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The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals 1,2 , undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics 3,4 . Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints 5 , and setpoints are patient-specific, with the typical healthy adult's nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years. Haematological setpoints reflect a deep physiologic phenotype enabling investigation of acquired and genetic determinants of haematological regulation and its variation among healthy adults. Setpoints in apparently healthy adults were associated with significant variation in clinical risk: absolute risk of some common diseases and morbidities varied by more than 2% (heart attack and stroke, diabetes, kidney disease, osteoporosis), and absolute risk of all-cause 10 year mortality varied by more than 5%. Setpoints also define patient-specific reference intervals and personalize the interpretation of subsequent test results. In retrospective analysis, setpoints improved sensitivity and specificity for evaluation of some common conditions including diabetes, kidney disease, thyroid dysfunction, iron deficiency and myeloproliferative neoplasms. This study shows CBC setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults., Competing Interests: Competing interests: Mass General Brigham submitted a provisional patent application (63/695,679) on 17 September 2024, related to diagnostic and prognostic applications of haematological setpoints that includes B.H.F., M.T.R., V.T. and J.M.H. as inventors., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Early, accurate determination of disease severity in an emergency setting is paramount for improving patient outcomes and healthcare costs. Monocyte anisocytosis, quantified as monocyte distribution width (MDW), has been shown to correspond with immune dysregulation. We hypothesize that MDW is broadly associated with illness severity related to sepsis and serious infection in children., Methods: We designed a retrospective study to analyze MDW, as measured by UniCel DxH 900 analyzer, on whole blood samples that were collected from children presenting for medical care between 4/2020-9/2022. SIRS criteria and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were calculated, and source of infection was documented. Outcomes were compared by t-test or ANOVA, and receiver operating characteristic (ROC) curves assessed accuracy of MDW in identifying sepsis in children., Results: We analyzed samples from 394 children presenting with illness to two pediatric medical centers. MDW was significantly higher in children with sepsis (28.2 ± 7.8) than children with suspected or confirmed infection who did not display signs of sepsis (21.5 ± 5.2). A ROC curve comparing MDW of children with sepsis against infected children without sepsis displayed an area under the curve of 0.78, suggesting MDW may serve as a useful tool in identifying children with sepsis., Discussion: When children present to the urgent care/emergency setting with signs of infection, MDW may serve as a prompt tool to aid clinicians in identifying those who are at high risk for severe illness and require closer monitoring/intervention compared to those who may be safely discharged home., (Copyright © 2024 by the Shock Society.)

Maternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy., Competing Interests: All authors confirm that there are no conflicts of interest pertaining to the content of the manuscript entitled: “Parathyroid Hormone-Related Peptide Induced Hypercalcemia of Pregnancy due to Mammary Hyperplasia.” All authors have no disclosures to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

No tools quantify the experience, psychological, and practical impact of receiving a diagnosis from a non-deficit perspective. Autism is increasingly late diagnosed in adulthood. The Impact of Diagnosis Scale (IODS) was initially developed for borderline personality disorder. We aimed to develop a revised version suitable for autistic adults and potentially other diagnostic groups. Following a trial of a preliminary revision, the researchers and autistic research advisors co-produced an expanded pool of 46 items, scored on 7-point Likert-type scale, within 6 hypothesized domains. Scale reduction processes were applied to data from 125 formally diagnosed autistic adults. Following iterative rounds of factor analysis using maximum likelihood estimation with Promax rotation, 22 items were retained across 4 domains to comprise the IODS-R. The IODS-R adds new understanding to the experience of receiving an autism diagnosis in adulthood. It may be useful for evaluating diagnostic services and other diagnostic groups., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To examine the accuracy of different periods of continuous glucose monitoring (CGM), hemoglobin A1c (HbA1c), and their combination for estimating mean glycemia over 90 days (AG90)., Research Design and Methods: We retrospectively studied 985 CGM periods of 90 days with <10% missing data from 315 adults (86% of whom had type 1 diabetes) with paired HbA1c measurements. The impact of mean red blood cell age as a proxy for nonglycemic effects on HbA1c was estimated using published theoretical models and in comparison with empirical data. Given the lack of a gold standard measurement for AG90, we applied correction methods to generate a reference (eAG90) that we used to assess accuracy for HbA1c and CGM., Results: Using 14 days of CGM at the end of the 90-day period resulted in a mean absolute error (95th percentile) of 14 (34) mg/dL when compared with eAG90. Nonglycemic effects on HbA1c led to a mean absolute error for average glucose calculated from HbA1c of 12 (29) mg/dL. Combining 14 days of CGM with HbA1c reduced the error to 10 (26) mg/dL. Mismatches between CGM and HbA1c >40 mg/dL occurred more than 5% of the time., Conclusions: The accuracy of estimates of eAG90 from limited periods of CGM can be improved by averaging with an HbA1c-based estimate or extending the monitoring period beyond ∼26 days. Large mismatches between eAG90 estimated from CGM and HbA1c are not unusual and may persist due to stable nonglycemic factors., (© 2024 by the American Diabetes Association.)

Vaccines are the most effective mechanism for ending the COVID-19 pandemic. However, reluctance to accept vaccines has hindered the efforts of health authorities to combat the virus. In Haiti, as of July 2021, less than 1% of the country's population has been fully vaccinated in part due to vaccine hesitancy. Our goal was to assess Haitian attitudes toward COVID-19 vaccination and investigate the primary reasons for Moderna vaccine hesitancy. We conducted a cross-sectional survey across three rural Haitian communities, in September 2021. The research team used electronic tablets to collect quantitative data from 1,071 respondents, selected randomly across the communities. We report descriptive statistics and identify variables associated with vaccine acceptance using logistic regression built using a backward stepwise approach. Among 1,071 respondents, the overall acceptance rate was 27.0% (n = 285). The most common reason for vaccine hesitancy was "concern about side effects" (n = 484, 67.1%) followed by "concern about contracting COVID-19 from the vaccine" (n = 472, 65.4%). Three-quarters of respondents (n = 817) identified their healthcare workers as their most trustworthy source for information related to the vaccine. In the bivariate analysis, male gender ( p  = .06) and no history of drinking alcohol ( p  < .001) were significantly associated with being more likely to take the vaccine. In the final reduced model, only those with a history of drinking alcohol were significantly more likely to take the vaccine (aOR = 1.47 (1.23, 1.87) p  < .001). The acceptance rate for the COVID-19 vaccine is low, and public health experts should design and strengthen vaccination campaigns to combat misinformation and public distrust.

Lay Abstract: Autistic burnout is something autistic people have been talking about for a while (see #AutBurnout and #AutisticBurnout on social media). Recently, researchers published two different definitions of autistic burnout. We wanted to test these definitions. We wanted to confirm the duration and frequency of autistic burnout. That is, how long and how often do people get autistic burnout? We surveyed 141 autistic adults who had autistic burnout. We used descriptive statistics, content analysis and reflexive thematic analysis to analyse the survey responses. Autistic adults strongly agreed with the definition published by Higgins et al. How long and how often people get autistic burnout was not clear. Participants told us they have both short and long episodes. Participants told us that autistic burnout leads to exhaustion. They needed to withdraw from being with other people. They needed to stay away from autism unfriendly places. Many had been misdiagnosed as having depression, anxiety, bipolar disorder, borderline personality disorder or other conditions. We need increased awareness of autistic burnout. Autistic people need more help. More research is needed, we need to have bigger studies to understand autistic burnout.

Lay Abstract: Autistic burnout has been talked about by autistic adults for some time on blogs and in social media. Now, research describes fatigue, exhaustion and other related symptoms experienced by autistic people. We need new ways to help identify autistic burnout. In this study, we tested a new questionnaire called the AASPIRE Autistic Burnout Measure, and we investigated things that are linked to worse autistic burnout. We also trialled a group of Autistic Burnout Severity Items that we made. Working with an autistic researcher, we made the Autistic Burnout Severity Items based on published definitions of autistic burnout. Autistic adults ( n  = 141) who had experienced autistic burnout completed an online survey. We found that autistic burnout was connected to masking and depression. The Autistic Burnout Measure tool was associated with depression but not with masking. It was not very accurate in telling apart participants who were currently experiencing burnout versus those who were reporting on their past experience. The Autistic Burnout Severity Items might have problems with subscales adding together to measure autistic burnout. More work is needed on how to measure autistic burnout. Our research and other recent studies show autistic people experience a combination of exhaustion, withdrawal and problems with their concentration and thinking. Burnout seems to be linked to the stress experienced by autistic people in their daily lives. We need more research to understand the difference between autistic burnout and other conditions and experiences. We need to develop assessment tools that can help identify this burnout.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCL shmiR , median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 10 9 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCL shmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCL shmiR vs. 61% in HU High Responders (p = 0.004). BCL shmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects., (© 2023. Springer Nature Limited.)

Examination of red blood cell (RBC) morphology in peripheral blood smears can help diagnose hematologic diseases, even in resource-limited settings, but this analysis remains subjective and semiquantitative with low throughput. Prior attempts to develop automated tools have been hampered by their poor reproducibility and limited clinical validation. Here, we present a novel, open-source machine-learning approach (denoted as RBC-diff) to quantify abnormal RBCs in peripheral smear images and generate an RBC morphology differential. RBC-diff cell counts showed high accuracy for single-cell classification (mean AUC, 0.93) and quantitation across smears (mean R2, 0.76 compared with experts, interexperts R2, 0.75). RBC-diff counts were concordant with the clinical morphology grading for 300 000+ images and recovered the expected pathophysiologic signals in diverse clinical cohorts. Criteria using RBC-diff counts distinguished thrombotic thrombocytopenic purpura and hemolytic uremic syndrome from other thrombotic microangiopathies, providing greater specificity than clinical morphology grading (72% vs 41%; P < .001) while maintaining high sensitivity (94% to 100%). Elevated RBC-diff schistocyte counts were associated with increased 6-month all-cause mortality in a cohort of 58 950 inpatients (9.5% mortality for schist. >1%, vs 4.7% for schist; <0.5%; P < .001) after controlling for comorbidities, demographics, clinical morphology grading, and blood count indices. RBC-diff also enabled the estimation of single-cell volume-morphology distributions, providing insight into the influence of morphology on routine blood count measures. Our codebase and expert-annotated images are included here to spur further advancement. These results illustrate that computer vision can enable rapid and accurate quantitation of RBC morphology, which may provide value in both clinical and research contexts., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To study the longitudinal effects of both glucocorticoids and tocilizumab, an interleukin-6 receptor inhibitor, on hemoglobin A 1c (HbA 1c ) levels during glucocorticoid tapering., Methods: We analyzed patients with complete data from the Giant Cell Arteritis Clinical Research Study (GiACTA) to investigate the impact of both glycemic and nonglycemic factors on changes in HbA 1c levels over the 52-week trial. Giant cell arteritis (GCA) patients were randomized to receive either tocilizumab or placebo in addition to glucocorticoids. We used a multivariable mixed-effects model to evaluate associations of HbA 1c level with daily glucocorticoid dose, randomization to receive tocilizumab, and red blood cell count in patients with and those without diabetes mellitus at baseline, over 52 weeks., Results: In 209 patients, the median HbA 1c level decreased by 0.50% (P < 0.01) in the group that received both tocilizumab and glucocorticoids (tocilizumab/glucocorticoid) and by 0.10% (P < 0.01) in the glucocorticoid-only group. Randomization to tocilizumab/glucocorticoid was associated with lower HbA 1c (β = -0.209% in those without diabetes, P < 0.01; β = -0.290% in those with diabetes, P = 0.23). These changes had a sizable impact on glucose tolerance classification: 42.5% of patients in the tocilizumab/glucocorticoid group improved from prediabetes status to normal, compared to only 12.5% of patients treated with glucocorticoids alone. Daily glucocorticoid dose was associated with HbA 1c level in patients with baseline diabetes (β = 0.018%/mg, P < 0.01) and those without baseline diabetes (β = 0.005%/mg, P < 0.01)., Conclusion: Tocilizumab treatment was associated with a substantial reduction in HbA 1c level, independent of glucocorticoid exposure, which may be achieved through a combination of glycemic and nonglycemic effects., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes. In sickle cell disease (SCD), blockage of intrasplenic sickled RBCs is observed in infants splenectomized due to acute splenic sequestration crisis (ASSC). This life-threatening RBC pooling and organ swelling event is plausibly triggered or enhanced by intra-tissular hypoxia. We present an oxygen-mediated spleen-on-a-chip platform for in vitro investigations of the homeostatic balance in the spleen. To demonstrate and validate the benefits of this general microfluidic platform, we focus on SCD and study the effects of hypoxia on splenic RBC retention and elimination. We observe that RBC retention by IESs and RBC-macrophage adhesion are faster in blood samples from SCD patients than those from healthy subjects. This difference is markedly exacerbated under hypoxia. Moreover, the sickled RBCs under hypoxia show distinctly different phagocytosis processes from those non-sickled RBCs under hypoxia or normoxia. We find that reoxygenation significantly alleviates RBC retention at IESs, and leads to rapid unsickling and fragmentation of the ingested sickled RBCs inside macrophages. These results provide unique mechanistic insights into how the spleen maintains its homeostatic balance between splenic RBC retention and elimination, and shed light on how disruptions in this balance could lead to anemia, splenomegaly, and ASSC in SCD and possible clinical manifestations in other hematologic diseases.

Inflammation is the physiologic reaction to cellular and tissue damage caused by trauma, ischemia, infection, and other pathologic conditions. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not well established. Here we studied inflammatory recovery from trauma, ischemia, and infection by tracking longitudinal dynamics of clinical laboratory measurements in hospitalized patients. We identified a universal recovery trajectory defined by exponential WBC decay and delayed linear growth of platelet count (PLT). Co-regulation of WBC-PLT dynamics is a fundamental mechanism of acute inflammatory recovery and provides a generic approach for identifying high-risk patients: 32x relative risk (RR) of adverse outcomes for cardiac surgery, 9x RR of death from COVID-19, 9x RR of death from sepsis, and 5x RR of death from myocardial infarction., (© 2022. The Author(s).)

Permutation invariant neural networks are a promising tool for making predictions from sets. However, we show that existing permutation invariant architectures, Deep Sets and Set Transformer, can suffer from vanishing or exploding gradients when they are deep. Additionally, layer norm, the normalization of choice in Set Transformer, can hurt performance by removing information useful for prediction. To address these issues, we introduce the "clean path principle" for equivariant residual connections and develop set norm (sn), a normalization tailored for sets. With these, we build Deep Sets++ and Set Transformer++, models that reach high depths with better or comparable performance than their original counterparts on a diverse suite of tasks. We additionally introduce Flow-RBC, a new single-cell dataset and real-world application of permutation invariant prediction. We open-source our data and code here: https://github.com/rajesh-lab/deep&#95;permutation&#95;invariant.

Background: Researchers routinely evaluate novel biomarkers for incorporation into clinical risk models, weighing tradeoffs between cost, availability, and ease of deployment. For risk assessment in population health initiatives, ideal inputs would be those already available for most patients. We hypothesized that common hematologic markers (eg, hematocrit), available in an outpatient complete blood count without differential, would be useful to develop risk models for cardiovascular events., Methods: We developed Cox proportional hazards models for predicting heart attack, ischemic stroke, heart failure hospitalization, revascularization, and all-cause mortality. For predictors, we used 10 hematologic indices (eg, hematocrit) from routine laboratory measurements, collected March 2016 to May 2017 along with demographic data and diagnostic codes. As outcomes, we used neural network-based automated event adjudication of 1 028 294 discharge summaries. We trained models on 23 238 patients from one hospital in Boston and evaluated them on 29 671 patients from a second one. We assessed calibration using Brier score and discrimination using Harrell's concordance index. In addition, to determine the utility of high-dimensional interactions, we compared our proportional hazards models to random survival forest models., Results: Event rates in our cohort ranged from 0.0067 to 0.075 per person-year. Models using only hematology indices had concordance index ranging from 0.60 to 0.80 on an external validation set and showed the best discrimination when predicting heart failure (0.80 [95% CI, 0.79-0.82]) and all-cause mortality (0.78 [0.77-0.80]). Compared with models trained only on demographic data and diagnostic codes, models that also used hematology indices had better discrimination and calibration. The concordance index of the resulting models ranged from 0.75 to 0.85 and the improvement in concordance index ranged up to 0.072. Random survival forests had minimal improvement over proportional hazards models., Conclusions: We conclude that low-cost, ubiquitous inputs, if biologically informative, can provide population-level readouts of risk.

Sickle cell disease (SCD) is characterized by sickle hemoglobin (HbS) which polymerizes under deoxygenated conditions to form a stiff, sickled erythrocyte. The dehydration of sickle erythrocytes increases intracellular HbS concentration and the propensity of erythrocyte sickling. Prevention of this mechanism may provide a target for potential SCD therapy investigation. Ionophores such as monensin can increase erythrocyte sodium permeability by facilitating its transmembrane transport, leading to osmotic swelling of the erythrocyte and decreased hemoglobin concentration. In this study, we treated 13 blood samples from patients with SCD with 10 nM of monensin ex vivo. We measured changes in cell volume and hemoglobin concentration in response to monensin treatment, and we perfused treated blood samples through a microfluidic device that permits quantification of blood flow under controlled hypoxia. Monensin treatment led to increases in cell volume and reductions in hemoglobin concentration in most blood samples, though the degree of response varied across samples. Monensin-treated samples also demonstrated reduced blood flow impairment under hypoxic conditions relative to untreated controls. Moreover, there was a significant correlation between the improvement in blood flow and the decrease in hemoglobin concentration. Thus, our results demonstrate that a reduction in intracellular HbS concentration by osmotic swelling improves blood flow under hypoxic conditions. Although the toxicity of monensin will likely prevent it from being a viable clinical treatment, these results suggest that osmotic swelling should be investigated further as a potential mechanism for SCD therapy.

Moral injury is an array of symptoms theorized to develop in response to morally injurious events, defined as events that challenge one's core moral beliefs and expectations about the self, others, and world. Recent measures of moral injury have distinguished self-directed moral injury (e.g., moral injury symptoms that emerge following the perpetration of morally injurious events) from other-directed moral injury, the symptoms of which are believed to stem from one's response to actions that others have committed (e.g., within-rank violence, failures of leadership, and acts of betrayal committed by trusted others or institutions). Using a convenience sample of 154 primarily former military women, the present study examined if other-directed moral injury symptoms (e.g., anger, betrayal, and mistrust) associated with military experience would mediate the association between military sexual harassment and mental health and substance abuse symptoms. Results demonstrated that 85.8% ( n = 127) of the of this sample of women veterans reported experiencing sexual harassment during their military service. Using a single mediation model, we further demonstrated that other-directed moral injury mediated the association between sexual harassment experience and mental health symptoms. Given the percentage of women veterans who reported sexual harassment, these results suggest that additional training for military members, and particularly, military leaders, is necessary to begin to reduce sexual harassment. In addition, mental health providers who work with current and former military members should consider how other-directed moral injury may be associated with mental health symptoms among women veterans who have experienced sexual harassment while in the military.

Characterization of blood flow rheology in hematological disorders is critical for understanding disease pathophysiology. Existing methods to measure blood rheological parameters are limited in their physiological relevance, and there is a need for new tools that focus on the microcirculation and extract properties at finer resolution than overall flow resistance. Herein, we present a method that combines microfluidic systems and powerful object-tracking computational technologies with mathematical modeling to separate the red blood cell flow profile into a bulk component and a wall component. We use this framework to evaluate differential contributions of effective viscosity and wall friction to the overall resistance in blood from patients with sickle cell disease (SCD) under a range of oxygen tensions. Our results demonstrate that blood from patients with SCD exhibits elevated frictional and viscous resistances at all physiologic oxygen tensions. Additionally, the viscous resistance increases more rapidly than the frictional resistance as oxygen tension decreases, which may confound analyses that extract only flow velocities or overall flow resistances. Furthermore, we evaluate the impact of transfusion treatments on the components of the resistance, revealing patient variability in blood properties that may improve our understanding of the heterogeneity of clinical responses to such treatments. Overall, our system provides a new method to analyze patient-specific blood properties and can be applied to a wide range of hematological and vascular disorders.

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor + (LepR + ) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Sickle cell anemia (SCA) is a disease that affects red blood cells (RBCs). Healthy RBCs are highly deformable objects that under flow can penetrate blood capillaries smaller than their typical size. In SCA there is an impaired deformability of some cells, which are much stiffer and with a different shape than healthy cells, and thereby affect regular blood flow. It is known that blood from patients with SCA has a higher viscosity than normal blood. However, it is unclear how the rigidity of cells is related to the viscosity of blood, in part because SCA patients are often treated with transfusions of variable amounts of normal RBCs and only a fraction of cells will be stiff. Here, we report systematic experimental measurements of the viscosity of a suspension varying the fraction of rigid particles within a suspension of healthy cells. We also perform systematic numerical simulations of a similar mixed suspension of soft RBCs, rigid particles, and their hydrodynamic interactions. Our results show that there is a rheological signature within blood viscosity to clearly identify the fraction of rigidified cells among healthy deformable cells down to a 5% volume fraction of rigidified cells. Although aggregation of RBCs is known to affect blood rheology at low shear rates, and our simulations mimic this effect via an adhesion potential, we show that such adhesion, or aggregation, is unlikely to provide a physical rationalization for the viscosity increase observed in the experiments at moderate shear rates due to rigidified cells. Through numerical simulations, we also highlight that most of the viscosity increase of the suspension is due to the rigidity of the particles rather than their sickled or spherical shape. Our results are relevant to better characterize SCA, provide useful insights relevant to rheological consequences of blood transfusions, and, more generally, extend to the rheology of mixed suspensions having particles with different rigidities, as well as offering possibilities for developments in the field of soft material composites.