervention. Overall, findings advocate for a system-level approach to improving health outcomes of autistic adults.

Lay abstract

Research has suggested that autistic adults may have a bigger chance of having mental health and physical health conditions such as depression, anxiety, sleep disorders, diabetes, obesity, and heart problems than adults without autism. Unfortunately, the unique healthcare needs of autistic adults are often overlooked, so it is not clear why autistic adults have worse health or what can be done to improve it. This study wants to find out the challenges autistic adults experience in taking care of their health and in going to different doctors. Researchers interviewed autistic adults across the country about their healthcare experiences. The interviewed autistic adults told the researchers about the barriers (things that did not help) and facilitators (things that did help) that impacted whether they received the care they needed. The researchers then organized what they learned from the autistic adults into a model called the Systems Engineering Initiative for Patient Safety model of work system and patient safety. This model explains how different parts of a healthcare system (person, tasks, technology and tools, environment, and organization) interact with one another and impact the healthcare experiences and outcomes of the patients in their care, like autistic adults. Overall, this study advocates for a systems-level approach to improving the healthcare experiences of autistic adults and their health outcomes.
Neat plasma proteomics: getting the best out of the worst
Authors: Metatla Ines , Roger Kevin , Chhuon Cerina , Ceccacci Sara , Chapelle Manuel , Pierre-Olivier Schmit  , Demichev Vadim , Guerrera Ida Chiara
Published: March 2024

Plasma proteomics holds immense potential for clinical research and biomarker discovery, serving as a non-invasive "liquid biopsy" for tissue sampling. Mass spectrometry (MS)-based proteomics, thanks to improvement in speed and robustness, emerges as an ideal technology for exploring the plasma proteome for its unbiased and highly specific protein identification and quantification. Despite its potential, plasma proteomics is still a challenge due to the vast dynamic range of protein abundance, hindering the detection of less abundant proteins. Different approaches can help overcome this challenge. Conventional depletion methods face limitations in cost, throughput, accuracy, and off-target depletion. Nanoparticle-based enrichment shows promise in compressing dynamic range, but cost remains a constraint. Enrichment strategies for extracellular vesicles (EVs) can enhance plasma proteome coverage dramatically, but current methods are still too laborious for large series. Neat plasma remains popular for its cost-effectiveness, time efficiency, and low volume requirement. We used a test set of 33 plasma samples for all evaluations. Samples were digested using S-Trap and analyzed on Evosep One and nanoElute coupled to a timsTOF Pro using different elution gradients and ion mobility ranges. Data were mainly analyzed using library-free searches using DIA-NN. This study explores ways to improve proteome coverage in neat plasma both in MS data acquisition and MS data analysis. We demonstrate the value of sampling smaller hydrophilic peptides, increasing chromatographic separation, and using library-free searches. Additionally, we introduce the EV boost approach, that leverages on the extracellular vesicle fraction to enhance protein identification in neat plasma samples. Globally, our optimized analysis workflow allows the quantification of over 1000 proteins in neat plasma with a 24SPD throughput. We believe that these considerations can be of help independently of the LC–MS platform used.
Derivation of the Difficult Airway Physiological Score (DAPS) in adults undergoing endotracheal intubation in the emergency department
Authors: Waheed Shahan , Razzak Junaid Abdul , Khan Nadeemullah , Raheem Ahmed , Mian Asad Iqbal
Published: March 2024

Background

Prediction of serious outcomes among patients with physiological instability is crucial in airway management. In this study, we aim to develop a score to predict serious outcomes following intubation in critically ill adults with physiological instability by using clinical and laboratory parameters collected prior to intubation.

Method

This single-center analytical cross-sectional study was conducted in the Emergency Department from 2016 to 2020. The airway score was derived using the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) methodology. To gauge model’s performance, the train-test split technique was utilized. The discrete random number generation approach was used to divide the dataset into two groups: development (training) and validation (testing). The validation dataset’s instances were used to calculate the final score, and its validity was measured using ROC analysis and area under the curve (AUC). By computing the Youden’s J statistic using the metrics sensitivity, specificity, positive predictive value, and negative predictive value, the discriminating factor of the additive score was determined.

Results

The mean age of the 1021 patients who needed endotracheal intubations was 52.2 years (± 17.5), and 632 (62%) of them were male. In the development dataset, there were 527 (64.9%) physiologically difficult airways, 298 (36.7%) post-intubation hypotension, 124 (12%) cardiac arrest, 347 (42.7%) shock index > 0.9, and 456 [56.2%] instances of pH < 7.3. On the contrary, in the validation dataset, there were 143 (68.4%) physiologically difficult airways, 33 (15.8%) post-intubation hypotension, 41 (19.6%) cardiac arrest, 87 (41.6%) shock index > 0.9, and 121 (57.9%) had pH < 7.3, respectively. There were 12 variables in the difficult airway physiological score (DAPS), and a DAPS of 9 had an area under the curve of 0.857. The accuracy of DAPS was 77%, the sensitivity was 74%, the specificity was 83.3%, and the positive predictive value was 91%.

Conclusion

DAPS demonstrated strong discriminating ability for anticipating physiologically challenging airways. The proposed model may be helpful in the clinical setting for screening patients who are at high risk of deterioration.
Predictors of COVID-19 vaccine uptake: an online three-wave survey study of US adults
Authors: Thorpe Alistair , Fagerlin Angela , Drews Frank A. , Shoemaker Holly , Brecha Federica S. , Scherer Laura D.
Published: March 2024

Background

To effectively promote vaccine uptake, it is important to understand which people are most and least inclined to be vaccinated and why. In this study, we examined predictors of COVID-19 vaccine uptake and reasons for non-vaccination.

Methods

We conducted an online English-language survey study in December-2020, January-2021, and March-2021. A total of 930 US respondents completed all surveys. Multiple logistic regression models were run to test whether the early vaccine eligibility, demographic factors, and psychological factors predict getting at least one dose of a COVID-19 vaccination in January-2021 and in March-2021.

Results

The proportion of respondents who received ≥ 1-dose of a COVID-19 vaccine increased from 18% (January) to 67% (March). Older age predicted vaccine uptake in January (OR = 2.02[95%CI = 1.14–3.78], p < .001) and March (10.92[6.76–18.05], p < .001). In January, additional predictors were higher numeracy (1.48[1.20–1.86], p < .001), COVID-19 risk perceptions (1.35[1.03–1.78], p = .029), and believing it is important adults get the COVID-19 vaccine (1.66[1.05–2.66], p = .033). In March, additional predictors of uptake were believing it is important adults get the COVID-19 vaccine (1.63[1.15–2.34], p = .006), prior COVID-19 vaccine intentions (1.37[1.10–1.72], p = .006), and belief in science (0.84[0.72–0.99], p = .041). Concerns about side effects and the development process were the most common reasons for non-vaccination. Unvaccinated respondents with no interest in getting a COVID-19 vaccine were younger (0.27[0.09–0.77], p = .016), held negative views about COVID-19 vaccines for adults (0.15[0.08–0.26], p < .001), had lower trust in healthcare (0.59[0.36–0.95], p = .032), and preferred to watch and wait in clinically ambiguous medical situations (0.66[0.48–0.89], p = .007).

Conclusions

Evidence that attitudes and intentions towards COVID-19 vaccines were important predictors of uptake provides validation for studies using these measures and reinforces the need to develop strategies for addressing safety and development concerns which remain at the forefront of vaccine hesitancy.