bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer
Authors: Lopez de Rodas Miguel , Nagineni Venkata , Ravi Arvind , Datar Ila J , Mino-Kenudson Mari , Corredor German , Barrera Cristian , Behlman Lindsey , Rimm David L , Herbst Roy S , Madabhushi Anant , Riess Jonathan W , Velcheti Vamsidhar , Hellmann Matthew D , Gainor Justin , Schalper Kurt A 
Published: June 2022

BackgroundTumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored.MethodsWe used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8+cytotoxic T cells, CD4+helper T cells and CD20+B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao’s Q Index (RQI)).ResultsTILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8+T cells were the most abundant subset. Higher density of stromal CD8+cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort.ConclusionBaseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC.
Cardiovascular medication in patients with raised NT-proBNP, but no heart failure in the SHEAF registry
Authors: Wolodimeroff Elena , Garg Pankaj , Swift Andrew J , Fent Graham , Lewis Nigel , Rogers Dominic , Charalampopoulos Athanasios , Al-Mohammad Abdallah 
Published: June 2022

ObjectivesWe aim to assess the association of cardiovascular medications with outcomes of patients referred to the diagnostic heart failure (HF) clinic with symptoms or signs of possible HF, raised N-terminal pro-brain-type natriuretic peptide (NT-proBNP) but no evidence of HF on transthoracic echocardiography (TTE).MethodsData were collected prospectively into the Sheffield HEArt Failure (SHEAF) registry between April 2012 and January 2020. The inclusion criteria were symptoms or signs suggestive of HF, NT-proBNP >400 pg/mL, but no evidence of HF on TTE. Cox proportional-hazards regression model was used to investigate the association between the survival time of patients and different cardiovascular medications. The outcome was defined as all-cause mortality.ResultsFrom the SHEAF registry, we identified 1766 patients with raised NT-proBNP with no evidence of HF on TTE. Survival was higher among the younger patients, and among those with hypertension or atrial fibrillation (AF). Mortality was increased with male gender, valvular heart disease and chronic kidney disease. Using univariate Cox proportional-hazards regression, the only cardiac therapeutic agent independently associated with all-cause mortality was beta-blocker (HR 0.86; 95% CI: 0.77 to 0.97; p=0.02). The use of beta-blockers was significantly higher in patients with AF (63% vs 39%, p<0.01) and hypertension (51% vs 42%, p<0.01). However, using multivariate Cox proportional-hazards regression to adjust for all variables associated with mortality, the influence of beta-blockers became non-significant (HR 0.96; 95% CI: 0.85 to 1.1, p=0.49).ConclusionWhen all variables associated with mortality are considered, none of the cardiovascular agents are associated with the improved survival of patients with suspected HF, raised NT-proBNP but no HF on echocardiography.
High rate of left ventricular hypertrophy on screening echocardiography among adults living with HIV in Malawi
Authors: Hoffman Risa M , Chibwana Florence , Banda Ben Allan , Kahn Daniel , Gama Khumbo , Boas Zachary P , Chimombo Mayamiko , Kussen Chiulemu , Currier Judith S , Namarika Dan , van Oosterhout Joep , Phiri Sam , Moses Agnes , Currier Jesse W , Sigauke Hitler , Moucheraud Corrina , Canan Tim 
Published: June 2022

BackgroundThere are limited data on structural heart disease among people living with HIV in southern Africa, where the success of antiretroviral therapy (ART) has drastically improved life expectancy and where risk factors for cardiovascular disease are prevalent.MethodsWe performed a cross-sectional study of screening echocardiography among adults (≥18 years) with HIV in Malawi presenting for routine ART care. We used univariable and multivariable logistic regression to evaluate correlates of abnormal echocardiogram.ResultsA total of 202 individuals were enrolled with a median age of 45 years (IQR 39–52); 52% were female, and 27.7% were on antihypertensive medication. The most common clinically significant abnormality was left ventricular hypertrophy (LVH) (12.9%, n=26), and other serious structural heart lesions were rare (<2% with ejection fraction less than 40%, moderate-severe valve lesions or moderate-severe pericardial effusion). Characteristics associated with abnormal echocardiogram included older age (OR 1.04, 95% CI 1.01 to 1.08), higher body mass index (OR 1.09, 95% CI 1.02 to 1.17), higher mean systolic blood pressure (OR 1.03, 95% CI 1.02 to 1.05) and higher mean diastolic blood pressure (OR 1.03, 95% CI 1.01 to 1.05). In a multivariable model including age, duration on ART, body mass index, and systolic and diastolic blood pressure, only mean body mass index (adjusted OR 1.10, 95% CI 1.02 to 1.19), systolic blood pressure (aOR 1.05, 95% CI 1.03 to 1.08) and diastolic blood pressure (aOR 0.96, 95% CI 0.92 to 1.00) remained associated with abnormal echocardiogram.ConclusionsLVH was common in this population of adults on ART presenting for routine care and was associated with elevated blood pressure. Further research is needed to characterise the relationship between chronic hypertension, LVH and downstream consequences, such as diastolic dysfunction and heart failure in people living with HIV.
Deep Genetic Programming Trees Are Robust
Authors: Langdon William B. 
Published: June 2022

We sample the genetic programming tree search space and show it is smooth, since many mutations on many test cases have little or no fitness impact. We generate uniformly at random high-order polynomials composed of 12,500 and 750,000 additions and multiplications and follow the impact of small changes to them. From information theory, 32 bit floating point arithmetic is dissipative, and even with 1,501 test cases, deep mutations seldom have any impact on fitness. Absolute difference between parent and child evaluation can grow as well as fall further from the code change location, but the number of disrupted fitness tests falls monotonically. In many cases, deeply nested expressions are robust to crossover syntax changes, bugs, errors, run time glitches, perturbations, and so on, because their disruption falls to zero, and so it fails to propagate beyond the program.
Targeted Nursing Combined with Endoscopic Submucosal Injection of Carbon Nanoparticles in the Treatment of Colorectal Cancer
Authors: Yin Libo 
Published: June 2022

Aim. To evaluate the effectiveness of targeted nursing in an endoscopic submucosal injection of carbon nanoparticles to locate colorectal cancer. Methods. From September 2017 to September 2019, 82 patients with colorectal cancer who underwent endoscopic submucosal injection of carbon nanoparticles for locating the tumor were recruited and assigned via the random number table method (1 : 1) to receive either conventional nursing (control group) or targeted nursing (observation group). Outcome measures included psychological status, compliance, nursing satisfaction, quality of life, and daily living ability. Results. After intervention, the self-rating anxiety scale (SAS) scores and self-rating depression scale (SDS) scores were decreased in both groups, with lower results in the observation group (

P

< 0.001). Patients given target nursing were associated with higher compliance and nursing satisfaction of patients versus conventional nursing (

P

< 0.05). Patients receiving targeted nursing had a better quality of life versus those receiving conventional nursing (

P

< 0.001). Targeted nursing resulted in a higher Barthel index (BI) in patients versus conventional nursing 1 d, 7 d, and 14 d after nursing (

P

< 0.05). Conclusion. Targeted nursing alleviates the negative emotions of patients with colorectal cancer and improves their compliance, nursing satisfaction, daily living ability, and quality of life.
Moving Beyond Patient-Level Drivers of Racial/Ethnic Disparities in Childhood Cancer
Authors: Ji Xu , Sohn Heeju , Sil Soumitri , Castellino Sharon M. 
Published: June 2022

Abstract
Racial/ethnic disparities in childhood cancer survival persist despite advances in cancer biology and treatment. Survival rates are consistently lower among non-Hispanic Black and Hispanic children as compared with non-Hispanic White children across a range of hematologic cancers and solid tumors. We provide a framework for considering complex systems and social determinants of health in research examining the drivers of racial/ethnic disparities in childhood cancer survival, given that pediatric patients’ interactions with the healthcare system are filtered through their caregiver, family, and societal structure. Dismantling the multi-level (patient, family, healthcare system, and structural) barriers into modifiable drivers is critical to developing policies and interventions toward equitable health outcomes. This commentary highlights areas at the family, healthcare system, and society levels that merit closer examination and proposes actions and interventions to support improvements across these levels.
See recently published article in the November issue of CEBP, Racial/Ethnic Disparities in Childhood Cancer Survival in the United States p. 2010.
cDC1 Vaccines Drive Tumor Rejection by Direct Presentation Independently of Host cDC1
Authors: Ferris Stephen T. , Ohara Ray A. , Ou Feiya , Wu Renee , Huang Xiao , Kim Sunkyung , Chen Jing , Liu Tian-Tian , Schreiber Robert D. , Murphy Theresa L. , Murphy Kenneth M. 
Published: June 2022

Abstract

As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in Irf8 +32–/– mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8+ T cells in vitro. However, injection of GMDCs into tumors in Irf8 +32–/– mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 +32–/– mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy.
See related Spotlight by Hubert et al., p. 918
Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis
Authors: Park Kyoungmin , Li Qian , Lynes Matthew D. , Yokomizo Hisashi , Maddaloni Ernesto , Shinjo Takanori , St-Louis Ronald , Li Qin , Katagiri Sayaka , Fu Jialin , Clermont Allen , Park Hyunseok , Wu I-Hsien , Yu Marc Gregory , Shah Hetal , Tseng Yu-Hua , King George L. 
Published: June 2022

Background:
Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT).

Methods:

Studies used various endothelial transgenic and deletion mutant
ApoE
−/−
mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT.

Results:

Enhancing insulin’s actions on endothelial cells and NO production in
ECIRS1
transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester (
L
-NAME), an inhibitor of eNOS, in
ECIRS1
mice and
eNOSKO
mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from
ECIRS1
mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in
ApoE
−
/−
mice.

Conclusions:
Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.
A New Model for Isolating the Marine Heatwave Changes under Warming Scenarios
Authors: Wang Shengpeng , Jing Zhao , Sun Di , Shi Jian , Wu Lixin 
Published: June 2022

Abstract
Marine heatwaves (MHWs) exert devastating impacts on ecosystems. Understanding their responses to anthropogenic forcing has attracted rapidly growing scientific interest. Given the disparate adaptation capacity and mobility among marine species, it is crucial to disentangle changes of MHWs related to the rising mean temperature from those to the changing temperature variability. It has been suggested that the latter’s effects could be isolated by replacing a fixed baseline with a moving one for calculating the climatological mean and percentile metrics in MHW analysis. In this study, the effects of a moving baseline on MHW statistics (annual MHW days and cumulative intensity) changes in a warming climate are systematically evaluated based on simulations from simple stochastic climate models and a set of coupled general circulation models in the Community Earth System Model Large Ensemble project. On the one hand, a moving baseline does not necessarily remove the influences of rising mean temperature on MHW changes and will artificially cause negative trends in MHW statistics when the ocean exhibits an accelerated warming rate as in the RCP8.5 scenario. On the other hand, it always underestimates the effects of changing temperature variability on MHW changes. We propose a new model that adopts a “partial” moving baseline combined with a local linear detrending to isolate MHW changes caused by changing temperature variability.

Significance Statement
A new model is proposed to isolate marine heatwave changes caused by changing temperature variability from those by rising mean temperature under greenhouse warming.
Suicides in Aboriginal and non-Aboriginal people following hospital admission for suicidal ideation and self-harm: A retrospective cohort data linkage study from the Northern Territory
Authors: Leckning Bernard , Borschmann Rohan , Guthridge Steven , Silburn Sven R , Hirvonen Tanja , Robinson Gary W 
Published: June 2022

Purpose: This study aimed to explore risk factors for suicide in Aboriginal and non-Aboriginal people following hospital admission for suicidal ideation and self-harm in the Northern Territory, Australia to help clarify opportunities for improved care and intervention for these population groups. Methods: Individuals with at least one hospital admission involving suicidal ideation and/or self-harm between 1 July 2001 and 31 December 2013 were retrospectively recruited and followed up using linked mortality records to 31 December 2014. Survival analyses stratified by Indigenous status identified socio-demographic and clinical characteristics from index hospital admissions associated with suicide. Results: Just over half of the 4391 cohort members identified as Aboriginal ( n = 2304; 52.4%). By 2014, 281 deaths were observed comprising 68 suicides, representing a 2.6% and 2.0% probability of suicide for Aboriginal and non-Aboriginal people, respectively. After adjusting for other characteristics, a higher risk of suicide was associated with male sex (Aboriginal adjusted hazard ratio: 4.14; 95% confidence interval: [1.76, 9.75]; non-Aboriginal adjusted hazard ratio: 5.96; 95% confidence interval: [1.98, 17.88]) and repeat hospital admissions involving self-harm (Aboriginal adjusted hazard ratio: 1.37; 95% confidence interval: [1.21, 1.55]; non-Aboriginal adjusted hazard ratio: 1.29; 95% confidence interval: [1.10, 1.51]). Severe mental disorders were associated with a four times higher risk of suicide (adjusted hazard ratio: 4.23; 95% confidence interval: [1.93, 9.27]) in Aboriginal people only. Conclusion: The findings highlight non-clinical risk factors for suicide that suggest the need for comprehensive psychosocial assessment tailored to Aboriginal and non-Aboriginal people hospitalised with suicidal ideation or self-harm. Implementing appropriate management and aftercare within a broader public health framework is needed to support recovery and reduce long-term suicide risk in the community, especially for Aboriginal people and males.
Hospital inpatient admissions of children of mothers with severe mental illness: A Western Australian cohort study
Authors: Pierce Matthias , Di Prinzio Patsy , Dalman Christina , Abel Kathryn M , Morgan Vera A 
Published: June 2022

Background: Children of parents with mental illness face a number of adversities, potentially contributing to poor health. Aim: The aim of this study was to quantify the association between maternal severe mental illness and children’s hospital admissions. Method: Record linkage cohort study of 467,945 children born in Western Australia between 1 January 1980 and 31 December 2001. Follow-up was from age 28 days until fifth birthday. Linked registers captured information on potential confounders. Rate ratios and adjusted rate ratios measured relative change in the numbers of admissions and total days of stay, while rate differences measured absolute change in outcomes. Cause-specific increases were calculated for ICD-9 chapters and for ‘potentially preventable’ conditions. Results: After adjusting for potential confounders, children of mothers with severe mental illness had a 46% relative increased rate in hospital admissions (95% confidence interval = [38%, 54%]) and an absolute increase in 0.69 extra days in hospital per child, per year (95% confidence interval = [0.67, 0.70]). The relative increase in admissions was greatest in the child’s first year of life (adjusted rate ratio = 1.76, 95% confidence interval = [1.64, 1.88]; rate difference = 0.32, 95% confidence interval = [0.30, 0.34]). Rates of admissions were increased for a range of causes, particularly injuries, infections and respiratory disease, and for conditions classified as ‘potentially preventable’. Conclusion: Children of mothers with severe mental illness have a substantial excess in hospital use compared to children of well mothers. This vulnerable group should be targeted with interventions to avert preventable morbidity and premature mortality in later life.
Orientation Comes First: Becoming Aware of Spatial Disorientation Interferes with Cognitive Performance
Authors: Landman Annemarie , Kalogeras Dimitrios , Houben Mark , Groen Eric L. 
Published: June 2022

Background Previous research has shown that experiencing motion stimuli negatively impacts cognitive performance. Objective In the current study, we investigate whether this impact relates to Type-II spatial disorientation (SD), to motion stimulus magnitude, or to an interaction of these factors. Method Stimuli for participants ( n = 23) consisted of Earth-vertical yaw rotations on a rotating chair in a completely darkened room. In the surprise condition, the stimulus started with subthreshold acceleration, followed by suprathreshold deceleration to a non-zero velocity, inducing a sensation of rotation that is opposite to the actual rotation revealed when the lights were switched on. In the no-surprise condition, the same changes in velocity were used, but starting from (almost) zero velocity, which induced a sensation of rotation in the same direction as the actual rotation. Participants performed a self-paced arithmetic task and measurement of their cognitive performance started after the environment was revealed. Stimulus magnitude was operationalized through higher or lower peak suprathreshold deceleration. Results The results revealed that counting speed decreased significantly when participants were surprised, constituting a large effect size. The proportion of counting errors likewise increased significantly when participants were surprised, but only in the high-magnitude condition. Application The findings suggest that surprise caused by the recognition of SD has an involuntary disruptive effect on cognition, which may impact performance of piloting tasks. These results are relevant when modeling motion stimuli effects on performance, and when developing SD awareness training for pilots.