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Existing research demonstrates gender- and race/ethnicity-based inequities in college outcomes. Separately, recent research suggests a relationship between time poverty and college outcomes for student parents and online students. However, to date, no studies have empirically explored whether differential access to time as a resource for college may explain differential outcomes by gender or race/ethnicity. To address this, this study explored the relationship between time poverty, gender or race/ethnicity, and college outcomes at a large urban public university with two and four year campuses. Time poverty explained a significant proportion of differential outcomes (retention and credit accumulation) by gender and race/ethnicity. More time-poor groups also dedicated a larger proportion of their (relatively limited) discretionary time to their education, suggesting that inequitable distributions of time may contribute to other negative outcomes (e.g., reduced time for sleep, exercise, healthcare). This suggests that time poverty is a significant but understudied equity issue in higher education.

Background or Context: The COVID-19 pandemic may be considered a focusing event that has drawn greater attention to the physical and mental health of community college students. Purpose, Objective, Research Question, or Focus of Study: This study examined community college students' self-reported life stressors pre- and post-pandemic-onset to identify any reported differences, both in occurrence and in impact on course completion. Research Design: Surveys were collected after the COVID-19 pandemic onset at the City University of New York's largest community college. The 529 students enrolled in STEM subjects were asked about potentially stressful life events experienced during spring 2020 and how strongly these impacted the time or energy they had for their studies (response rate 88.2%). Conclusions or Recommendations: Students' reporting of the presence of life stressors, as well as their rating of the impact on their studies, were significantly predictive of subsequent course outcomes. However, stressors reported as beginning "prior" to the pandemic had a larger and more significant relationship with course outcomes than those reported as beginning after pandemic onset. Further, stressors were already highly prevalent prepandemic, with over three-quarters of students reporting them. Although the pandemic may have drawn attention to the existence and impact of stressors, it may simply be a focusing event that drew heightened attention to a preexisting issue. Results from this study indicate that life stress may significantly impact the outcomes of community college students even outside of pandemic conditions, suggesting that this is a critical area for community colleges to address.

Abstract Antiphospholipid syndrome (APS), cryoglobulinemia, and monoclonal gammopathies are variably accompanied by thrombotic complications. We describe a patient with recurrent skin microvascular thrombosis, APS, cryoglobulinemia, marginal zone lymphoma, and IgMκ monoclonal gammopathy, responsive to chemoimmunotherapy. The cryoglobulin fraction contained the IgMκ paraprotein, while antiphospholipid antibodies (aPL) were predominantly in the cryosupernatant. A retrospective analysis of aPL‐positive patients in our institution showed that 8.1% co‐expressed monoclonal gammopathy. These overlap patients had thrombotic complications and most had recurrences. Patients with multiple gammopathies of thrombotic significance may have several autoantibodies and constitute a high‐risk group.

The solid speciation of some radiologically important radioelements has been examined in soils sampled at the former Semipalatinsk (Nuclear) Test Site (STS) and at Kurdai, the site of a former major uranium mining operation − both situated in Kazakhstan. Specifically, the partitioning of radiostrontium, radiocaesium and plutonium has been examined using sequential extraction on selected soils from the test site, while the partitioning of radium and uranium has been evaluated in soils at Kurdai. The data show that at the STS, in general, little (if any) of the radiostrontium, radiocaesium and plutonium is in an exchangeable form, with the great bulk of the radiostrontium and radiocaesium in a strongly bound or refractory form. In the case of plutonium, the proportion in a strongly bound or refractory form varies from 40% to 95% depending on site and appears to be a function of the explosive yield involved. At the Kurdai ore deposit, less than 5% of the uranium and radium is in an exchangeable form, with some 35-60% of the uranium and the bulk of the radium in a strongly bound or residual form.

Abstract The international GEOTRACES program has been instrumental in demonstrating how marine sediments are a critical source of dissolved Fe to the world's oceans. Here, we present dissolved iron (dFe) from the GEOTRACES North Pacific GP15 section, which, alongside other sediment‐source tracers (including dissolved δ56Fe, Mn, 228Ra, and particulate Fe), allows for identification of the dFe provenance of three distinct dFe depth maxima at the Alaskan margin. Two of these (shelf and abyssal depths) are of local Alaskan sedimentary origin. The third, a mid‐depth dFe maximum with an absence of 228Ra, is an advected signal that, based on tracer data from Western Pacific GEOTRACES transects and circulation models, must be advected from sedimentary sources on the Asian margin, ∼5,000 km away. This study illustrates the importance of measuring diagnostic sedimentary tracers like radium when assigning local margins as sedimentary sources of marine trace metal budgets.

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

Abstract Nickel stable isotopes (δ60Ni) provide insight to Ni biogeochemistry in the modern and past oceans. Here, we present the first Pacific Ocean high‐resolution dissolved Ni concentration and δ60Ni data, from the US GEOTRACES GP15 cruise. As in other ocean basins, increases in δ60Ni toward the surface ocean are observed across the entire transect, reflecting preferential biological uptake of light Ni isotopes, however the observed magnitude of fractionation is larger in the tropical Pacific than the North Pacific Subtropical Gyre. Such surface ocean fractionation by phytoplankton should accumulate isotopically lighter Ni in the deep Pacific, yet we find that North Pacific deep ocean δ60Ni is similar to previously reported values from the deep Atlantic. Finally, we find that seawater dissolved δ60Ni in regions with hydrothermal input can be either higher or lower than background deep ocean δ60Ni, depending on vent geochemistry and proximity.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Understanding the dynamics of acute HIV infection can offer valuable insights into the early stages of viral behavior, potentially helping uncover various aspects of HIV pathogenesis. The standard viral dynamics model explains HIV viral dynamics during acute infection reasonably well. However, the model makes simplifying assumptions, neglecting some aspects of HIV infection. For instance, in the standard model, target cells are infected by a single HIV virion. Yet, cellular multiplicity of infection (MOI) may have considerable effects in pathogenesis and viral evolution. Further, when using the standard model, we take constant infected cell death rates, simplifying the dynamic immune responses. Here, we use four models-1) the standard viral dynamics model, 2) an alternate model incorporating cellular MOI, 3) a model assuming density-dependent death rate of infected cells and 4) a model combining (2) and (3)-to investigate acute infection dynamics in 43 people living with HIV very early after HIV exposure. We find that all models qualitatively describe the data, but none of the tested models is by itself the best to capture different kinds of heterogeneity. Instead, different models describe differing features of the dynamics more accurately. For example, while the standard viral dynamics model may be the most parsimonious across study participants by the corrected Akaike Information Criterion (AICc), we find that viral peaks are better explained by a model allowing for cellular MOI, using a linear regression analysis as analyzed by R2. These results suggest that heterogeneity in within-host viral dynamics cannot be captured by a single model. Depending on the specific aspect of interest, a corresponding model should be employed.

Hemolytic-uremic syndrome (HUS) is a rare complication of an infection with Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS), characterized by severe acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, and specific therapy is still lacking. Thrombomodulin (TM) is a multi-domain transmembrane endothelial cell protein and its N-terminal domain has been implicated in the pathophysiology of some cases of HUS. Indeed, the administration of recombinant human TM (rhTM) may have efficacy in HUS. We used a Stx-based murine model of HUS to characterize the role of the N-terminal domain of TM. We show that mice lacking that domain (TMLed (−/−)) are more sensitive to Stx, with enhanced HUS progression seen at 4 days and increased mortality at 7 days post-HUS induction. In spite of these changes, renal function was less affected in surviving Stx-challenged TMLed (−/−) mice compared to their wild-type counterparts TMLed (+/+) at 7 days. Contrary to few clinical case reports from Japan, the administration of rhTM (0.06 mg/kg) to wild-type mice (C57BL/6J) with HUS did not protect against disease progression. This overall promising, but also contradictory body of evidence, requires further systematic preclinical and clinical investigations to clarify the role of TM in HUS as a potential therapeutic strategy.

Abstract Background Congenital talipes equinovarus (clubfoot) is a common musculoskeletal anomaly, with a suspected multifactorial etiopathogenesis. Herein, we used publicly available data to ascertain liveborn infants with clubfoot delivered in Denmark during 1994–2021, and to classify co-occurring congenital anomalies, estimate annual prevalence, and compare clubfoot occurrence with maternal smoking rates, a commonly reported risk factor. Characterizing this nationwide, liveborn cohort provides a population-based resource for etiopathogenic investigations and life course surveillance. Methods This case-cohort study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,315,282 liveborn infants delivered during 1994–2021 in Denmark to Danish parents. Among these, 2,358 infants (65.1% male) were ascertained with clubfoot and classified as syndromic (co-occurring chromosomal, genetic, or teratogenic syndromes) and nonsyndromic (isolated or co-occurring multiple congenital anomalies [MCA]). Annual prevalence estimates and corresponding 95% confidence intervals (CIs) for children with nonsyndromic clubfoot were estimated using Poisson regression and compared with population-based, maternal annual smoking rates obtained from publicly available resources. Results Infants most often presented with nonsyndromic clubfoot (isolated = 88.6%; MCA = 11.4%); limb and heart anomalies were the most frequently identified MCAs. Prevalence (per 1,000 liveborn infants) was 1.52 (CI 1.45–1.58) for isolated and 0.19 (CI 0.17–0.22) for MCA clubfoot. Prevalence estimates for both isolated and MCA clubfoot remained relatively stable during the study period, despite marked decreases in population-based maternal smoking rates. Conclusions From 1994 to 2021, prevalence of nonsyndromic clubfoot in Denmark was relatively stable. Reduction in population-level maternal smoking rates did not seem to impact prevalence estimates, providing some support for the suspected multifactorial etiopathogenesis of this anomaly. This nationwide, liveborn cohort, ascertained and clinically characterized using publicly available data from the Danish Biobank Register, provides a population-based clinical and biological resource for future etiopathogenic investigations and life course surveillance.

Background: Diapers represent a unique financial burden for those with young children. Pre-pandemic, approximately one in three U.S. households with young children reported diaper need or an insufficient supply of diapers. To support this population, policymakers, clinicians, and service providers need a better understanding of the groups most commonly affected and the ways that families cope with deprivation. Methods: An online survey was administered between February and July 2021 to a national sample of U.S. caregivers of at least one child aged 0–4 years in diapers (n = 881), investigating diaper need, diaper access, and how household expenses are balanced and prioritized vis-à-vis diapers. We use bivariate and multivariable models to assess factors associated with diaper need, and examine coping strategies, tradeoffs made to purchase diapers, and how caregivers would reallocate their money if diapers were accounted for. Findings: The prevalence of diaper need (46 %) exceeded pre-pandemic estimates. Diaper need was more prevalent among Hispanic respondents, lower income respondents, cloth diaper users, those with more than one child in diapers, caretakers with depression, and those with a negative financial change in the past year. Caretakers with diaper need were more likely to utilize a range of resources to access diapers and to use diapers for longer than desired to extend their supply. Those with diaper need also made more economic tradeoffs to afford diapers and indicated that they would reallocate resources to cover other unmet basic needs if they did not have to buy diapers. Interpretation: Our results indicate elevated levels of diaper need even after the U.S. economy had largely rebounded and raise concerns that inequities in diaper access may impact families’ abilities to meet other basic needs. Diapers may be an important target for policies and interventions aimed at improving the well-being of families with young children.

Summary: The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of reactive oxygen species in promoting these lesions. Based on these results, we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.

Spring viremia of carp virus (SVCV) is a rhabdovirus that primarily infects cyprinid finfishes and causes a disease notifiable to the World Organization for Animal Health. Amphibians, which are sympatric with cyprinids in freshwater ecosystems, are considered non-permissive hosts of rhabdoviruses. The potential host range expansion of SVCV in an atypical host species was evaluated by testing the susceptibility of amphibians native to the Pacific Northwest. Larval long-toed salamanders Ambystoma macrodactylum and Pacific tree frog Pseudacris regilla tadpoles were exposed to SVCV strains from genotypes Ia, Ib, Ic, or Id by either intraperitoneal injection, immersion, or cohabitation with virus-infected koi Cyprinus rubrofuscus. Cumulative mortality was 100% for salamanders injected with SVCV, 98–100% for tadpoles exposed to virus via immersion, and 0–100% for tadpoles cohabited with SVCV-infected koi. Many of the animals that died exhibited clinical signs of disease and SVCV RNA was found by in situ hybridization in tissue sections of immersion-exposed tadpoles, particularly in the cells of the gastrointestinal tract and liver. SVCV was also detected by plaque assay and RT-qPCR testing in both amphibian species regardless of the virus exposure method, and viable virus was detected up to 28 days after initial exposure. Recovery of infectious virus from naïve tadpoles cohabited with SVCV-infected koi further demonstrated that SVCV transmission can occur between classes of ectothermic vertebrates. Collectively, these results indicated that SVCV, a fish rhabdovirus, can be transmitted to and cause lethal disease in two amphibian species. Therefore, members of all five of the major vertebrate groups (mammals, birds, reptiles, fish, and amphibians) appear to be vulnerable to rhabdovirus infections. Future research studying potential spillover and spillback infections of aquatic rhabdoviruses between foreign and domestic amphibian and fish species will provide insights into the stressors driving novel interclass virus transmission events.

Summary: Background: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. Methods: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. Findings: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. Interpretation: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. Funding: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

In-host models have been essential for understanding the dynamics of virus infection inside an infected individual. When used together with biological data, they provide insight into viral life cycle, intracellular and cellular virus–host interactions, and the role, efficacy, and mode of action of therapeutics. In this review, we present the standard model of virus dynamics and highlight situations where added model complexity accounting for intracellular processes is needed. We present several examples from acute and chronic viral infections where such inclusion in explicit and implicit manner has led to improvement in parameter estimates, unification of conclusions, guidance for targeted therapeutics, and crossover among model systems. We also discuss trade-offs between model realism and predictive power and highlight the need of increased data collection at finer scale of resolution to better validate complex models.

ABSTRACT: Background: Little is known about the distribution of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to patients participating in state medical cannabis programs. The Minnesota cannabis program requires third-party testing of products with limited formulations of cannabis for distribution to patients. Objective: To characterize the distribution of cannabis products, their CBD/THC content, and dosing among patients with qualifying conditions. Methods: This is a retrospective analysis of ∼50% of registered users receiving medical cannabis in Minnesota (June 16, 2016, to November 15, 2019). Data included formulation, CBD/THC prescribed doses, and qualifying conditions. The primary end points were calculated using daily dose and duration of use. Comparisons were made for CBD and THC total daily dose dispensed, patient age, and approved product. Nonparametric statistical tests were used (significance was set at p < 0.05). Results: A total of 11,520 patients were listed with 1 qualifying condition. The most common condition was intractable pain (60.0%). Median dispensation duration varied from 53 days (cancer) to 322 days (muscle spasms). Most (≥62.8%) patients across all qualifying conditions received both CBD and THC. Median THC dose was lower in older (≥65 years) compared with younger adults with intractable pain (p < 0.0001) and cancer patients (p = 0.0152), and the same pattern was found CBD dose with seizure (p = 0.0498) patients. For commercial products with Food and Drug Administration indications, the median CBD total daily dose was 86.9% lower than the recommended doses for patients with seizures (Epidiolex: Jazz Pharmaceuticals, Palo Alto CA) and median THC total daily dose was 65.3% (Syndros: Benuvia Manufacturing, Round Rock, TX) or 79.3% lower (Marinol: Banner Pharmacaps, Inc., High Point, NC) for cancer patients. Conclusions: A majority of patients received products containing both CBD and THC. Dosages varied by age group and were lower than recommended for conditions with Food and Drug Administration-approved products. Complex pharmacokinetics of THC and CBD, possible age-related changes in physiology, unknown efficacy, and potential for drug interactions all increase the need for monitoring of patients receiving cannabis products. (Curr Ther Res Clin Exp. 2023; 84:XXX–XXX)

Despite more focused attention in the wake of the COVID-19 pandemic, high online attrition remains both a concern and a mystery; gaps in our knowledge exist as to why students so often do not complete online courses. Pre-pandemic, and using a sample of 780 students who dropped out of fully online courses (or the same course face-to-face) from a large university system in the Northeast U.S., students were explicitly asked about their specific reasons for course withdrawal. All students enrolled in a fully online course (or a face-to-face section of the same course) at the City University of New York (CUNY) in fall 2015 were invited to take the online survey from which this study data was taken. Results indicate that there were distinct differences in the patterns of reasons given by online and face-to-face students: although the perceived quality of the instructor/instruction was deemed important to student persistence in both modalities, it seemed to be of greater importance face-to-face than online. Furthermore, issues related to time were found to be more prominent reasons for dropping for online learners than face-to-face learners. Findings from this study shed new light on the impetus for online attrition, with implications for online policy and course design in a post-pandemic era.

Background: Therapeutic trials are critical to improving outcomes for individuals diagnosed with Duchenne muscular dystrophy (DMD). Understanding predictors of clinical trial participation could maximize enrollment. Methods: Data from six sites (Colorado, Iowa, Piedmont region North Carolina, South Carolina, Utah, and western New York) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) were analyzed. Clinical trial participation and individual-level clinical and sociodemographic characteristics were obtained from medical records for the 2000–2015 calendar years. County-level characteristics were determined from linkage of the most recent county of residence identified from medical records and publicly available federal datasets. Fisher’s exact and Wilcoxon two-sample tests were used with statistical significance set at one-sided p-value (net site: 3.7–27.3%) of 358 individuals with DMD. Corticosteroids, tadalafil, and ataluren (PTC124) were the most common trial medications recorded. Fewer non-Hispanic blacks or Hispanics than non-Hispanic whites participated in clinical trials. Trial participants tended to reside in counties with lower percentages of non-Hispanic blacks. Conclusion: Understanding characteristics associated with clinical trial participation is critical for identifying participation barriers and generalizability of trial results. MD STARnet is uniquely able to track clinical trial participation through surveillance and describe patterns of participation.

The antiviral remdesivir has been approved by regulatory bodies such as the European Medicines Agency (EMA) and the US Food and Drug administration (FDA) for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose–activity relationships. Here, we employ a computational model that allows drug efficacy predictions based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby describe a drug regimen that may select for resistance. Our results differ from predictions using prodrug dose–response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in the lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend more clinical trials with dosing regimens that substantially increase the levels of RDV-TP and/or pair remdesivir with companion antivirals.

Abstract: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder initiated by antibodies to complexes between platelet factor 4 (PF4) and heparin. The risk of recurrent thromboembolism persists after heparin is cleared and platelet activation leading to release of PF4 has dissipated. We asked whether antigenic complexes between polyphosphates and PF4 released from activated platelets might intensify or sustain the prothrombotic phenotype of HIT. PF4 forms stable, ultralarge complexes with polyphosphates of various sizes, including those released from platelets, which are recognized by the HIT-like monoclonal KKO, an immunoglobulin G2bκ monoclonal heparin/PF4 binding antibody, and by human HIT antibodies. KKO helps to protect PF4/polyphosphate complexes from degradation by phosphatases. Complement is activated when HIT antibodies bind to PF4/polyphosphate complexes and PF4 reverses the inhibition of complement by polyphosphates. Polyphosphates and PF4 are stored primarily in separate granules in resting platelets, but they colocalize when the cells are activated. Platelets activated by subaggregating doses of thrombin receptor activating peptide release polyphosphates and PF4, which form antigenic complexes that allow KKO to further activate platelets in the absence of heparin and exogenous PF4. These studies suggest that thrombin- or immune complex–mediated release of endogenous antigenic PF4/polyphosphate complexes from platelets may augment the prothrombotic risk of HIT and perpetuate the risk of thrombosis after heparin has been discontinued.