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Damià Valero-Bover,1,2 David Monterde,2,3 Gerard Carot-Sans,1,2 Miguel Cainzos-Achirica,4,5 Josep Comin-Colet,6– 8 Emili Vela,1,2 Montse Clèries,1,2 Júlia Folguera,1,2 Sònia Abilleira,9 Miquel Arrufat,3 Yolanda Lejardi,3 Òscar Solans,2,10 Toni Dedeu,11 Marc Coca,1,2 Pol Pérez-Sust,1 Caridad Pontes,1,2,12 Jordi Piera-Jiménez1,2,13 1Catalan Health Service, Barcelona, Spain; 2Digitalization for the Sustainability of the Healthcare System (DS3) – Institut d’Investigacions Biomèdiques de Bellvitge (IDIBELL), Barcelona, Spain; 3Catalan Institute of Health, Barcelona, Spain; 4Center for Outcomes Research, Houston Methodist, Houston, TX, USA; 5Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 6Cardiology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain; 7Department of Medicine, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain; 8CIBER Cardiovascular (CIBERCV), L’Hospitalet de Llobregat, Barcelona, Spain; 9CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 10Health Department, eHealth Unit, Barcelona, Spain; 11WHO European Centre for Primary Health Care, Almaty, Kazakhstan; 12Department of Pharmacology, Autonomous University of Barcelona, Barcelona, Spain; 13Faculty of Informatics, Telecommunications and Multimedia, Universitat Oberta de Catalunya, Barcelona, SpainCorrespondence: Jordi Piera-Jiménez, Catalan Health Service, Gran Via de les Corts Catalanes 587, Barcelona, 08007, Spain, Tel +34 93 403 85 85, Email jpiera@catsalut.catPurpose: To assess the contribution of age and comorbidity to the risk of critical illness in hospitalized COVID-19 patients using increasingly exhaustive tools for measuring comorbidity burden.Patients and Methods: We assessed the effect of age and comorbidity burden in a retrospective, multicenter cohort of patients hospitalized due to COVID-19 in Catalonia (North-East Spain) between March 1, 2020, and January 31, 2022. Vaccinated individuals and those admitted within the first of the six COVID-19 epidemic waves were excluded from the primary analysis but were included in secondary analyses. The primary outcome was critical illness, defined as the need for invasive mechanical ventilation, transfer to the intensive care unit (ICU), or in-hospital death. Explanatory variables included age, sex, and four summary measures of comorbidity burden on admission extracted from three indices: the Charlson index (17 diagnostic group codes), the Elixhauser index and count (31 diagnostic group codes), and the Queralt DxS index (3145 diagnostic group codes). All models were adjusted by wave and center. The proportion of the effect of age attributable to comorbidity burden was assessed using a causal mediation analysis.Results: The primary analysis included 10,551 hospitalizations due to COVID-19; of them, 3632 (34.4%) experienced critical illness. The frequency of critical illness increased with age and comorbidity burden on admission, irrespective of the measure used. In multivariate analyses, the effect size of age decreased with the number of diagnoses considered to estimate comorbidity burden. When adjusting for the Queralt DxS index, age showed a minimal contribution to critical illness; according to the causal mediation analysis, comorbidity burden on admission explained the 98.2% (95% CI 84.1– 117.1%) of the observed effect of age on critical illness.Conclusion: Comorbidity burden (when measured exhaustively) explains better than chronological age the increased risk of critical illness observed in patients hospitalized with COVID-19.Keywords: COVID-19, comorbidities, comorbidity burden, risk assessment, hospitalized patients, case-mix tool

David Monterde,1,2 Gerard Carot-Sans,2,3 Miguel Cainzos-Achirica,4,5 Sònia Abilleira,1,6 Marc Coca,2,3 Emili Vela,2,3 Montse Clèries,2,3 Damià Valero-Bover,2,3 Josep Comin-Colet,7– 9 Luis García-Eroles,2,3 Pol Pérez-Sust,3 Miquel Arrufat,1 Yolanda Lejardi,1 Jordi Piera-Jiménez2,3,10 1Catalan Institute of Health, Barcelona, Spain; 2Digitalization for the Sustainability of the Healthcare System (DS3), Sistema de Salut de Catalunya, Barcelona, Spain; 3Servei Català de la Salut, Barcelona, Spain; 4Center for Outcomes Research, Houston Methodist, Houston, TX, USA; 5Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 6CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 7Department of Cardiology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain; 8Bioheart-Cardiovascular Diseases Research Group (Idibell), L’Hospitalet de Llobregat, Barcelona, Spain; 9Department of Clinical Sciences, School of Medicine, Universität de Barcelona - UB, L’Hospitalet de Llobregat, Barcelona, Spain; 10Open Evidence Research Group, Universitat Oberta de Catalunya, Barcelona, SpainCorrespondence: Jordi Piera-JiménezServei Català de la Salut (CatSalut), Travessera de les Corts, 131-159 (Edifici Olímpia), Barcelona, 08028, SpainTel +34 634283110Email jpiera@catsalut.catBackground: Comorbidity burden has been identified as a relevant predictor of critical illness in patients hospitalized with coronavirus disease 2019 (COVID-19). However, comorbidity burden is often represented by a simple count of few conditions that may not fully capture patients’ complexity.Purpose: To evaluate the performance of a comprehensive index of the comorbidity burden (Queralt DxS), which includes all chronic conditions present on admission, as an adjustment variable in models for predicting critical illness in hospitalized COVID-19 patients and compare it with two broadly used measures of comorbidity.Materials and Methods: We analyzed data from all COVID-19 hospitalizations reported in eight public hospitals in Catalonia (North-East Spain) between June 15 and December 8 2020. The primary outcome was a composite of critical illness that included the need for invasive mechanical ventilation, transfer to ICU, or in-hospital death. Predictors including age, sex, and comorbidities present on admission measured using three indices: the Charlson index, the Elixhauser index, and the Queralt DxS index for comorbidities on admission. The performance of different fitted models was compared using various indicators, including the area under the receiver operating characteristics curve (AUROCC).Results: Our analysis included 4607 hospitalized COVID-19 patients. Of them, 1315 experienced critical illness. Comorbidities significantly contributed to predicting the outcome in all summary indices used. AUC (95% CI) for prediction of critical illness was 0.641 (0.624– 0.660) for the Charlson index, 0.665 (0.645– 0.681) for the Elixhauser index, and 0.787 (0.773– 0.801) for the Queralt DxS index. Other metrics of model performance also showed Queralt DxS being consistently superior to the other indices.Conclusion: In our analysis, the ability of comorbidity indices to predict critical illness in hospitalized COVID-19 patients increased with their exhaustivity. The comprehensive Queralt DxS index may improve the accuracy of predictive models for resource allocation and clinical decision-making in the hospital setting.Keywords: comorbidity, multimorbidity, COVID-19, hospitalization, risk

Sequencing technologies has provided the basis of most modern genome sequencing studies due to its high base-level accuracy and relatively low cost. One of the most demanding step is mapping reads to the human reference genome. The reliance on a single reference human genome could introduce substantial biases in downstream analyses. Pangenomic graph reference representations offer an attractive approach for storing genetic variations. Moreover, it is possible to include known variants in the reference in order to make read mapping, variant calling, and genotyping variant-aware. Only recently a framework for variation graphs, vg [Garrison E, Adam MN, Siren J, et al. Variation graph toolkit improves read mapping by representing genetic variation in the reference. Nat Biotechnol 2018;36:875–9], have improved variation-aware alignment and variant calling in general. The major bottleneck of vg is its high cost of reads mapping to a variation graph. In this paper we study the problem of SNP calling on a variation graph and we present a fast reads alignment tool, named VG SNP-Aware. VG SNP-Aware is able align reads exactly to a variation graph and detect SNPs based on these aligned reads. The results show that VG SNP-Aware can efficiently map reads to a variation graph with a speedup of 40× with respect to vg and similar accuracy on SNPs detection.

Santiago Jiménez-Marrero,1,2 Miguel Cainzos-Achirica,1– 4 David Monterde,5 Luis Garcia-Eroles,5 Cristina Enjuanes,1,2 Sergi Yun,1,2,6 Alberto Garay,1,2 Pedro Moliner,1,2 Lidia Alcoberro,1,2 Xavier Corbella,2,6,7 Josep Comin-Colet1,2,8 1Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 2Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; 3Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 4School of Medicine and Health Sciences, International University of Catalonia, Barcelona, Spain; 5Healthcare Information and Knowledge Unit, Catalan Health Service, Barcelona, Spain; 6Department of Internal Medicine, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 7Hestia Chair in Integrated Health and Social Care, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain; 8Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, SpainCorrespondence: Josep Comin-ColetHospital Universitari de Bellvitge, Department of Cardiology, 19th Floor, Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barcelona, SpainTel +34932607078Email jcomin@bellvitgehospital.catBackground: The aims of the present analysis are to estimate the prevalence of five key chronic cardiovascular, metabolic and renal conditions at the population level, the prevalence of renin–angiotensin–aldosterone system inhibitor (RAASI) medication use and the magnitude of potassium (K+) derangements among RAASI users.Methods and Results: We used data from more than 375,000 individuals, 55 years of age or older, included in the population-based healthcare database of the Catalan Institute of Health between 2015 and 2017. The conditions of interest were chronic heart failure (CHF), chronic kidney disease (CKD), diabetes mellitus, ischemic heart disease and hypertension. RAASI medications included angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists (MRAs) and renin inhibitors. Hyperkalemia was defined as K+ levels > 5.0 mEq/L and hypokalemia as K+ < 3.5 mEq/L. The prevalence of chronic cardiovascular, metabolic and renal conditions was high, and particularly that of hypertension (prevalence ranging from 48.2% to 48.9%). The use of at least one RAASI medication was almost ubiquitous in these patients (75.2– 77.3%). Among RAASI users, the frequency of K+ derangements, mainly of hyperkalemia, was very noticeable (12% overall), particularly in patients with CKD or CHF, elderly individuals and users of MRAs. Hypokalemia was less frequent (1%).Conclusion: The high prevalence of K+ derangements, and particularly hyperkalemia, among RAASI users highlights the real-world relevance of K+ derangements, and the importance of close monitoring and management of K+ levels in routine clinical practice. This is likely to benefit a large number of patients, particularly those at higher risk.Keywords: chronic heart failure, chronic kidney disease, heart failure, hyperkalemia, hypertension, potassium

Early and Late Cretaceous alkaline and alkaline–carbonatitic complexes from southern Brazil are located along the main tectonic lineaments of the South America Platform. Calcium-, magnesium-, and ferrocarbonatites are well represented and frequently associated even in the same complex. Primary carbonates present significant variations in C–O isotopic compositions, which are mainly due to isotope exchange with H2O–CO2-rich hydrothermal fluids, whereas fractional crystallization or liquid immiscibility probably affects the δ18O and δ13C values by no more than 2δ‰. Our isotope exchange model implies that the most significant isotopic variations took place in a hydrothermal environment, e.g., in the range 400–80°C, involving fluids with the CO2/H2O ratio ranging from 0.8 to 1. Sr–Nd–Pb isotope systematics highlight heterogeneous mixtures between HIMU and EMI mantle components, similar to the associated alkaline rocks and the flood tholeiites from southern Brazil. In spite of the strong variation shown by C–O isotopes, Sr–Nd–Pb–Os isotopic systematics could be related to an isotopically enriched source where the chemical heterogeneities reflect a depleted mantle “metasomatized” by small-volume melts and fluids rich in incompatible elements. These fluids are expected to have promoted crystallization of K-rich phases in the mantle, which produced a veined network variously enriched in LILE and LREE. The newly formed veins (enriched component) and peridotite matrix (depleted component) underwent a different isotopic evolution with time as reflected by the carbonatites. These conclusions may be extended to the whole Paraná–Etendeka system, where isotopically distinct parent magmas were generated following two main enrichment events of the subcontinental lithospheric mantle at 2.0–1.4 and 1.0–0.5 Ga, respectively, as also supported by Re–Os systematics. The mantle sources preserved the isotopic heterogeneities over a long time, suggesting a nonconvective lithospheric mantle beneath different cratons or intercratonic regions. Overall, the data indicate that the alkaline–carbonatitic magmatism originated from a locally heterogeneous subcontinental mantle.

We present a comprehensive overview of the geochemical characteristics and evolution of the carbonatites from the southern Brazilian Platform (Paraná Basin). The carbonatites from different complexes display large compositional variability in terms of abundances of incompatible and rare earth elements. This is in agreement with an origin from heterogeneous lithospheric sources, as confirmed by isotopic data (see Speziale et al., this issue). The characteristic major and trace element abundances of these carbonatites present compelling evidence for invoking liquid unmixing as the main mechanism of their formation and evolution albeit few exceptions. We propose an evolutionary trend for the Brazilian carbonatites, which can be summarized as following: exsolution of the primary Ca- or Mg-carbonatitic liquids systematically takes place at the phonolite-peralkaline phonolite stage of magma differentiation; this is followed by progressive Fe-enrichment and by final emplacement of fluorocarbonatites associated with hydrothermal fluids.

David Monterde,1 Miguel Cainzos-Achirica,2,3 Yolima Cossio-Gil,4,5 Luis García-Eroles,6 Pol Pérez-Sust,7 Miquel Arrufat,1 Candela Calle,8 Josep Comin-Colet,3,9 César Velasco4,5 1Catalan Institute of Health, Barcelona, Spain; 2Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 3Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 4Vall d’Hebron Hospital, Barcelona, Spain; 5Vall d’Hebron Research Institute (VHIR), Barcelona, Spain; 6Catalan Health Service, Barcelona, Spain; 7Catalan Health Department, Barcelona, Spain; 8Catalan Institute of Oncology (ICO), Barcelona, Spain; 9University of Barcelona, Barcelona, SpainCorrespondence: David MonterdeDepartment of Statistics, Information Systems, Catalan Institute of Health, Gran via De Les Corts Catalanes 587, Barcelona 08007, SpainTel +34 934824642Email dmonterde@gencat.catBackground: Accurate risk adjustment is crucial for healthcare management and benchmarking.Purpose: We aimed to compare the performance of classic comorbidity functions (Charlson’s and Elixhauser’s), of the All Patients Refined Diagnosis Related Groups (APR-DRG), and of the Queralt Indices, a family of novel, comprehensive comorbidity indices for the prediction of key clinical outcomes in hospitalized patients.Material and Methods: We conducted an observational, retrospective cohort study using administrative healthcare data from 156,459 hospital discharges in Catalonia (Spain) during 2018. Study outcomes were in-hospital death, long hospital stay, and intensive care unit (ICU) stay. We evaluated the performance of the following indices: Charlson’s and Elixhauser’s functions, Queralt’s Index for secondary hospital discharge diagnoses (Queralt DxS), the overall Queralt’s Index, which includes pre-existing comorbidities, in-hospital complications, and principal discharge diagnosis (Queralt Dx), and the APR-DRG. Discriminative ability was evaluated using the area under the curve (AUC), and measures of goodness of fit were also computed. Subgroup analyses were conducted by principal discharge diagnosis, by age, and type of admission.Results: Queralt DxS provided relevant risk adjustment information in a larger number of patients compared to Charlson’s and Elixhauser’s functions, and outperformed both for the prediction of the 3 study outcomes. Queralt Dx also outperformed Charlson’s and Elixhauser’s indices, and yielded superior predictive ability and goodness of fit compared to APR-DRG (AUC for in-hospital death 0.95 for Queralt Dx, 0.77– 0.93 for all other indices; for ICU stay 0.84 for Queralt Dx, 0.73– 0.83 for all other indices). The performance of Queralt DxS was at least as good as that of the APR-DRG in most principal discharge diagnosis subgroups.Conclusion: Our findings suggest that risk adjustment should go beyond pre-existing comorbidities and include principal discharge diagnoses and in-hospital complications. Validation of comprehensive risk adjustment tools such as the Queralt indices in other settings is needed.Keywords: benchmarking, case-mix, comorbidity, discrimination, multimorbidity, Queralt’s indices, risk

The exploration of 1D magnetism, frequently portrayed as spin chains, constitutes an actively pursued research field that illuminates fundamental principles in many-body problems and applications in magnonics and spintronics. The inherent reduction in dimensionality often leads to robust spin fluctuations, impacting magnetic ordering and resulting in novel magnetic phenomena. Here, structural, magnetic, and optical properties of highly anisotropic 2D van der Waals antiferromagnets that uniquely host spin chains are explored. First-principle calculations reveal that the weakest interaction is interchain, leading to essentially 1D magnetic behavior in each layer. With the additional degree of freedom arising from its anisotropic structure, the structure is engineered by alloying, varying the 1D spin chain lengths using electron beam irradiation, or twisting for localized patterning, and spin textures are calculated, predicting robust stability of the antiferromagnetic ordering. Comparing with other spin chain magnets, these materials are anticipated to bring fresh perspectives on harvesting low-dimensional magnetism.

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors. METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence. RESULTS: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group. CONCLUSIONS: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.

The introduction of localized electronic states into a metal can alter its physical properties, for example enabling exotic metal physics including heavy fermion and strange metal behaviour. A common source of localized states in such systems are partially filled 4f and 5f shells because of the inherently compact nature of those orbitals. The interaction of electrons in these orbitals with the conduction sea is well described by the Kondo framework. However, there have also been observations of Kondo-like behaviour in 3d transition metal oxides and in 4d- and 5d-containing van der Waals heterostructures. This calls for a broader consideration of the physical requirements for Kondo systems. Here we show transport and thermodynamic hallmarks of heavy fermion and strange metal behaviour that arise in the kagome metal Ni3In, wherein the source of localized states is destructive interference-induced band flattening of partially filled Ni 3d states. With magnetic field and pressure tuning, we also find evidence that the system is proximate to quantum criticality, extending the analogy to f-electron Kondo lattices. These observations highlight the role of hopping frustration in metallic systems as a potential source for strong correlations. Additionally, this suggests a lattice-driven approach to realizing correlated metals with non-trivial band topology.

People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10+CD27- B cells, CD20+CD27- B cells, and B-cell populations with aberrant features (CD20+CD27+CXCR4+CD71+ B cells and CD20+CXCR4+cMYC+ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20+CD27+CD24+CXCR4+CXCR5+ B cells, CD20+CD27+CD10+CD24+CXCR4+cMYC+ B cells, and a cluster of CD20+CXCR4hiCD27-CD24+CXCR5+CD40+CD4+AICDA+ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20+CXCR4+CXCR5+cMYC+AICDA+ B cells and a cluster of germinal center B-cell-like cells (CD19-CD20+CXCR4+Bcl-6+PD-L1+cMYC+) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19+CD24hiCD38hi cMYC+ AICDA+ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.

Recently, kagome lattice materials have emerged as a new model material platform for discovering and engineering novel quantum phases of matter. In this work, we elucidate the driving mechanism of the 3 × 3 charge order in a newly discovered kagome metal ScV6Sn6. Through multimodal investigations combining angle-resolved photoemission spectroscopy, phonon dispersion calculations, and phase diagram study, we identify the central role of unstable planar Sn and Sc phonon modes, while the electronic instability and van Hove singularities originating from the V kagome lattice have a marginal influence. Our results highlight that the 3 × 3 charge order in ScV6Sn6 is fundamentally distinguished from the electronically driven 2 × 2 charge order in the canonical kagome system AV3Sb5, uncovering a new mechanism to induce symmetry-breaking phase transition in kagome lattice materials.

β2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss results in acquired resistance to immune checkpoint blockade (ICB) therapies. However, there have been well-documented cases of B2M-inactivated tumors responding to ICB, justifying investigation of how an antitumor immune response can be generated to tumors without surface MHC class I. We knocked out B2M in three murine models with varying baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy and analyzed the immune responses. MC38 and YUMMER2.1 without B2M responded to anti-PD-1 alone or with an IL2 agonist, and this was mediated by CD4+ T cells and natural killer (NK) cells. The more aggressive B16 without B2M expression only partially responded to the IL2 agonist, and this was dependent on NK cells. When analyzing nearly 300 pretreatment biopsies from patients with melanoma receiving PD-1 blockade-based therapies, we found infrequent B2M mutations or homozygous loss but more frequent LOH or copy-number gains. B2M LOH was enriched in biopsies from patients without response to therapy, and these biopsies were more frequently infiltrated by activated NK cells. We conclude that in the absence of B2M, activation of CD4+ T cells and NK cells can mediate responses to murine models of PD-1 blockade therapy. In addition, in human melanoma, the intratumoral presence of activated NK cells upon partial B2M loss likely selects against tumor escape through low surface MHC class I expression.

Transgenic T-cell receptor (TCR) T cell-based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic and proteomic analysis of preinfusion clinical TCR T-cell therapy products revealed that TNFα cytokine functionality of CD8+ T cells and phospho-STAT3 signaling in these cells were both associated with superior clinical responsiveness to therapy. By contrast, CD4+ T-helper 2 cell cytokine profiles were associated with inferior clinical responses. In parallel, preinfusion levels of IL15, Flt3-L, and CX3CL1 were all found to be associated with clinical response to therapy. These results have implications for the development of therapeutic biomarkers and identify potential targets for enrichment in the design of transgenic TCR T-cell therapies for solid tumors.

This study aimed to identify the main stressors in the transition and adaptation processes to higher education in nursing students. Two reflective groups were conducted with 136 students. The thematic-reflexive analysis revealed that the main stressors were the excessive workload of course activities, the need for maturation, psychological pressure, and lack of financial resources. The results demonstrated the need for monitoring students throughout the course, especially in the early years, as well as the continuity of welcoming activities. University care programs can help adapt to the course, also functioning as mental health promoters.

Olatz Urbina,1 Olivia Ferrández,1 Sònia Luque,1 Santiago Grau,1,2 Sergi Mojal,3 Rosa Pellicer,1 Marta Riu,4 Esther Salas,1 Josep Comin-Colet5 1Pharmacy Department, Hospital Universitari del Mar, Barcelona, Spain; 2Universitat Autònoma de Barcelona, Barcelona, Spain; 3Department of Statistics, Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain; 4Department of Epidemiology and Health Services Evaluation, CIBER de Epidemiología y Salud Pública (CIBERESP), Hospital Universitari del Mar, Barcelona, Spain; 5Heart Failure Unit, Cardiology Department, Hospital Universitari del Mar, Barcelona, Spain Background: Because of the high incidence of drug-related problems (DRPs) among hospitalized patients with cardiovascular diseases and their potential impact on morbidity and mortality, it is important to identify the most susceptible patients, who therefore require closer monitoring of drug therapy.Purpose: To identify the profile of patients at higher risk of developing at least one DRP during hospitalization in a cardiology ward.Method: We consecutively included all patients hospitalized in the cardiology ward of a teaching hospital in 2009. DRPs were identified through a computerized warning system designed by the pharmacy department and integrated into the electronic medical record.Results: A total of 964 admissions were included, and at least one DRP was detected in 29.8%. The variables associated with a higher risk of these events were polypharmacy (odds ratio [OR]=1.228; 95% confidence interval [CI]=1.153–1.308), female sex (OR=1.496; 95% CI=1.026–2.180), and first admission (OR=1.494; 95% CI=1.005–2.221).Conclusion: Monitoring patients through a computerized warning system allowed the detection of at least one DRP in one-third of the patients. Knowledge of the risk factors for developing these problems in patients admitted to hospital for cardiovascular problems helps in identifying the most susceptible patients. Keywords: cardiovascular diseases, patient safety, drug therapy monitoring, computerized provider order entry, clinical pharmacist, pharmacy warning system

Abstract In rare earth nickelates (RENiO3), electron-lattice coupling drives a concurrent metal-to-insulator and bond disproportionation phase transition whose microscopic origin has long been the subject of active debate. Of several proposed mechanisms, here we test the hypothesis that pairs of self-doped ligand holes spatially condense to provide local spin moments that are antiferromagnetically coupled to Ni spins. These singlet-like states provide a basis for long-range bond and spiral spin order. Using magnetic resonant X-ray scattering on NdNiO3 thin films, we observe the chiral nature of the spin-disproportionated state, with spin spirals propagating along the crystallographic (101)ortho direction. These spin spirals are found to preferentially couple to X-ray helicity, establishing the presence of a hitherto-unobserved macroscopic chirality. The presence of this chiral magnetic configuration suggests a potential multiferroic coupling between the noncollinear magnetic arrangement and improper ferroelectric behavior as observed in prior studies on NdNiO3 (101)ortho films and RENiO3 single crystals. Experimentally-constrained theoretical double-cluster calculations confirm the presence of an energetically stable spin-disproportionated state with Zhang-Rice singlet-like combinations of Ni and ligand moments.

Abstract Strongly correlated materials respond sensitively to external perturbations such as strain, pressure, and doping. In the recently discovered superconducting infinite-layer nickelates, the superconducting transition temperature can be enhanced via only ~ 1% compressive strain-tuning with the root of such enhancement still being elusive. Using resonant inelastic x-ray scattering (RIXS), we investigate the magnetic excitations in infinite-layer PrNiO2 thin films grown on two different substrates, namely SrTiO3 (STO) and (LaAlO3)0.3(Sr2TaAlO6)0.7 (LSAT) enforcing different strain on the nickelates films. The magnon bandwidth of PrNiO2 shows only marginal response to strain-tuning, in sharp contrast to the enhancement of the superconducting transition temperature T c in the doped superconducting samples. These results suggest the bandwidth of spin excitations of the parent compounds is similar under strain while T c in the doped ones is not, and thus provide important empirics for the understanding of superconductivity in infinite-layer nickelates.

ABSTRACT: The study investigated guanidinoacetic acid (GAA) supplementation with varying dietary digestible arginine (Arg) and glycine+serine (Gly+Ser) concentrations in the starter phase, exploring respective carry-over effects on growth performance, blood chemistry, incidence of pectoral myopathies and proximate composition in broilers. A total of 2,800 one-day-old male broiler chicks were distributed in a central composite design with 2 factors and double experimental mesh, represented by supplementation or omission of 0.6 g per kg of GAA, with a central point represented by 107% of Arg and 147% of Gly+Ser, 4 factorial points (combinations of Arg/Gly+Ser concentrations: 96.4/132.5%; 117.6/132.5%; 96.4/161.5%, and 117.6/132.5%), and 4 axial points (combinations of axial points estimated for Arg and Gly+Ser, with the central points of 92/147%; 122/147%; 107/126.5, and 107/167.5%), totaling 18 treatments, 4 repetitions to factorial and axial points, 24 replicates to the central point, and 25 birds per pen. Feed conversion ratio (FCR) from d 1 to 10 had a linear response (P = 0.009) for the decreasing Arg content and a quadratic response (P = 0.047) for Gly+Ser concentrations. Broilers supplemented GAA had lower FCR compared with nonsupplemented groups from d 1 to 10 (P = 0.048) and d 1 to 42 (P = 0.026). Aspartate aminotransferase (AST) exhibited increasing and decreasing linear effects as a function of Arg (P = 0.008) and Gly+Ser (P = 0.020) concentrations, respectively. Guanidinoacetic acid decreased serum AST (P = 0.028). Guanidinoacetic acid reduced moderate + severe (P = 0.039) and mild (P = 0.015) Wooden Breast scores. The occurrence of normal White Striping increased (P = 0.002), while severe score was reduced (P = 0.029) with GAA supplementation. In conclusion, increased digestible Arg:Lys and 14% and 6% above the recommendations (107% and 147%), respectively, provided improved FCR during the starter phase. Dietary GAA supplementation (0.6 g per kg) improved FCR, reduced severity of breast myopathies and appears to have reduced muscle damage in broilers fed plant-based diets.