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Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Background: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. Methods: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Results: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P =0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P =0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P =0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P =0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P =0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P =0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P =0.053) and correlated with SCI volume (ρ=0.49, P =0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Conclusions: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

Background: A rare, monogenic cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), is associated with progressive cerebral ischemia and accelerated vascular cognitive impairment, resulting in premature death. We hypothesized that low cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF), as metrics of microvascular ischemia, would predict growth of white matter lesions (WML) and other neuroimaging manifestations of cSVD. Methods: We prospectively performed sequential brain MRI in a cohort of RVCL-S participants. Pseudocontinuous arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal appearing white matter (NAWM), respectively. WMLs were manually delineated on FLAIR. WM volumes were segmented and quantified. Diffusion tensor imaging (DTI) was used to measure NAWM mean diffusivity (MD). Results: Each of 14 RVCL-S participants underwent a median of 4.5 scans (IQR 3 - 6.75) with a median of 6.5 months (IQR 5.8 - 8.6) between scans performed over 2.9 years (IQR 2.0 - 4.2). Elevated NAWM OEF from the previous MRI, but not CBF, was associated with WML growth (ρ = 0.672, p < 0.0001), WM atrophy (ρ = 0.654, p < 0.0001), and increased MD (ρ = 0.714, p < 0.0001, Figure). After adjusting for age, sex, previous WML volume, and participant, previous OEF remained an independent predictor of WML growth (β = 7.04 (1.08, 13.01), p = 0.021). NAWM OEF was not retained in the mixed models predicting WM atrophy and MD. Conclusion: We found evidence that hypoxic-ischemic physiology, as measured by elevated OEF in NAWM, independently predicted WML growth. Previous OEF was associated with WM atrophy and decrease in microstructural integrity on follow-up. This work suggests that ischemia in normal brain regions may be a harbinger of disease progression in patients with RVCL-S, an inherited cSVD. Additionally, OEF may serve as a potential predictive biomarker in sporadic cSVD.

Introduction: Metabolic demand changes throughout childhood as the brain develops, peaking in the 2 nd decade of life. Cerebral blood flow (CBF) is dynamic throughout childhood, likely in response to the increased metabolic demand of brain development. Cerebrovascular reactivity (CVR) reflects the ability to further increase CBF in response to a stimulus, such as carbon dioxide (CO 2 ). We hypothesized that gray matter oxygen metabolism (GM CMRO 2 ) is increased in younger children, corresponding to higher GM CBF and lower GM CVR. Methods: CVR was calculated as the proportional change of a subject’s MRI-measured blood oxygen level dependent signal in response to an increase in end-tidal CO 2 administered by the RespirAct® RA-MR™ device. GM CMRO 2 was calculated voxel-by-voxel as the product of GM CBF (arterial spin labeling), GM oxygen extraction fraction (asymmetric spin echo), and arterial oxygen content (= Hb х (oxygen saturation)х1.34). Univariate relationships were tested using Spearman’s correlation coefficient, and corrected for multiple comparisons. Results: GM CVR, CBF, and CMRO 2 were calculated for 15 healthy participants (ages 8-19, 7 male). GM CMRO 2 was highest in young children and decreased with age (ρ=-0.68, P=0.005), as did CBF (ρ =-0.67, P=0.006). CVR was lower in young children, increasing with age (ρ=0.58, P=0.02). However, while GM CVR correlated with CBF (ρ=-0.64, P=0.01) it did not significantly associate with CMRO 2 (ρ=-0.43, P=0.114). Conclusion: Although GM CMRO 2 and CVR both have age-related changes, CVR does not directly correlate with CMRO 2 . Rather, their relationship may be moderated through other influences on CBF, as further study will investigate. Figure: Linear fits and 95% confidence intervals of subject data, including age, GM CBF, and GM CMRO 2 , versus GM CVR. P-values are from Spearman’s test for monotonic correlation.

Background Up to 20% of patients with cerebellar infarcts will develop malignant edema and deteriorate clinically. Radiologic measures, such as initial infarct size, aid in identifying individuals at risk. Studies of anterior circulation stroke suggest that mapping early edema formation improves the ability to predict deterioration; however, the kinetics of edema in the posterior fossa have not been well characterized. We hypothesized that faster edema growth within the first hours after acute cerebellar stroke would be an indicator for individuals requiring surgical intervention and those with worse neurological outcomes. Methods Consecutive patients admitted to the neurological intensive care unit with acute cerebellar infarction were retrospectively identified. Hypodense regions of infarct and associated edema, “infarct–edema”, were delineated by using ABC/2 for all computed tomography (CT) scans up to 14 days from last known well. To examine how rate of infarct–edema growth varied across clinical variables and surgical intervention status, nonlinear and linear mixed-effect models were performed over 2 weeks and 2 days, respectively. In patients with at least two CT scans, multivariable logistic regression examined clinical and radiological predictors of surgical intervention (defined as extraventricular drainage and/or posterior fossa decompression) and poor clinical outcome (discharge to skilled nursing facility, long-term acute care facility, hospice, or morgue). Results Of 150 patients with acute cerebellar infarction, 38 (25%) received surgical intervention and 45 (30%) had poor clinical outcome. Age, admission National Institutes of Health Stroke Scale (NIHSS) score, and baseline infarct–edema volume did not differ, but bilateral/multiple vascular territory involvement was more frequent (87% vs. 50%, p p = 0.002). Of 67 patients with at least two scans, after adjusting for baseline infarct–edema volume, vascular territory, and NIHSS, infarct–edema growth rate over the first 2 days (odds ratio 2.55; 95% confidence interval 1.40–4.65) was an independent, and the strongest, predictor of surgical intervention. Further, early infarct–edema growth rate predicted poor clinical outcome (odds ratio 2.20; 95% confidence interval 1.30–3.71), independent of baseline infarct–edema volume, brainstem infarct, and NIHSS. Conclusions Early infarct–edema growth rate, measured via ABC/2, is a promising biomarker for identifying the need for surgical intervention in patients with acute cerebellar infarction. Additionally, it may be used to facilitate discussions regarding patient prognosis.

Primary central nervous system lymphoma-ophthalmic variant (PCNSL-O) is an ocular subset of PCNSL predominantly involving subretinal pigment epithelium space, retina, and vitreous. The ophthalmic manifestations can precede, occur simultaneously, or follow other compartments of the CNS. Clinical trials have resulted in a significantly improved outcome in PCNSL patients over the past 2 decades, with a higher proportion of patients receiving frontline high dose methotrexate-based polychemotherapy regimens with curative intent; however, the current management of PCNSL-O remains controversial owing to lack of prospective data. The goals of PCNSL-O treatment are both to achieve local (ocular) control and to prevent tumor-specific mortality from further CNS involvement. Despite achieving high rates of ocular control with intravitreal agents like methotrexate and rituximab, the overall survival is poor, as 65-85% of patients eventually succumb to CNS disease. Few studies define the role of systemic chemotherapy with/without local treatment as a first line induction treatment for PCNSL-O considering limiting factors such as ocular penetration of systemically administered drugs and treatment related neurotoxicity. Also, the role of adjuvant treatment for PCNSL-O to prevent CNS progression and to improve overall survival is unknown. In this systematic review of the literature, we analyze treatment outcomes of various regimens (local, systemic, and combination) in terms of local control, CNS progression, and overall survival.

BACKGROUND AND PURPOSE: Asymmetries in the circle of Willis have been associated with several conditions, including migraines and stroke, but they may also be age-dependent. This study examined the impact of age and age-dependent changes in cerebral perfusion on circle of Willis anatomy in healthy children and adults. MATERIALS AND METHODS: We performed an observational, cross-sectional study of bright and black-blood imaging of the proximal cerebral vasculature using TOF-MRA and T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (T2-SPACE) imaging at the level of the circle of Willis in 23 healthy children and 43 healthy adults (4–74 years of age). We compared arterial diameters measured manually and cerebral perfusion via pseudocontinuous arterial spin-labeling between children and adults. RESULTS: We found that the summed cross-sectional area of the circle of Willis is larger in children than in adults, though the effect size was smaller with T2-SPACE-based measurements than with TOF-MRA. The circle of Willis is also more symmetric in children, and nonvisualized segments occur more frequently in adults than in children. Moreover, the size and symmetry of the circle of Willis correlate with cerebral perfusion. CONCLUSIONS: Our results demonstrate that the circle of Willis is different in size and symmetry in healthy children compared with adults, likely associated with developmental changes in cerebral perfusion. Further work is needed to understand why asymmetric vasculature develops in some but not all adults.

Context: Previous research suggests that several knee-specific patient-reported outcome measures have poor measurement properties. The patient-reported outcomes knee assessment tool (PROKAT) was created to improve assessment of knee-specific function. Examination of the measurement properties of this new measure is critical to determine its clinical value. Objective: Examine the measurement properties of the PROKAT. Design: Cross-sectional study. Setting: Clinical athletic training setting. Patients or Other Participants: The pilot study included 32 student-athletes (mean age = 20.78 [1.01], males = 56.30%). The full study included 203 student-athletes (mean age = 21.46 [4.64], males = 54.70%) from 3 separate institutions. The participants were recruited for both the pilot and full study using face-to-face and electronic (eg, email and social media sites) communications. Intervention(s): Evaluation of the measurement properties of the PROKAT occurred using the Rasch partial-credit model. Main Outcome Measures: Infit and outfit statistics, item step difficulties, person ability parameters, category function, item and test information functions, and Cronbach alpha. An independent samples t test was used to evaluate the differences in injured and noninjured athletes’ scores. Results: The Rasch partial-credit model analysis of pilot test items and qualitative participant feedback were used to modify the initial PROKAT. Evaluation of the revised PROKAT (32 items) indicated 27 items had acceptable model–data fit. The injured athletes scored significantly worse than the noninjured athletes (t188 = 12.89; P Conclusions: A major advantage of this study was the use of the Rasch measurement and the targeted population. Compared with alternative knee-specific patient-reported outcome measures (eg, Knee Injury Osteoarthritis Outcome Score, International Knee Documentation Committee Subjective Knee Form), the PROKAT has low ceiling effects in athletic populations. In addition, evidence suggests the measure may be capable of distinguishing between injured and noninjured athletes.

Context: Documentation of patient outcomes following injury is critical to ensure that patients are receiving the best care. Several patient-reported outcome measures (PROMs) have been developed to assess knee-related function following injury; however, there is limited data investigating the measurement properties of these instruments using Rasch model analyses. Objective: To evaluate the measurement properties of several PROMs through application of the Rasch measurement model. Design: Cross-sectional study. Setting: Clinical setting. Patients or Other Participants: A convenience sample of 160 adults (mean age = 28.08 [10.95] y; male = 38.10%) were recruited for this study. Data collected were combined with existing pilot data from an earlier study containing de-identified Knee Injury and Osteoarthritis Outcome Score (KOOS) data from 79 adults with knee injuries resulting in a total sample size of 239 adults. Intervention(s): Psychometric evaluation of the KOOS, International Knee Documentation Committee subjective knee form, and the Marx Activity Rating Scale using the Rasch partial credit model. Main Outcome Measures: Infit and outfit statistics, item step difficulties, person ability parameters, category function, and item and test information functions. Results: Large ceiling effects were present in the KOOS and International Knee Documentation Committee subjective knee form. Of the 65 items examined in this study, 35 items showed poor measurement properties. Item step difficulty for the remaining 30 items ranged from −5.45 (least difficult) to 0.57 logits (most difficult). The 5-category response options did not function well. Measurement precision decreased significantly as ability score increased beyond 0.30 logits. Conclusions: Despite their use in clinical practice, several items showed poor measurement properties. Future studies are needed to develop and evaluate novel items that are suitable for measuring knee-related function in high-functioning populations to ensure continuity of PROMs as individuals recover from injuries.

Purpose Sickle cell anemia is a blood disorder that alters the morphology and the oxygen affinity of the red blood cells. Cerebral oxygen extraction fraction measurements using quantitative BOLD contrast have been used for assessing inadequate oxygen delivery and the subsequent risk of ischemic stroke in sickle cell anemia. The BOLD signal in MRI studies relies on Δ χ do , the bulk volume susceptibility difference between fully oxygenated and fully deoxygenated blood. Several studies have measured Δ χ do for normal hemoglobin A (HbA). However, it is not known whether the value is different for sickle hemoglobin. In this study, Δ χ do was measured for both HbA and sickle hemoglobin. Methods Six sickle cell anemia patients and 6 controls were recruited. Various blood oxygenation levels were achieved through in vivo manipulations to keep the blood close to its natural state. To account for the differences in oxygen affinity, Hill's equations were used to translate partial pressure of oxygen to oxygen saturation for HbA, sickle hemoglobin, and fetal hemoglobin (HbF) separately. The pH and PCO2 corrections were performed. Temperature and magnetic field drift were controlled for. A multivariate generalized linear mixed model with random participant effect was used. Results Assuming that Δ χ do is similar for HbA and HbF and that Δ χ metHb is 5/4 of Δ χ do for HbA, it was found that the Δ χ do values for HbA and sickle hemoglobin were not statistically significantly different from each other. Conclusion The same Δ χ do value can be used for both types of hemoglobin in quantitative BOLD analysis.

ObjectiveTo determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD).MethodsControl participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location.ResultsOf 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g,p <0.001), increased OEF (0.35 vs 0.25,p <0.001), increased MD (0.76 vs 0.72 × 10−3mm2s−1,p= 0.005), and decreased FA (0.40 vs 0.42,p= 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19,p= 0.035), but not CBF (β = 0.00,p= 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort.ConclusionElevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

Bioconjugates are important next-generation drugs and imaging agents. Assembly of these increasingly complex constructs requires precise control over processing conditions, which is a challenge for conventional manual synthesis. This inadequacy has motivated the pursuit of new approaches for efficient, controlled modification of high-molecular-weight biologics such as proteins, carbohydrates, and nucleic acids. We report a novel, hands-free, semiautomated platform for synthetic manipulation of biomolecules using acoustically responsive microparticles as three-dimensional reaction substrates. The microfluidic reactor incorporates a longitudinal acoustic trap that controls the chemical reactions within a localized acoustic field. Forces generated by this field immobilize the microscale substrates against the continuous flow of participating chemical reagents. Thus, the motion of substrates and reactants is decoupled, enabling exquisite control over multistep reaction conditions and providing high-yield, high-purity products with minimal user input. We demonstrate these capabilities by conjugating clinically relevant antibodies with a small molecule. The on-bead synthesis comprises capture of the antibody, coupling of a fluorescent tag, product purification, and product release. Successful capture and modification of a fluorescently labeled antibody are confirmed via fold increases of 49 and 11 in the green (antibody)- and red (small-molecule dye)-channel median intensities determined using flow cytometry. Antibody conjugates assembled on acoustically responsive, ultrasound-confined microparticles exhibit similar quality and quantity to those prepared manually by a skilled technician.

Purpose Investigate the influence of tumor size by American Joint Committee on Cancer (AJCC) stage, Collaborative Ocular Melanoma Study (COMS) size, tumor largest basal diameter (LBD), and tumor thickness on prognostication by gene expression profiling (GEP) class. Design Two-center retrospective study. Participants Two hundred fifteen consecutive patients diagnosed with posterior uveal melanoma over a 5-year period who were evaluated with prognostic fine-needle aspiration biopsy at the time of primary treatment. Methods Patient demographics, tumor clinical size, AJCC stage, COMS size, GEP class, presence of metastasis, and mortality data were collected. Metastasis-free-survival (MFS) was defined as time to metastasis or death from any cause. Comparisons were made using Pearson chi-square tests or Fisher exact tests for categorical factors, and t tests or Kruskal–Wallis tests for continuous measures. Cox proportional hazards models were fit to identify whether size measurements increased the prognostic discrimination index (C-statistic). Main Outcome Measures Metastasis-free-survival. Results The average follow-up interval was 22.0 months (range, 12.0–37.0 months). Eighty-nine tumors were class 1A, 48 class 1B, and 78 class 2. Twenty-one patients developed metastatic disease detected by surveillance and confirmed by liver biopsy. Three-year MFS was 96% for class 1 and 63% for class 2. Five-year MFS was 96% for class 1 and 49% for class 2. All size measures significantly improved prognostic discrimination index by GEP class, as shown by increase in the C-statistic with addition of size variables (C-statistic 0.750 GEP alone, 0.830 GEP with AJCC [P = 0.016], 0.822 GEP with COMS [P Conclusions Incorporation of tumor size enhances the prognostic discrimination index of the GEP test in patients with posterior uveal melanoma. All size tumor parameters are equivalent in their ability to enhance GEP prognostication.

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N = 159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p 0.001), hemoglobin was not different between AC and SCA cohorts (p = 0.459). Whole brain OEF was higher in AC compared to HC (p 0.001), but lower compared to SCA (p = 0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p = 0.001) while there was no longer a difference between AC versus HC (p = 0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

We evaluated the impact of PET respiratory motion correction (MoCo) in a phantom and patients. Moreover, we proposed and examined a PET MoCo approach using motion vector fields (MVFs) from a deep-learning reconstructed short MRI scan.The evaluation of PET MoCo was performed in a respiratory motion phantom study with varying lesion sizes and tumor to background ratios (TBRs) using a static scan as the ground truth. MRI-based MVFs were derived from either 2000 spokes (MoCoMRI-assisted PET MoCo methods provided similar results to static scans across most lesions with varying TBRs in the phantom. Both MoCoAn MRI-assisted PET MoCo method was evaluated using the ground truth in a phantom study. In patients with hepatic lesions, PET MoCo images improved quantitative and qualitative metrics based on only 30-40 s of MRI motion modeling data.

Individuals with sickle cell disease (SCD) face ongoing risk of multi-organ ischemia resulting in chronic disability, frequent hospitalizations, and early mortality. The relationship between hemoglobin (Hb) S polymerization, erythrocyte sickling, and tissue ischemia has been of great interest. Oxygen off-loading and increasing deoxy-Hb concentration promote HbS polymerization, the latter, which has been linked to early erythrocyte deformation or “reversible” sickling. Eventually, severe polymerization weakens the cell membrane, leading to “irreversibly” sickled cells. Whether the degree of polymerization and the cell's morphologic state, in turn, influence oxygen binding and thus, tissue oxygen availability has been of interest, but technically challenging to study in patients. Over two decades, Wang and colleagues developed an imaging platform, photoacoustic microscopy (PAM), which offers two unique aspects compared to other intravital microscopy systems: (1) high resolution in vivo human imaging using the cuticle as the window to a highly organized vascular bed capable of imaging single capillary loops, and (2) measurements of oxy- and deoxy-Hb levels within single capillaries and single erythrocytes. In this study, we aimed to: (1) characterize capillary morphology and hemodynamic/oxygen metabolic properties in the cuticle nailbed of individuals with SCD compared to healthy controls and (2) track single erythrocytes along the capillary loop to obtain measurements of erythrocyte elongation (ellipticity index, EI) and oxygen saturation before and after tissue oxygen exchange. We hypothesized that erythrocyte EI, as an index of HbS polymerization, would be associated with decreased arteriolar oxygen saturation and/or increased oxygen extraction fraction (OEF) across capillaries—representing compromised “oxygen reserve.”