Seafloor primary production in a changing Arctic Ocean.

Phytoplankton and sea ice algae are traditionally considered to be the main primary producers in the Arctic Ocean. In this Perspective, we explore the importance of benthic primary producers (BPPs) encompassing microalgae, macroalgae, and seagrasses, which represent a poorly quantified source of Arctic marine primary production. Despite scarce observations, models predict that BPPs are widespread, colonizing ~3 million km2 of the extensive Arctic coastal and shelf seas. Using a synthesis of published data and a novel model, we estimate that BPPs currently contribute ~77 Tg C y-1 of primary production to the Arctic, equivalent to ~20 to 35% of annual phytoplankton production. Macroalgae contribute ~43 Tg C y-1, seagrasses contribute ~23 Tg C y-1, and microalgae-dominated shelf habitats contribute ~11 to 16 Tg C y-1. Since 2003, the Arctic seafloor area exposed to sunlight has increased by ~47,000 km2 y-1, expanding the realm of BPPs in a warming Arctic. Increased macrophyte abundance and productivity is expected along Arctic coastlines with continued ocean warming and sea ice loss. However, microalgal benthic primary production has increased in only a few shelf regions despite substantial sea ice loss over the past 20 y, as higher solar irradiance in the ice-free ocean is counterbalanced by reduced water transparency. This suggests complex impacts of climate change on Arctic light availability and marine primary production. Despite significant knowledge gaps on Arctic BPPs, their widespread presence and obvious contribution to coastal and shelf ecosystem production call for further investigation and for their inclusion in Arctic ecosystem models and carbon budgets.

Coupling substrate-trapping with proximity-labeling to identify protein tyrosine phosphatase PTP1B signaling networks.

The ability to define functional interactions between enzymes and their substrates is crucial for understanding biological control mechanisms; however, such methods face challenges in the transient nature and low stoichiometry of enzyme-substrate interactions. Now, we have developed an optimized strategy that couples substrate-trapping mutagenesis to proximity-labeling mass spectrometry for quantitative analysis of protein complexes involving the protein tyrosine phosphatase PTP1B. This methodology represents a significant shift from classical schemes; it is capable of being performed at near-endogenous expression levels and increasing stoichiometry of target enrichment without a requirement for stimulation of supraphysiological tyrosine phosphorylation levels or maintenance of substrate complexes during lysis and enrichment procedures. Advantages of this new approach are illustrated through application to PTP1B interaction networks in models of HER2-positive and Herceptin-resistant breast cancer. We have demonstrated that inhibitors of PTP1B significantly reduced proliferation and viability in cell-based models of acquired and de novo Herceptin resistance in HER2-positive breast cancer. Using differential analysis, comparing substrate-trapping to wild-type PTP1B, we have identified multiple unreported protein targets of PTP1B with established links to HER2-induced signaling and provided internal validation of method specificity through overlap with previously identified substrate candidates. Overall, this versatile approach can be readily integrated with evolving proximity-labeling platforms (TurboID, BioID2, etc.), and is broadly applicable across all PTP family members for the identification of conditional substrate specificities and signaling nodes in models of human disease.

New insights into QTNs and potential candidate genes governing rice yield via a multi-model genome-wide association study.

BACKGROUND: Rice (Oryza sativa L.) is one of the globally important staple food crops, and yield-related traits are prerequisites for improved breeding efficiency in rice. Here, we used six different genome-wide association study (GWAS) models for 198 accessions, with 553,229 single nucleotide markers (SNPs) to identify the quantitative trait nucleotides (QTNs) and candidate genes (CGs) governing rice yield. RESULTS: Amongst the 73 different QTNs in total, 24 were co-localized with already reported QTLs or loci in previous mapping studies. We obtained fifteen significant QTNs, pathway analysis revealed 10 potential candidates within 100kb of these QTNs that are predicted to govern plant height, days to flowering, and plot yield in rice. Based on their superior allelic information in 20 elite and 6 inferior genotypes, we found a higher percentage of superior alleles in the elite genotypes in comparison to inferior genotypes. Further, we implemented expression analysis and enrichment analysis enabling the identification of 73 candidate genes and 25 homologues of Arabidopsis, 19 of which might regulate rice yield traits. Of these candidate genes, 40 CGs were found to be enriched in 60 GO terms of the studied traits for instance, positive regulator metabolic process (GO:0010929), intracellular part (GO:0031090), and nucleic acid binding (GO:0090079). Haplotype and phenotypic variation analysis confirmed that LOC_OS09G15770, LOC_OS02G36710 and LOC_OS02G17520 are key candidates associated with rice yield. CONCLUSIONS: Overall, we foresee that the QTNs, putative candidates elucidated in the study could summarize the polygenic regulatory networks controlling rice yield and be useful for breeding high-yielding varieties.

SpeedFlower: a comprehensive speed breeding protocol for indica and japonica rice.

To increase rice yields and feed billions of people, it is essential to enhance genetic gains. However, the development of new varieties is hindered by longer generation times and seasonal constraints. To address these limitations, a speed breeding facility has been established and a robust speed breeding protocol, SpeedFlower is developed that allows growing 4-5 generations of indica and/or japonica rice in a year. Our findings reveal that a high red-to-blue (2R > 1B) spectrum ratio, followed by green, yellow and far-red (FR) light, along with a 24-h long day (LD) photoperiod for the initial 15 days of the vegetative phase, facilitated early flowering. This is further enhanced by 10-h short day (SD) photoperiod in the later stage and day and night temperatures of 32/30 °C, along with 65% humidity facilitated early flowering ranging from 52 to 60 days at high light intensity (800 µmol m-2 s-1). Additionally, the use of prematurely harvested seeds and gibberellic acid treatment reduced the maturity duration by 50%. Further, SpeedFlower was validated on a diverse subset of 198 rice accessions from 3K RGP panel encompassing all 12 distinct groups of Oryza sativa L. classes. Our results confirmed that using SpeedFlower one generation can be achieved within 58-71 days resulting in 5.1-6.3 generations per year across the 12 sub-groups. This breakthrough enables us to enhance genetic gain, which could feed half of the world's population dependent on rice.

Leishmania antigens activated CD4+ T cells expressing CD200R receptors are the prime IL-10 producing phenotype and an important determinant of visceral leishmaniasis pathogenesis.

The excessive production of IL-10, an anti-inflammatory cytokine, by Leishmania antigen-activated T cells is supposed to be a key player in the onset and progression of visceral leishmaniasis (VL). The IL-10-producing sources in VL remain unidentified and uncharacterized. In this study, we reveal that antigen-activated CD4+ T cells, i.e., CD44+CD4+ T cells expressing CD200R receptors, are the prime IL-10-producing phenotypes in Leishmania donovani infection-induced pathogenesis. These phenotypes are separate from CD25+Foxp3+CD4+ T regulatory cells, which are classical IL-10-producing phenotypes. In order to ascertain the role of CD200R and CD25 receptors in IL-10 overexpression-associated VL pathogenesis, we abrogated CD200R and CD25 receptor-mediated signaling in the infected mice. The splenic load of parasites and the size of the liver and spleen were significantly reduced in CD200-blocked mice as compared to CD25-blocked mice. Further, the CD200 blocking polarized CD4+ T cells to pro-inflammatory cytokines-producing phenotypes, as we observed a higher frequency of IFN-γ, TNF-α, and IL-12 positive cells as compared to controls including the CD25 blocking. Our findings suggest that in L. donovani infection-induced pathogenesis the expression of CD200R on antigen-activated T cells helps them to acquire IL-10-producing abilities as part of its one of the survival strategies. However, more studies would be warranted to better understand CD200R receptors role in VL pathogenesis and to develop the next generation of therapeutic and prophylactic control measures.

Folded interferometer to measure coherence-polarization matrix.

We present and experimentally demonstrate a new, to the best of our knowledge, technique to quantitatively measure coherence-polarization (BCP) matrix with correlations of only two Stokes fluctuations. The BCP matrix is a square matrix with four elements that involves two-point correlations among orthogonal polarization components. A theoretical framework of the technique is developed, and its viability is demonstrated by a proof of principle experiment. Experimental tests and measurement of the elements of the BCP matrix of statistically stationary beams are demonstrated.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

BACKGROUND: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. METHODS: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. RESULTS: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. SUMMARY: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Detecting topological index of randomly scattered V-point singularities using Stokes correlations.

Topological defects in vector fields constitute polarization singularities that have numerous applications in classical and quantum optics. These beams are inhomogeneously polarized and are shown to self-heal under symmetric amplitude perturbations. Polarization singular beams are characterized using a singularity index that can be detected using Stokes polarimetry or other interferometric and diffraction approaches. However, the information about the singularity index is lost when these beams travel through random scattering media; this results in a spatially fluctuating polarization pattern known as polarization speckle. This paper proposes and experimentally demonstrates a new method to detect the topological index of these randomly scattered V-point singularities using higher-order Stokes correlations in a lensless condition. A detailed theoretical basis is developed, and the performance of the technique is demonstrated by retrieving the signature of polarization singularities with Poincaré-Hopf index |η|=1 and |η|=2. We also demonstrate that by studying the intensity-intensity correlations of the polarization speckle, it is possible to differentiate between different vector beams having the same magnitude as the Poincaré-Hopf index.

Microscopic pathways of transition from low-density to high-density amorphous phase of water.

In recent years, much attention has been devoted to understanding the pathways of phase transition between two equilibrium condensed phases (such as liquids and solids). However, the microscopic pathways of transition involving non-equilibrium, non-diffusive amorphous (glassy) phases still remain poorly understood. In this work, we have employed computer simulations, persistence homology (a tool rooted in topological data analysis), and machine learning to probe the microscopic pathway of pressure-induced non-equilibrium transition between the low- and high-density amorphous (LDA and HDA, respectively) ice phases of the TIP4P/2005 and ST2 water models. Using persistence homology and machine learning, we introduced a new order parameter that unambiguously identifies the LDA- and HDA-like local environments. The LDA phase transitions continuously and collectively into the corresponding HDA phase via a pre-ordered intermediate phase during the isothermal compression. The local order parameter susceptibilities show a maximum near the transition pressure (P*)-suggesting maximum structural heterogeneities near P*. The HDA-like clusters are structurally ramified and spatially delocalized inside the LDA phase near the transition pressure. We also found manifestations of the first-order low-density to high-density liquid transition in the sharpness of the order parameter change during the LDA to HDA transition. We further investigated the (geometrical) structures and topologies of the LDA and HDA ices formed via different protocols and also studied the dependence of the (microscopic) pathway of phase transition on the protocol followed to prepare the initial LDA phase. Finally, the method adopted here to study the phase transition pathways is not restricted to the system under consideration and provides a robust way of probing phase transition pathways involving any two condensed phases at both equilibrium and out-of-equilibrium conditions.

Fetal Right Heart Strain in Systemic Right Ventricles and Impact on Post-surgical Outcomes.

Patients with hypoplastic left heart syndrome (HLHS) and its variants rely on the right ventricle (RV) to provide cardiac output. Diminished RV systolic function has been associated with poor clinical outcomes in this population. Echocardiographic strain has emerged as a useful method to quantify RV deformation. We aimed to describe fetal strain in the systemic RV and further investigate if there was any correlation with clinical outcomes. We conducted a retrospective, single center study evaluating strain in fetuses with systemic RV. We measured fetal RV global longitudinal strain (GLS) and segmental strain using Tomtec 2D speckle tracking software and compared these findings to controls. Fifty patients with systemic RV were included in the study group with controls matched one to one for each echocardiogram. Ten patients died after first-stage palliation. GLS was reproducible, with interobserver ICC 0.82. There was no statistically significant difference in GLS among different HLHS subtypes. Abnormal GLS did not correlate with worse clinical outcomes. GLS in systemic RVs in the 2nd and 3rd trimester did not vary significantly throughout gestation and did not correlate with clinical outcomes. Risk factors associated with poor outcome were mainly postnatal. Multi-centered studies are needed to determine if these findings hold true in a larger sample size.

Prevalence and risk factors for chronic pulmonary aspergillosis in chronic obstructive pulmonary disease patients with acute exacerbations.

Chronic obstructive pulmonary disease (COPD) patients often experience acute exacerbations requiring hospitalization. Recently, attention has focused on Aspergillus sensitization in the airways of these COPD patients. This study aimed to assess the prevalence of chronic pulmonary aspergillosis (CPA) in COPD patients with acute exacerbations and identify associated risk factors. A cross-sectional descriptive study was conducted at the Jawaharlal Institute of Postgraduate Medical Education and Research from January 2021 to June 2022. Sixty-one COPD patients presenting with acute exacerbations were included. Demographic details, blood investigations, and sputum examinations were performed for all patients. A high-resolution computed tomography thorax was conducted for eligible patients. The prevalence of CPA among patients with an acute exacerbation of COPD was found to be 9.8%, with chronic cavitary pulmonary aspergillosis being the most common presentation (50%). Among post-tubercular COPD patients, the prevalence of CPA was significantly higher at 22.7%. Hemoptysis (p<0.001) and a previous history of tuberculosis (p=0.008) were associated with Aspergillus sensitization. This study highlights the substantial prevalence of CPA in COPD patients with acute exacerbations, particularly in those with a history of tuberculosis. Early recognition and targeted management of CPA in COPD patients may improve outcomes and reduce hospitalization rates. Further large-scale multi-center studies are needed to validate these findings and comprehensively address the impact of CPA on all COPD patients.

Neuroprotective responses of quercetin in regulation of biochemical, structural, and neurobehavioral effects in 28-day oral exposure of iron in rats.

BACKGROUND: Iron is one of the essential metals that functions as a cofactor in various biological cascades in the brain. However, excessive iron accumulation in the brain may lead to neurodegeneration and may show toxic effects. Quercetin, a pigment flavonoid compound, has been proven to be a potent antioxidant and anti-inflammatory that can inhibit lipid peroxidation during metal-induced neurotoxicity. Although iron-induced neuroinflammation and neurodegeneration have been reported in many studies, but the proof for its exact mechanisms needs to be explored. PURPOSE: The key target of the study was to explore the neuroprotective effect of quercetin after oral exposure of iron in rats and explore its underlying molecular mechanisms. RESULTS: The outcomes of the study have shown that oral exposure to ferrous sulfate may modulate behavioral paradigms such as locomotor activity, neuromuscular coordination, and increased anxiety level. The pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), apoptotic protein (caspase 3), beta-amyloid and phosphorylated tau were found to be increased on iron exposure. Also, the expressions of ferritin heavy and light chain, BACE-1 and GFAP expressions were altered. These behavioral, structural, and biochemical alterations in the brain were significantly and dose-dependently reversed by treatment with quercetin. CONCLUSION: The current study provides a fundamental understanding of molecular signaling pathways, and structural proteins implicated in iron-induced neurotoxicity along with the ameliorative effects of quercetin.

Reactivation of varicella zoster virus following trigeminal schwannoma resection.

Varicella zoster is found exclusively in humans. Infected people with this virus result in chickenpox followed by dormant virus within neural ganglia. This dormant virus, once activated, may affect any ganglia or nerves of the body but most commonly involves the thoracic, cervical and trigeminal nerves in decreasing order of frequency. We review three such cases in which manipulation of the trigeminal ganglion resulted in reactivation of varicella at homologous operative sites. Each patient underwent surgeries in which the trigeminal ganglion was manipulated for the resection of trigeminal schwannoma under a microscope through various approaches. All three patients developed reactivation of varicella at homologous operative sites. A thorough history of chickenpox infection should be taken in patients who are undergoing surgeries for trigeminal pathology. Early diagnosis should be made once any vesicular lesions are seen with prompt treatment. Reassurance and counselling are necessary in these patients. If possible, prophylaxis may be started in all such patients. Further studies are warranted to determine the exact cause of reactivation.

Quantification of Radiomics features of Peritumoral Vasogenic Edema extracted from fluid-attenuated inversion recovery images in glioblastoma and isolated brain metastasis, using T1-dynamic contrast-enhanced Perfusion analysis.

The peritumoral vasogenic edema (PVE) in brain tumors exhibits varied characteristics. Brain metastasis (BM) and meningioma barely have tumor cells in PVE, while glioblastoma (GB) show tumor cell infiltration in most subjects. The purpose of this study was to investigate the PVE of these three pathologies using radiomics features in FLAIR images, with the hypothesis that the tumor cells might influence textural variation. Ex vivo experimentation of radiomics analysis of T1-weighted images of the culture medium with and without suspended tumor cells was also attempted to infer the possible influence of increasing tumor cells on radiomics features. This retrospective study involved magnetic resonance (MR) images acquired using a 3.0-T MR machine from 83 patients with 48 GB, 21 BM, and 14 meningioma. The 93 radiomics features were extracted from each subject's PVE mask from three pathologies using T1-dynamic contrast-enhanced MR imaging. Statistically significant (< 0.05, independent samples T-test) features were considered. Features maps were also computed for qualitative investigation. The same was carried out for T1-weighted cell line images but group comparison was carried out using one-way analysis of variance. Further, a random forest (RF)-based machine learning model was designed to classify the PVE of GB and BM. Texture-based variations, especially higher nonuniformity values, were observed in the PVE of GB. No significance was observed between BM and meningioma PVE. In cell line images, the culture medium had higher nonuniformity and was considerably reduced with increasing cell densities in four features. The RF model implemented with highly significant features provided improved area under the curve results. The possible infiltrative tumor cells in the PVE of the GB are likely influencing the texture values and are higher in comparison with BM PVE and may be of value in the differentiation of solitary metastasis from GB. However, the robustness of the features needs to be investigated with a larger cohort and across different scanners in the future.

2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide analogs as potential antagonists of Urotensin II receptor.

THE PURPOSE OF THE ARTICLE: To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile. MATERIALS AND METHODS: Structure-activity-relationship (SAR) studies on 2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in in vitro cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted in vitro profile were evaluated further in mouse pressor response model to generate the in vivo proof of concept for UII receptor antagonization. RESULTS AND CONCLUSIONS: We report herewith identification of 2-{N-[(2,4,5-trichlorophenoxy)acetyl]-N-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.

Hanbury Brown-Twiss approach for imaging through a dynamic scattering medium.

The Hanbury Brown-Twiss approach, associated with the correlation of intensity fluctuations at two different points in a wave field, unveils fundamental aspects of light. Here, we propose and experimentally demonstrate an imaging and phase recovery technique through a dynamic scattering medium using the Hanbury Brown-Twiss approach. A detailed theoretical basis is presented and verified by experimental demonstrations. To validate the application of the proposed technique, the randomness of the dynamically scattered light is exploited using temporal ergodicity for evaluating the correlation of intensity fluctuations and consequently applying it in the reconstruction of the object hidden behind the dynamic diffuser.

Smart reprograming of plants against salinity stress using modern biotechnological tools.

Climate change gives rise to numerous environmental stresses, including soil salinity. Salinity/salt stress is the second biggest abiotic factor affecting agricultural productivity worldwide by damaging numerous physiological, biochemical, and molecular processes. In particular, salinity affects plant growth, development, and productivity. Salinity responses include modulation of ion homeostasis, antioxidant defense system induction, and biosynthesis of numerous phytohormones and osmoprotectants to protect plants from osmotic stress by decreasing ion toxicity and augmented reactive oxygen species scavenging. As most crop plants are sensitive to salinity, improving salt tolerance is crucial in sustaining global agricultural productivity. In response to salinity, plants trigger stress-related genes, proteins, and the accumulation of metabolites to cope with the adverse consequence of salinity. Therefore, this review presents an overview of salinity stress in crop plants. We highlight advances in modern biotechnological tools, such as omics (genomics, transcriptomics, proteomics, and metabolomics) approaches and different genome editing tools (ZFN, TALEN, and CRISPR/Cas system) for improving salinity tolerance in plants and accomplish the goal of "zero hunger," a worldwide sustainable development goal proposed by the FAO.

Mesenchymal Stem Cell Therapy in the Treatment of Neurodegenerative Cerebellar Ataxias: a Systematic Review and Meta-analysis.

The objective of this study is to synthesise the findings of clinical studies in order to derive evidence for use of the mesenchymal stem cell (MSC) therapy in the treatment of neurodegenerative cerebellar ataxias. In order to find relevant studies for the systematic review, we searched through Medline (1985 to July 2020), PubMed and Clinical trial register. We included both single-arm and comparative studies in which MSCs were given as intervention in neurodegenerative ataxia patients at any time after the diagnosis. We used Joanna Briggs Institute (JBI) quality scale to evaluate the methodological qualities of the included studies. Our literature search obtained 81 publications. Three articles comprising a total of 47 patients were included in the meta-analysis. None of them were randomised controlled trials (RCTs). Pooled analysis noted that there was a decrease in the Berg Balance Scale (BBS)/Scale for the Assessment and Rating of Ataxia (SARA) score from pre to post assessment; however, the difference was statistically not significant (standardised mean difference (SMD) - 0.20; 95% CI - 0.78 to 0.38). No significant side effects were reported in any of the studies. We did not observe any statistically significant difference in the pooled mean difference in the International Cooperative Ataxia Rating Scale (ICARS) score between pre and post assessment in patients with ataxia after receiving the stem cells (SMD 0.36, 95% CI - 0.08 to 0.81). Our systematic review and meta-analysis concluded that MSC cell therapy appeared safe but provided insufficient evidence to support the use of MSCs to treat patients with neurodegenerative cerebellar ataxia at present. No l RCTs was available in the literature to test efficacy; therefore, well-designed RCTs are needed to ascertain the effectiveness of MSCs in patients with neurodegenerative cerebellar ataxias.

Prescription of guideline-directed medical therapies in patients with diabetes and chronic kidney disease from the CURE-CKD Registry, 2019-2020.

AIM: Guideline-directed medical therapy (GDMT) is designed to improve clinical outcomes. The study aim was to assess GDMT prescribing rates and prescribing-persistence predictors in patients with diabetes and chronic kidney disease (CKD) from the Center for Kidney Disease Research, Education, and Hope Registry. MATERIALS AND METHODS: Data were obtained from adults ≥18 years old with diabetes and CKD between 1 January 2019 and 31 December 2020 (N = 39 158). Baseline and persistent (≥90 days) prescriptions for GDMT, including angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist were assessed. RESULTS: The population age (mean ± SD) was 70 ± 14 years, and 49.6% (n = 19 415) were women. Baseline estimated glomerular filtration rate (2021 CKD-Epidemiology Collaboration creatinine equation) was 57.5 ± 23.0 ml/min/1.73 m2 and urine albumin/creatinine 57.5 mg/g (31.7-158.2; median, interquartile range). Baseline and ≥90-day persistent prescribing rates, respectively, were 70.7% and 40.4% for ACE inhibitor/ARB, 6.0% and 5.0% for SGLT2 inhibitors, and 6.8% and 6.3% for GLP-1 receptor agonist (all p < .001). Patients lacking primary commercial health insurance coverage were less likely to be prescribed an ACE inhibitor/ARB [odds ratio (OR) = 0.89; 95% confidence interval (CI) 0.84-0.95; p < .001], SGLT2 inhibitor (OR 0.72; 95% CI 0.64-0.81; p < .001) or GLP-1 receptor agonist (OR 0.89; 95% CI 0.80-0.98; p = .02). GDMT prescribing rates were lower at Providence than UCLA Health. CONCLUSIONS: Prescribing for GDMT was suboptimal and waned quickly in patients with diabetes and CKD. Type of primary health insurance coverage and health system were associated with GDMT prescribing.

HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression.

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.