Early State Research Articles

Evaluating Institutional Success: Regional Water Agreements with Tribal Nations

Abstract Since the early 1900s, U.S. national, tribal, and state institutions have been addressing conflicts over water entitlements of Native American tribes. The resulting regional water agreements encompass ensuring tribal access to water, defining entitlements for reliable future access, and providing environmental and financial benefits. Identifying approaches to evaluating institutional success in these regional water agreements is useful for effectively addressing current and future water disputes. This article discusses characteristics of eight water agreements that have occurred in the Southwestern United States, applying five economic criteria to evaluate success. The evaluation suggests that newer agreements perform better on the economic criteria, implying that learning about effective agreements is occurring over time. As threats to water quality and quantity intensify worldwide, understanding what contributes to successful regional water agreements becomes increasingly urgent.

Early state socialism and eugenics: Premarital medical certificates in Czechoslovakia, East Germany, and Poland in the aftermath of World War II

The article discusses the immediate post-war persistence and subsequent rejection of eugenics in East-Central European socialist states, exploring the case of premarital medical certificates. Building our analysis on published and archival sources, we show that immediately after the war, policies formulated at the governmental level were informed by eugenic ideas in medical expertise. Premarital medical certificates were aimed at combatting contagious diseases and thus securing a healthy population. Their legal status varied: in Poland, they were formally introduced; in the Soviet Occupied Zone and East Germany, Nazi law was abolished, but local officials still advocated for the introduction of certificates; and in Czechoslovakia, medical certificates were planned but not introduced. Despite these differences, after a short period between 1949 and 1950, the attempts to put a measure into practice ended in all three countries. We argue that the communist takeover and consolidation of power played a decisive role. After 1950, premarital medical certificates were not discussed again in Czechoslovakia or East Germany; in Poland, the debate re-emerged in 1959–60 during political liberalization.

Salivary Biomarker© In Biddable Hypertension Or Early Hyperglycaemic State Associated Ischemic Dilated Cardiomyopathy Related Myocardial Vessel Constriction

Salivary Biomarker© In Biddable Hypertension Or Early Hyperglycaemic State Associated Ischemic Dilated Cardiomyopathy Related Myocardial Vessel Constriction

Metabolic syndrome is linked to most cancers incidence.

Since many people die of either cancers or cardiovascular diseases worldwide, it is important to find the clinical pitfall that provokes cardiovascular diseases and cancer overall. Since metabolic syndrome (MetS) is largely linked to cardiovascular diseases, we have come to consider that MetS, even in its early state, may prime the occurrence of cancers overall. Indeed, the importance of MetS in causing pancreatic cancer has been proved using our large medical database. We analyzed Japanese healthcare and clinical data in 2005, who were followed up until 2020 and we examined the incidence of major cancers. At the enrollment, we examined the presence or absence of MetS judged by either Japanese criteria or NCEP/ATPIII. Of 2.7 million subjects without missing data, 102,930; 200,231; 237,420; 63,435; 76,172; and 2,422 subjects suffered lung, stomach, colon, liver and prostate cancer, respectively, and myelogenous leukemia during follow-up. MetS, defined by Japanese criteria, increased (p < 0.005 each) the incidence of cancer with a hazard ratio (HR) of 1.03-1.47 for lung, stomach, colon, liver, prostate cancers, and myelogenous leukemia. According to Japanese criteria, cancer incidence in the pre-stage MetS group was comparable to the MetS group. The results were almost identical when we defined MetS using NCEP ATP III. Taken together, we conclude that MetS is linked to majority of cancers.

State and law of the Chaghadai Ulus and early Timurid state as they were seen by foreign contemporaries

Research objectives: An analysis of official documents and notes of foreign contemporaries to clarify some aspects of political and legal life of the Chaghadai Ulus and early Timurid state in the 13th– beginning of 15th centuries. Materials and methods of research: The basic materials are official documents (diplomatic correspondence), travelers’ reports and notes, diaries and memoirs of travelers from different countries of Europe and Asia who visited the Chaghadai Ulus with different missions in the analyzed period as well as some official documents (diplomatic correspondence) between foreign and Mongol rulers. The methods of research are formal and historical legal research of historical documents, comparative legal analysis as well as historical approach in general. Scientific novelty: The state structure and legal relations in the Chaghadai Ulus and early Timurid state still have not been objects of special research. The author proposes to use works of foreign contemporaries as a tool to clarify some questions of political and legal life in the Chaghadaid state, finding similarities with other Chinggisid states and specific features of the region, its traditions, etc. Results of the research: The information of the analyzed historical documents, naturally, doesn’t allow one to reconstruct all aspects of political structure of Chaghadai Ulus and early Timurid state and their legal system in general, but adds valuable details to the information of other sources on history of this state – that is, historical chronicles (mainly of Timurid age) and legal monuments (khans’ yarliks and other official documents of the ulus). At that, we cannot ignore the fact that the Chaghadai Ulus before Timur was not considered as a full and authoritative member of international relations which is why contemporaries paid more attention to other Chinggisid states: The Golden Horde, Ilkhanate, Yuan Empire. However, the analysis of contemporaries’ notes could stimulate scholars to study some specific aspects of the Chaghadai Ulus’ history which were not researched before.

Research on the Spatial–Temporal Distribution and Morphological Characteristics of Ancient Settlements in the Sichuan Basin

An investigation into the spatial–temporal distribution characteristics of ancient settlements and their relationship with the environment in the Sichuan Basin can enhance our understanding of the evolution of the regional human–land relationship. Utilizing kernel density analysis by GIS, this paper obtained the spatial distribution characteristics of 1100 settlements in the Neolithic, Shang–Zhou, and Qin to Southern Dynasties periods. Subsequently, a GIS spatial analysis was performed to examine the distribution of these settlements in relation to the natural environment, focusing on four aspects: elevation, slope, aspect, and water buffer zone. The results demonstrate that: (1) The distribution of settlements from the Neolithic to the Southern Dynasties has expanded from the Chengdu Plain in the west and the Xiajiang Area in the east to the hilly areas in the center. (2) The settlements in the Neolithic and Shang–Zhou periods are predominantly located at elevations between 300–600 m, slopes between 0–3°, aspects between 135–225°, distances to rivers between 0–1000 m, and soil choice on Luvisols, Cambisols, Regosols, and Anthrosols. The influence of aspect on settlements during the Qin–Southern Dynasties period was notably reduced. The settlements mainly grow in the Chengdu Plain and the smaller plains along the river from the Neolithic to the Southern Dynasties in the Sichuan Basin. (3) The emergence and advancement of primitive agriculture, the construction of early water conservancy facilities, commercial and trade exchanges, and the establishment of regimes led to a shift from a double core to a more dispersed distribution in the Sichuan Basin from the Neolithic to the Southern Dynasties periods. The evolution of settlements reflects the adaption and competition of the residents to the natural environment in the Sichuan Basin. Furthermore, it provides insights into the complex social development in the region, ranging from the formation of early states to the establishment of the Qin and Han Empires.

Inhibition of PI3Kγ/δ signaling promotes an early memory state in CAR T cells and enhances their in vivo persistence and efficacy

Inhibition of PI3Kγ/δ signaling promotes an early memory state in CAR T cells and enhances their in vivo persistence and efficacy

LineageVAE: reconstructing historical cell states and transcriptomes toward unobserved progenitors.

Single-cell RNA sequencing (scRNA-seq) enables comprehensive characterization of the cell state. However, its destructive nature prohibits measuring gene expression changes during dynamic processes such as embryogenesis or cell state divergence due to injury or disease. Although recent studies integrating scRNA-seq with lineage tracing have provided clonal insights between progenitor and mature cells, challenges remain. Because of their experimental nature, observations are sparse, and cells observed in the early state are not the exact progenitors of cells observed at later time points. To overcome these limitations, we developed LineageVAE, a novel computational methodology that utilizes deep learning based on the property that cells sharing barcodes have identical progenitors. LineageVAE is a deep generative model that transforms scRNA-seq observations with identical lineage barcodes into sequential trajectories toward a common progenitor in a latent cell state space. This method enables the reconstruction of unobservable cell state transitions, historical transcriptomes, and regulatory dynamics at a single-cell resolution. Applied to hematopoiesis and reprogrammed fibroblast datasets, LineageVAE demonstrated its ability to restore backward cell state transitions and infer progenitor heterogeneity and transcription factor activity along differentiation trajectories. The LineageVAE model was implemented in Python using the PyTorch deep learning library. The code is available on GitHub at https://github.com/LzrRacer/LineageVAE/.

Association between Multi-Domain Lifestyle and Objective Cognitive Impairment in Elderly People with SCD and MCI in Chinese Communities.

Controlling the lifestyle associated with dementia risk can delay the process of cognitive decline. Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early states in the development of dementia and are also the window period for early intervention in dementia. The purpose of this study was to explore the association between multi-domain lifestyle and objective cognitive impairment in elderly people with SCD and MCI in Chinese communities and to provide reference for effective implementation of precise health management measures to reduce the risk of dementia. A total of 265 middle-aged and elderly volunteers recruited from the community were divided into SCD group (107 cases), MCI group (80 cases), and healthy control (HC) group (78 cases). All participants received clinical interview, examination, and cognitive assessments. The total Dementia Risk Reduction Lifestyle Scale (DRRLS) scores in the HC, SCD, and MCI groups [110.00 (11.25) vs. 101.00 (10.00) vs. 79.50 (20.75)] exhibited statistically significant differences among them. The total score of the DRRLS showed a significant negative correlation with the Trail-Making Test (TMT), and significant positive correlations with both the Verbal Fluency Test (VFT) and Auditory Verbal Learning Test (AVLT) scores (p < 0.05). After adjusting for confounding factors, such as age and years of education, multiple linear regression analysis revealed several points. In the SCD group, brain-strengthening exercise and interpersonal relationship scores were negatively correlated with TMT scores (β = -11.257, -15.077; all p < 0.05), while health responsibility, smoking control behavior, and interpersonal relationship scores were positively correlated with AVLT scores (β = 0.485, 0.344, and 0.406; all p < 0.05). In the MCI Group, brain-strengthening exercise, brain-healthy diet, and interpersonal relationship were negatively correlated with TMT (β = -22.011, -16.206, -11.696; all p < 0.01), whereas health responsibility, mental activity, smoking control behavior, interpersonal relationship, and stress management were positively correlated with AVLT (β = 0.450, 0.435, 0.308, 0.256, 0.607; all p < 0.05). In Chinese communities, the unhealthy lifestyle of elderly individuals with SCD and MCI is significantly associated with cognitive function impairment. The greater their unhealthy lifestyle habits, the more pronounced the scope and severity of cognitive function impairment becomes. Furthermore, different dimensions of lifestyle have varying impacts on cognitive domains.

Development, evaluation and application of propidium monoazide (PMA) based methodologies on viable cell quantification of Pediococcus acidilactici in rice noodles products

Pediococcus acidilactici provides a special taste during dough fermentation, but its improper presence will accelerate the spoilage of rice noodles products. In this study, propidium monoazide (PMA) based methodologies on viable cells quantification of P. acidilactici were developed, evaluated and applied in rice noodles products. Prior to qPCR and RT-qPCR detection, PMA treatment was included to effectively remove the residual DNA from membrane-compromised (dead) cells. Firstly, considering the influence of food component and PMA on qPCR result determination, 4 standard curves corresponding Ct value to P. acidilactici cell number were established in 4 different rice noodle products, respectively. The 4 standard curves were subsequently applied for viable cell quantification of P. acidilactici. Secondly, mimicking the storage conditions of rice noodles products and growth states of P. acidilactici, planktonic and biofilm (early, mediate, mature) cells in 4 types of rice noodles products stored at −20 °C and 4 °C were taken into consideration to evaluate the efficiency of PMA-qPCR for viable cell quantification. Thirdly, stress response gene expression in P. acidilactici was monitored by PMA-RT-qPCR and compared with culturable and viable cell number quantification. The PMA-qPCR method with specific standard curves for 4 types of rice noodle products was applicable for viable cell quantification of P. acidilactici in planktonic and biofilm (early, mediate, and mature) states. The planktonic and biofilm cells of P. acidilactici maintained high and stable in both culturable and viable cell number in different growth states, rice noodles products, and low temperature conditions, but acquired significantly different gene expression levels. The findings provided viable cells quantification methods and an alarm for P. acidilactici contamination risk in instant rice noodles products.

Structural transition of GP64 triggered by a pH-sensitive multi-histidine switch

The fusion of viruses with cellular membranes is a critical step in the life cycle of enveloped viruses. This process is facilitated by viral fusion proteins, many of which are conformationally pH-sensitive. The specifics of how changes in pH initiate this fusion have remained largely elusive. This study presents the cryo-electron microscopy (cryo-EM) structures of a prototype class III fusion protein, GP64, in its prefusion and early intermediate states, revealing the structural intermediates accompanying the membrane fusion process. The structures identify the involvement of a pH-sensitive switch, comprising H23, H245, and H304, in sensing the low pH that triggers the initial step of membrane fusion. The pH sensing role of this switch is corroborated by assays of cell-cell syncytium formation and dual dye-labeling. The findings demonstrate that coordination between multiple histidine residues acts as a pH sensor and activator. The involvement of a multi-histidine switch in viral fusion is applicable to fusogens of human-infecting thogotoviruses and other viruses, which could lead to strategies for developing anti-viral therapies and vaccines.

Patterns of early post-disturbance reorganization in Central European forests.

Disturbances catalyse change in forest ecosystems, and a climate-driven increase in disturbance activity could accelerate forest reorganization. Here, we studied post-disturbance forests after the biggest pulse of tree mortality in Central Europe in at least 170 years, caused by drought and bark beetle (Scolytinae) outbreaks in 2018-2020. Our objectives were to characterize the early state of tree regeneration after mortality, quantify patterns of reorganization relative to undisturbed reference conditions and assess how management and patch size affect forest reorganization after disturbance. We surveyed 1244 plots in 120 patches under managed (salvage-logged, often planted) and unmanaged (deadwood remaining on site, no planting) conditions in Germany. We found that regeneration density on disturbed sites was high (median 11 897 stems ha-1), resulting from a cohort of advance regeneration. Disturbances were strong drivers of change, with indications for resilience on only 36.3% of patches. Reassembly (i.e. a change in species composition) was the dominant pattern of reorganization (61.5%), and Picea abies forests changed most strongly. Post-disturbance management facilitated forest change, particularly promoting a change in species composition. The strength of reorganization increased with patch size. We conclude that the recent wave of tree mortality will likely accelerate forest change in Central Europe.

Effect of Age, Gender, Food Intake, Obesity, and Smoking on Serum Levels of Prolactin in Healthy Adults.

The objective of this study was to investigate the effect of age, gender, body mass index (BMI), food intake, and smoking on serum prolactin (PRL) levels among healthy adults. In total, 100 healthy adults (46 males and 54 females) aged ≥18 years were recruited. Serum PRL levels were measured after a 9 h overnight fast, 1 h postprandially (early), and 3 h postprandially (late). Mean PRL levels were significantly higher in females than males in the fasting, early, and late postprandial states. PRL levels were suppressed significantly after food intake in both genders. Mean PRL levels were significantly higher in younger individuals (<30 years) in the fasting and the early postprandial states compared to older individuals (≥30 years) and suppressed significantly after food intake in younger individuals only. Mean PRL levels were not significantly different between individuals with a normal BMI (<25 kg/m2) compared to those overweight and with obesity (BMI ≥ 25 kg/m2); however, PRL levels were significantly suppressed after food intake only in subjects with a normal BMI. Mean PRL levels did not differ significantly according to smoking status. PRL levels were suppressed significantly after food intake in nonsmokers only. Our data suggest that age, gender, and food intake should be considered when the serum PRL level is measured in clinical practice.

Reassessing the origins of Near Eastern obsidian vessels: Not as simple as “Central Anatolia”

In the 1960s, Renfrew and colleagues tested an obsidian vessel from Tepe Gawra in northern Iraq. The vessel was attributed to their “Group 1e-f” chemical type, which matched obsidian from the Acıgöl volcanic complex in central Turkey as well as unclear locations in eastern Turkey and Armenia. Renfrew and colleagues favored an attribution of the vessel to Acıgöl, and consequently, an association between obsidian vessels and central Turkey became widely held in the literature. Given the destructive nature of chemical analysis until the 21st century, obsidian vessels and fragments were almost never tested, so there were few chances to overturn or support this association. Furthermore, such vessels have attracted much attention as likely prestige objects. To consider value and meanings derived from a material’s source, however, it is crucial to have the correct identification of its origin. First I consider the available sourcing data for previously studied vessel fragments. Second I report my new source identifications for a vessel with an uncertain provenience in the Metropolitan Museum of Art, fragments from Ur, and the same vessel from Tepe Gawra tested by Renfrew and colleagues. Only the site located in south-central Turkey (Domuztepe) had polished artifact fragments from the obsidian sources of Cappadocia. For Mesopotamian (Tepe Gawra, Ur, Kenan Tepe) and Zagros (Tal-e Malyan) sites, the vessels instead derived from four sources in eastern Turkey: Sarıkamış 2, Nemrut Dağ 2, Bingöl B, and Meydan Dağ. Thus, the association between obsidian vessels and central Turkey must be abandoned, as must narratives based on this association (e.g., exchange between early states or elites in Cappadocia and Mesopotamia).

Identification and characterization of early human photoreceptor states and cell-state-specific retinoblastoma-related features.

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin, yet the developmental basis for their distinct behaviors is poorly understood. Here, we used deep full-length single-cell RNA-sequencing to distinguish post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastomagenesis. The analyses revealed early post-mitotic cone- and rod-directed populations characterized by higher THRB or NRL regulon activities, an immature photoreceptor precursor population with concurrent cone and rod gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Unexpectedly, both L/M cone and rod precursors co-expressed NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL and THRB isoforms and prematurely terminated THRB transcripts. Early L/M cone precursors exhibited successive expression of several lncRNAs along with MYCN , which composed the seventh most L/M-cone-specific regulon, and SYK , which contributed to the early cone precursors' proliferative response to RB1 loss. These findings reveal previously unrecognized photoreceptor precursor states and a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation.

Feminism, reproductive labour and the gendered welfare state in Britain’s National Insurance Act of 1911

Abstract In 1911, numerous women’s organizations, of varying political interests, mounted a campaign against the National Insurance Bill. Such opposition emerged despite feminist support for increased welfare provision in general and especially for the maternity benefit that the Bill proposed to introduce. Feminists criticized National Insurance for discriminating against women, especially its failure to recognize the economic contribution of women’s unwaged reproductive labour. They lobbied and campaigned for a series of amendments, some of which were successful. Feminist opposition to National Insurance sheds new light on an ongoing historiographical debate over the degree to which women were able to influence early welfare states prior to enfranchisement. Their activities cannot be easily contained within a framework of ‘maternalist feminism’, and call into question distinctions between ‘maternalist’/‘social’ feminism and ‘equality’ feminism, and middle-class and working-class women’s agendas. Instead, feminist campaigns around National Insurance reveal an early analysis of ‘social reproduction’ (the origins of which are usually traced back only to ‘second wave’ feminism) whereby British feminists participated in international conversations contesting the gendered definitions of work that went on to inform insurance-based welfare states across Europe.

Markerless three-dimensional gait analysis in healthy older adults: test–retest reliability and measurement error

In older adults, gait analysis may detect changes that signal early disease states, yet challenges in biomechanical screening limit widespread use in clinical or community settings. Recently, a markerless method from multi-camera video data has become accessible, making screenings less challenging. This study evaluated the test–retest reliability and measurement error of markerless gait kinematics and kinetics in healthy older adults. Twenty-nine healthy older adults performed gait analysis on two occasions, at preferred walking speed, using their everyday clothes. Lower limb angles and moments were averaged from 8 gait cycles. Integrated pointwise indices [Intraclass Correlation Coefficient (ICCA,K) and Standard Error of Measurement (SEM)] were calculated for curve data, as well as ICCA,K, and SEM [95 % confidence intervals] for selected peaks. Generally, kinematic ICCs were good (>0.75) and reasonably stable throughout the gait cycle, except for the hip kinematics during the swing phase in the sagittal plane and pelvis tilt and rotation. The integrated and peaks SEM were <2.4°. The reliability of kinetics was similar (ICC>0.75), except for the transverse hip moment and abduction peak, fluctuating more during the swing than through the stance phase. SEM were < 0.07Nm/Kg. In conclusion, these results showed good overall test–retest reliability for markerless gait kinematics and kinetics for the hip, knee, and ankle joints, moderate for the pelvis angles, and error levels of ≤5°, and SEM%≤5% for the sagittal plane. This supports this method’s use in assessing gait in healthy older adults, including kinetics, for which reliability data from markerless systems is difficult to find reported.

Transcription factor 4 is a key mediator of oncogenesis in neuroblastoma by promoting MYC activity.

Super-enhancer-associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix-loop-helix (bHLH) transcription factor 4 (TCF4; also known as E2-2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell-identity-specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome-wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP-seq) and TCF4 immunoprecipitation-mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T-box transcription factor TBX2, heart- and neural crest derivatives-expressed protein 2 (HAND2) and twist-related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F-driven gene regulatory networks that control cell cycle progression in cooperation with N-myc proto-oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c-MYC/MYCN oncogenic program that drives high-risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4-recruited factors are druggable, giving insight into potential therapies for high-risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development.

Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to-mesenchymal transition

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.

Continuum of Preshock to Classic Cardiogenic Shock in the Critical Care Cardiology Trials Network Registry

BackgroundThe prognostic implications of phenotypes along the preshock to cardiogenic shock (CS) continuum remain uncertain. ObjectivesThis study sought to better characterize pre- or early shock and normotensive CS phenotypes and examine outcomes compared to those with conventional CS. MethodsThe CCCTN (Critical Care Cardiology Trials Network) is a registry of contemporary cardiac intensive care units. Consecutive admissions (N = 28,703 across 47 sites) meeting specific criteria based on hemodynamic variables, perfusion parameters, and investigator-reported CS were classified into 1 of 4 groups or none: isolated low cardiac output (CO), heart failure with isolated hypotension, normotensive CS, or SCAI (Society of Cardiovascular Angiography and Intervention) stage C CS. Outcomes of interest were in-hospital mortality and incidence of subsequent hypoperfusion among pre- and early shock states. ResultsA total of 2,498 admissions were assigned to the 4 groups with the following distribution: 4.8% isolated low CO, 4.4% isolated hypotension, 12.1% normotensive CS, and 78.7% SCAI stage C CS. Overall in-hospital mortality was 21.3% (95% CI: 19.7%-23.0%), with a gradient across phenotypes (isolated low CO 3.6% [95% CI: 1.0%-9.0%]; isolated hypotension 11.0% [95% CI: 6.9%-16.6%]; normotensive CS 17.0% [95% CI 13.0%-21.8%]; SCAI stage C CS 24.0% [95% CI: 22.1%-26.0%]; global P < 0.001). Among those with an isolated low CO and isolated hypotension on admission, 47 (42.3%) and 56 (30.9%) subsequently developed hypoperfusion. ConclusionsIn a large contemporary registry of cardiac critical illness, there exists a gradient of mortality for phenotypes along the preshock to CS continuum with risk for subsequent worsening of preshock states. These data may inform refinement of CS definitions and severity staging.