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ß-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit ß (HBB) gene. In ß-thalassemia intermedia (ßTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1). In mice, DMT1 mediates normal iron absorption under physiological conditions and excessive iron absorption in pathological iron overload (e.g., hereditary hemochromatosis). Here, we hypothesized that DMT1 drives elevated iron absorption in ßTI. Accordingly, we crossed Hbbth3/+ mice, a pre-clinical model of ßTI, with intestine-specific DMT1 KO mice. Ablation of intestinal DMT1 in Hbbth3/+ mice caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia. DMT1 is thus required for iron absorption and iron loading in Hbbth3/+ mice. Based upon these outcomes, we further logically postulated that in vivo knockdown of intestinal DMT1 would mitigate iron loading in Hbbth3/+ mice. Ginger-derived, lipid nanoparticles carrying DMT1-specific (or control) siRNAs were administered by oral, intragastric gavage to 4-week-old Hbbth3/+ mice daily for 16 days. siRNA treatment reduced DMT1 expression by >80% and blunted iron loading, as indicated by significant reductions in liver iron and serum ferritin (which reflect body iron stores). These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in ßTI.

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Much of what we know about terrestrial life during the Carboniferous Period comes from Middle Pennsylvanian (~315-307 Mya) Coal Measures deposited in low-lying wetland environments1-5. We know relatively little about terrestrial ecosystems from the Early Pennsylvanian, which was a critical interval for the diversification of insects, arachnids, tetrapods, and seed plants6-10. Here we report a diverse Early Pennsylvanian trace and body fossil Lagerstätte (~320-318 Mya) from the Wamsutta Formation of eastern North America, distinct from coal-bearing deposits, preserved in clastic substrates within basin margin conglomerates. The exceptionally preserved trace fossils and body fossils document a range of vertebrates, invertebrates and plant taxa (n = 131), with 83 distinct foliage morphotypes. Plant-insect interactions include what may be the earliest evidence of insect oviposition. This site expands our knowledge of early terrestrial ecosystems and organismal interactions and provides ground truth for future phylogenetic reconstructions of key plant, arthropod, and vertebrate groups.

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Bow Hunter syndrome (BHS) is a rare disorder characterized by mechanical occlusion of the vertebral artery (VA) during neck rotation, resulting in symptomatic, transient, and positional vertebrobasilar insufficiency. We describe a case of a 76-year-old female who presented with dizziness and right ear tinnitus triggered by right head rotation. Her symptoms would immediately resolve upon returning her head to the neutral position. CT angiogram showed 80% stenosis of the left subclavian artery origin, 50%-70% stenosis of the proximal right internal carotid artery (ICA), and near occlusive stenoses of the origins of the bilateral VAs. After failing conservative management, the patient was treated with left subclavian artery stenting, followed by a right carotid endarterectomy (CEA) 6 weeks later. Follow-up at 1 month showed resolution of paroxysmal symptoms and no neurological sequelae. To our knowledge, there have not yet been reported cases of patients with concurrent BHS, subclavian artery stenosis, and carotid artery stenosis. We suggest that global revascularization via subclavian artery stenting and CEA may be considered as treatment for patients with BHS complicated by other cerebrovascular disease secondary to stenoses of the ICA and subclavian artery. This approach obviates the need for more complex surgery or endovascular intervention of the VA.

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Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with ß-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.

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INTRODUCTION: There are no guidelines or prospective studies defining the optimal surgical treatment for glioblastomas in older patients (≥70 years), for those with a limited functioning performance at presentation (Karnofsky Performance Scale ≤70) or for those with tumours in certain locations (midline, multifocal). Therefore, the decision between resection and biopsy is varied, among neurosurgeons internationally and at times even within an institution. This study aims to compare the effects of maximal tumour resection versus tissue biopsy on survival, functional, neurological and quality of life outcomes in these patient subgroups. Furthermore, it evaluates which modality would maximise the potential to undergo adjuvant treatment. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of an observational nature. Consecutive patients with glioblastoma will be treated with resection or biopsy and matched with a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients that have received adjuvant treatment with chemotherapy and radiotherapy. Secondary endpoints are (1) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months after surgery; (2) progression-free survival (PFS); (3) quality of life at 6 weeks, 3 months and 6 months after surgery and (4) frequency and severity of serious adverse events. The total duration of the study is 5 years. Patient inclusion is 4 years; follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media. TRIAL REGISTRATION NUMBER: NCT06146725.

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Optical atomic clocks1,2 use electronic energy levels to precisely keep track of time. A clock based on nuclear energy levels promises a next-generation platform for precision metrology and fundamental physics studies. Thorium-229 nuclei exhibit a uniquely low-energy nuclear transition within reach of state-of-the-art vacuum ultraviolet (VUV) laser light sources and have, therefore, been proposed for construction of a nuclear clock3,4. However, quantum-state-resolved spectroscopy of the 229mTh isomer to determine the underlying nuclear structure and establish a direct frequency connection with existing atomic clocks has yet to be performed. Here, we use a VUV frequency comb to directly excite the narrow 229Th nuclear clock transition in a solid-state CaF2 host material and determine the absolute transition frequency. We stabilize the fundamental frequency comb to the JILA 87Sr clock2 and coherently upconvert the fundamental to its seventh harmonic in the VUV range by using a femtosecond enhancement cavity. This VUV comb establishes a frequency link between nuclear and electronic energy levels and allows us to directly measure the frequency ratio of the 229Th nuclear clock transition and the 87Sr atomic clock. We also precisely measure the nuclear quadrupole splittings and extract intrinsic properties of the isomer. These results mark the start of nuclear-based solid-state optical clocks and demonstrate the first comparison, to our knowledge, of nuclear and atomic clocks for fundamental physics studies. This work represents a confluence of precision metrology, ultrafast strong-field physics, nuclear physics and fundamental physics.

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Tetraperoxo metal complexes are a category of dioxygen compounds with novel properties. One of their underconsidered applications is in direct air capture (DAC) reactions, whose study is of great interest in order to slow the effects of climate change. Through computational modeling, the present work considers a family of tetraperoxometalate complexes of the form [M(O2)4]x- that capture atmospheric CO2 to produce [MO(O2)2(CO3)]x- and O2. This reaction was experimentally documented with vanadium and serves as a model for analogous reactions with Group IV (x = 4; M = Ti, Zr, Hf), Group V (x = 3; M = V, Nb, Ta), and Group VI (x = 2; M = Cr, Mo, W) metal centers. Descriptors from density functional theory (DFT) calculations, including optimized structures, partial charges, and frontier orbital interactions, provide rationalization for predicted differences in reactivity. Of the nine complexes studied, [Ti(O2)4]4- and [W(O2)4]2-, respectively, represent the most and least efficient DAC reagents from their differing abilities to stabilize a bidentate peroxycarbonate (κ2-CO42-) intermediate in the proposed reaction mechanism.

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BACKGROUND: More than half of patients with cancer receive radiotherapy, which often requires daily treatments for several weeks. The impact of geographic and sociodemographic factors on the odds of patients with cancer being recommended radiotherapy, starting radiotherapy, and completing radiotherapy is not well understood. METHODS: This was a retrospective patient cohort study that included patients diagnosed with one of the 10 most common solid cancers from January 1, 2018, to December 31, 2021, in the National Cancer Database. The primary predictor was radial distance from a patient's home to their cancer treatment hospital. Other covariates included baseline patient characteristics (age, sex, comorbidities, metastatic disease, cancer site), sociodemographic characteristics (race, ethnicity, median income quartile, insurance status), geographic region, and facility type. The three primary outcomes were being recommended radiotherapy, starting recommended radiotherapy, and completing radiotherapy. RESULTS: Of the 3,068,919 patients included, patients living >50 miles away had lower odds of being recommended radiotherapy than those living <10 miles away. Compared to White patients, Asian and Hispanic patients had lower odds of being recommended radiotherapy, and Black patients had lower odds of starting recommended radiotherapy. Uninsured patients, those with Medicaid or Medicare, and patients in lower median income quartiles had lower odds of starting or completing radiotherapy. CONCLUSIONS: Geographic and sociodemographic factors impact access to radiotherapy at different levels in cancer care and understanding these factors could aid policymakers and practices in identifying and supporting at-risk patients.

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Feedstock variability represents a challenge in lignocellulosic biorefineries, as it can influence both lignocellulose deconstruction and microbial conversion processes for biofuels and biochemicals production. The impact of feedstock variability on microbial performance remains underexplored, and predictive tools for microbial behaviour are needed to mitigate risks in biorefinery scale-up. Here, twelve batches of corn stover were deconstructed via deacetylation, mechanical refining, and enzymatic hydrolysis to generate lignin-rich and sugar streams. These batches and their derived streams were characterised to identify their chemical components, and the streams were used as substrates for producing muconate and butyrate by engineered Pseudomonas putida and wildtype Clostridium tyrobutyricum, respectively. Bacterial performance (growth, product titers, yields, and productivities) differed among the batches, but no strong correlations were identified between feedstock composition and performance. To provide metabolic insights into the origin of these differences, we evaluated the effect of twenty-three isolated chemical components on these microbes, including three components in relevant bioprocess settings in bioreactors, and we found that growth-inhibitory concentrations were outside the ranges observed in the streams. Overall, this study generates a foundational dataset on P. putida and C. tyrobutyricum performance to enable future predictive models and underscores their resilience in effectively converting fluctuating lignocellulose-derived streams into bioproducts.

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Introduction: Exposure to harmful aerosols is of increasing public health concern due to the SARS-CoV-2 pandemic and wildland fires. These events have prompted risk reduction behaviors, notably the use of disposable respiratory protection. This project investigated whether craniofacial morphology impacts the efficiency of disposable masks (N95, KN95, surgical masks, KF94) most often worn by the public to protect against toxic and infectious aerosols. This project was registered with ClinicaltTrials.gov (NCT05388201; registration May 18, 2022). Methods: One-hundred participants (50 men, 50 women) visited the Environmental Protection Agency's Human Studies Facility in Chapel Hill, NC between 2022-2023. Craniometrics and 3D scans were used to separate participants into four clusters. Boosting and elastic net regression yielded five measurements (bizygomatic breadth, nose length, bizygomatic nasal arc, neck circumference, ear breadth) that were the best predictors of filtration efficiency based on overall model fit. Fitted filtration efficiency was quantified for each mask at baseline and when tightened using an ear-loop clip. Results: The mean unmodified mask performance ranged from 55.3% (15.7%) in the large KF94 to 69.5% (12.3%) in the KN95. Modified performance ranged from 66.3% (9.4%) in the surgical to 80.7% (12.0%) in the KN95. Clusters with larger face width and neck circumference had higher unmodified mask efficiency. Larger nose gap area and nose length decreased modified mask performance. Discussion: We identify face width, nose size, nose shape, neck circumference, and ear breadth as specific features that modulate disposable mask fit in both unmodified and modified conditions. This information can optimize guidance on respiratory protection afforded by disposable ear-loop masks.

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Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

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Pre-injury anxiety disorder may be a risk factor for poor outcomes following sportsrelated concussion. A systematic review was performed to characterize the relationship between pre-injury anxiety disorder and post-concussion symptom presentation and recovery time after sports-related concussions among children, adolescents, and young adults. A PRISMA-compliant literature search was conducted in Ovid MEDLINE, PsycINFO, EMBASE, and Scopus for articles published up to 25 January 2024. The initial query yielded 1358 unique articles. Articles that analyzed the relationship between pre-injury anxiety disorder and post-concussion symptoms and recovery time were included. A final cohort of 11 articles was extracted, comprising a total of 8390 study participants, of whom 921 had a history of pre-injury anxiety disorder. Pre-injury anxiety disorder was associated with prolonged time to return to sports activity and an increased incidence of physical, emotional, cognitive, and sleep-related symptoms. While the results of this review suggest an association between pre-injury anxiety disorder and post-concussion symptoms and recovery time, future studies should be more stringent regarding standardized anxiety disorder definitions, longitudinal assessment of post-concussion symptoms, anxiety disorder subtypes, and anxiety treatment history.

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BACKGROUND: Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. METHODS: 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. RESULTS: Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77-1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11-1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. CONCLUSIONS: EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression).Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box.

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Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this "hybrid" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.

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INTRODUCTION: Up to 90% of patients undergo inadequate resection for incidentally diagnosed T1b-T3 gallbladder cancer (GBC). We evaluated whether adjuvant therapies (ATs) are associated with prolonged overall survival (OS) for patients undergoing inadequate resection of T1b-T3 GBC. METHODS: Patients who underwent inadequate resection, defined as simple cholecystectomy, for T1b-T3, Nx-N2, and M0 GBC were identified from the National Cancer Database (2004-2016). Patient characteristics, variables associated with AT use, and OS were described using the chi-square test, multivariable logistical regression, Kaplan-Meier, and Cox proportional hazard models. RESULTS: Of 1386 patients who met inclusion criteria, most received no AT (64%), 20% received chemotherapy (CT), and 16% received chemoradiotherapy (CRT). Patients who received no AT were generally older (51% ≥ 75 y) and had no comorbidities (65% Charlson Comorbidity Index 0). Among those who received AT, CRT rather than CT, tended to be employed for patients who were older (≥75 y) or had more comorbidities (Charlson Comorbidity Index ≥1). Patients with advanced disease (T3, positive lymph nodes, or positive margins) were more likely to receive CRT. For T1b-T3 GBC, any AT was associated with prolonged median OS compared to no AT (22 months versus 15 mo, P < 0.01). Relative to no AT, CT (hazard ratio 0.76, 95% confidence interval 0.67-0.92) and CRT (0.59, 95% confidence interval 0.49-0.72) were associated with decreased risk of death. CONCLUSIONS: AT was associated with prolonged OS for patients with inadequately resected T1b-T3 GBC. CRT may have a role in treatment for patients with high-risk disease following inadequate resection of T1b-T3 GBC.

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Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

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BACKGROUND: Radiation therapy (RT) for breast cancer (BC) can result in subtle cardiac dysfunction that can occur early after treatment. In 2022, the European Society of Cardiology (ESC) published the first guidelines in cardio-oncology with a harmonized definition of cancer therapy-related cardiac dysfunction (CTRCD). The aim of this study was to evaluate CTRCD occurrence over 24 months of follow-up after RT in BC patients and to analyze the association with cardiac radiation exposure. METHODS: The prospective monocentric BACCARAT study included BC patients treated with RT without chemotherapy, aged 40-75 years, with conventional and 2D Speckle tracking echocardiography performed before RT, 6 and 24 months after RT. Based on ESC cardio-oncology guidelines, CTRCD and corresponding severity were defined with left ventricle ejection fraction and global longitudinal strain decrease, occurring at 6 or 24 months after RT. Dosimetry for whole heart, left ventricle (LV) and left coronary artery (left anterior descending and circumflex arteries (CX)) was considered to evaluate the association with CTRCD, based on logistic regressions (Odds Ratio - OR and 95% confidence interval - 95%CI). Youden index based on receiver operating characteristic curve analysis was used to identify the optimal threshold of dose-volume parameters for predicting CTRCD. RESULTS: The study included 72 BC patients with a mean age of 58 ± 8.2 years. A total of 32 (44%) patients developed CTRCD during follow-up: 20 (28%) mild CTRCD, 7 (9%) moderate CTRCD, and 5 (7%) severe CTRCD. Cardiac radiation doses were generally higher among patients with CTRCD rather than non-CTRCD. Dose-response relationships were significant for mean CX dose (OR = 2.48, 95%CI (1.12-5.51), p = 0.02) and marginally significant for V2 of LV (OR = 1.03 95%CI (1.00-1.06), p = 0.05). V2 of LV ≥ 36% and mean CX dose ≥ 1.40 Gy thresholds were determined to be optimal for predicting CTRCD. CONCLUSION: For BC patients treated with RT without chemotherapy, CTRCD can be observed in an important proportion of the population over 24 months after treatment. Left ventricle and circumflex coronary artery exposure were found to be associated with CTRCD and could be used for the prediction of such cardiotoxicity. Further research remains needed to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov Identifier- NCT02605512.

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INTRODUCTION: The field of orthopaedic surgery has disproportionately low numbers of women and underrepresented in medicine (URM) groups. Although the representation of women and URM in orthopaedics has increased over the past several years, the growth has not kept up with other surgical specialties. METHODS: This is a retrospective review of data presented by the Association of American Medical Colleges (AAMC) regarding US medical school faculty and department chair makeup in 2018 to 2022 and 2015 data from the AAMC Group on Women in Medicine and Sciences reports. Data regarding the sex and race/ethnicity of faculty and department chairs in orthopaedic surgery, a comparable surgical specialty (otolaryngology), surgery, and all medical fields were assessed. Otolaryngology was chosen as a comparable specialty because orthopaedic surgery and otolaryngology are the only two surgical specialties classified within the AAMC faculty report, separate from any medical counterpart. RESULTS: Among orthopaedic surgery, otolaryngology, surgery, and all clinical sciences, the representation of women and individuals from URM groups increased between 2015 and 2022. During this time, orthopaedic surgery had the lowest growth rate of the four groups in female faculty (+0.63%/year), URM faculty (+0.32%/year), and URM department chairs (+0.11%/year). However, orthopaedic surgery did have an increase in female department chairs (0.96%/year to 7% in 2022), similar to increases seen in surgery and all clinical sciences. DISCUSSION: The increase in representation in female and URM faculty and department chairs in orthopaedic surgery lags behind comparable fields and medicine as a whole. In addition, orthopaedic surgery had the lowest representation of female and URM faculty in 2015 and 2022. Improving the representation of female and URM orthopaedic faculty and department chairs is critical because this may encourage more diverse medical students to consider pursuing a career in the field.

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For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ± 0.4% for the free drug vs. 5.6 ± 0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ± 11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ± 16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention.