Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages.

Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of lowering blood pressure.

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.

A deoxyviolacein-based transposon insertion vector for pigmented tracer studies.

Pigments provide a simple means to rapidly visually ascertain the quantities or presence of specific microbes in a complex community. The selection of pigment-producing colonies that are simple to differentiate from common colony phenotypes provides a high degree of certainty for the identity of pigment-tagged strains. Successful employment of pigment production is dependent on various intrinsic factors related to proper levels of gene expression and pigment production that are not always easy to predict and vary within each microbe. We have constructed a simple transposon system that incorporates the genes for the production of deoxyviolacein, a pigment produced from intracellular reserves of the amino acid tryptophan, to randomly insert these genes throughout the genome. This tool allows the user to select from many thousands of potential sites throughout a bacterial genome for an ideal location to generate the desired amount of pigment. We have applied this system to a small selection of endophytes and other model bacteria to differentiate these strains from complex communities and confirm their presence after several weeks in natural environments. We provide two examples of applications using the pigments to trace strains following introduction into plant tissues or to produce a reporter strain for extracellular nitrogen compound sensing. We recognize that this tool could have far broader utility in other applications and microbes, and describe the methodology for use by the greater scientific community.

Inflammatory Alterations to Renal Lymphatic Endothelial Cell Gene Expression in Mouse Models of Hypertension.

INTRODUCTION: Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. METHODS: We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. RESULTS: Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p<0.01), 274 significantly enriched pathways (p<0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. CONCLUSION: These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.

Global patterns and drivers of fish reproductive potential on coral reefs.

Fish fecundity scales hyperallometrically with body mass, meaning larger females produce disproportionately more eggs than smaller ones. We explore this relationship beyond the species-level to estimate the "reproductive potential" of 1633 coral reef sites distributed globally. We find that, at the site-level, reproductive potential scales hyperallometrically with assemblage biomass, but with a smaller median exponent than at the species-level. Across all families, modelled reproductive potential is greater in fully protected sites versus fished sites. This difference is most pronounced for the important fisheries family, Serranidae. When comparing a scenario where 30% of sites are randomly fully protected to a current protection scenario, we estimate an increase in the reproductive potential of all families, and particularly for Serranidae. Such results point to the possible ecological benefits of the 30 × 30 global conservation target and showcase management options to promote the sustainability of population replenishment.

Precision control of ammonium release in Azotobacter vinelandii.

The capture and reduction of atmospheric dinitrogen gas to ammonium can be accomplished through the enzyme nitrogenase in a process known as biological nitrogen fixation (BNF), by a class of microbes known as diazotrophs. The diazotroph Azotobacter vinelandii is a model organism for the study of aerobic nitrogen fixation, and in recent years has been promoted as a potential producer of biofertilizers. Prior reports have demonstrated the potential to partially deregulate BNF in A. vinelandii, resulting in accumulation and extracellular release of ammonium. In many cases, deregulation requires the introduction of transgenic genes or elements to yield the desired phenotype, and the long-term stability of these strains has been reported to be somewhat problematic. In this work, we constructed two strains of A. vinelandii where regulation can be precisely controlled without the addition of any foreign genes or genetic markers. Regulation is maintained through native promoters found in A. vinelandii that can be induced through the addition of extraneous galactose. These strains result in varied degrees of regulation of BNF, and as a result, the release of extracellular ammonium is controlled in a precise, and galactose concentration-dependent manner. In addition, these strains yield high biomass levels, similar to the wild-type A. vinelandii strain and are further able to produce high percentages of the bioplastic polyhydroxybutyrate.

Beyond the M.D.: Transdisciplinary approaches of high-volume dual degree M.D./Masters programs at U.S. allopathic medical schools.

PURPOSE: Transdisciplinarity has been described as a fusion of theories, methods, and expertise across disciplinary boundaries to address complex, global problems. This approach has coincided with an increase in US medical schools offering masters degrees along with an MD degree to equip medical students to practice in complex, interconnected health systems. This study focused on medical schools that graduate the most dual degree students per year and explored the alignment of such programs with a transdisciplinary approach. METHODS: We identified 19 allopathic medical schools that annually graduated an average of 10 or more dual-degree students from 2015-2020. We surveyed these schools and asked participants to describe the reason(s) their institutions offered dual-degree programs. Two authors coded the narrative responses from the survey. RESULTS: Responses were received from 17 of the 19 schools. The analysis of participants' responses regarding their institutions' purpose for offering dual programs revealed several themes associated with a transdisciplinary approach to training. The most common themes were expand skill sets beyond a medical degree (73%), provide opportunity for interdisciplinary collaboration (67%), expand career interest and goals (60%), develop leaders (53%), enhance residency applications (47%) and further the institution's vision and mission (45%). CONCLUSIONS: This study is the first comprehensive evaluation of MD/Masters programs in the United States that includes a summary of the medical schools with the largest dual degree programs and their reasons for offering them. The findings support the hypothesis that allopathic medical schools recognize the need for a transdisciplinary approach to prepare students for the complexities in healthcare. These programs provide students with opportunities for additional areas of expertise, leadership development, enhancement of competitiveness for residency application, and interdisciplinary collaboration. Medical schools without dual-degree programs may consider developing these programs to provide benefits to students and institutions.

A polyethylene surrogate for microbial community enrichment and characterization.

Plastic pollution is a vast and increasing problem that has permeated the environment, affecting all aspects of the global food web. Plastics and microplastics have spread to soil, water bodies, and even the atmosphere due to decades of use in a wide range of applications. Plastics include a variety of materials with different properties and chemical characteristics, with polyethylene being a dominant fraction. Polyethylene is also an extremely persistent compound with slow rates of photodegradation or biodegradation. In this study, we developed a method to isolate communities of microbes capable of biodegrading a polyethylene surrogate. This method allows us to study potential polyethylene degradation over much shorter time periods. Using this method, we enriched several communities of microbes that can degrade the polyethylene surrogate within weeks. We also identified specific bacterial strains with a higher propensity to degrade compounds similar to polyethylene. We provide a description of the method, the variability and efficacy of four different communities, and key strains from these communities. This method should serve as a straightforward and adaptable tool for studying polyethylene biodegradation.

Stick-slip unfolding favors self-association of expanded HTT mRNA.

In Huntington's Disease (HD) and related disorders, expansion of CAG trinucleotide repeats produces a toxic gain of function in affected neurons. Expanded huntingtin (expHTT) mRNA forms aggregates that sequester essential RNA binding proteins, dysregulating mRNA processing and translation. The physical basis of RNA aggregation has been difficult to disentangle owing to the heterogeneous structure of the CAG repeats. Here, we probe the folding and unfolding pathways of expHTT mRNA using single-molecule force spectroscopy. Whereas normal HTT mRNAs unfold reversibly and cooperatively, expHTT mRNAs with 20 or 40 CAG repeats slip and unravel non-cooperatively at low tension. Slippage of CAG base pairs is punctuated by concerted rearrangement of adjacent CCG trinucleotides, trapping partially folded structures that readily base pair with another RNA strand. We suggest that the conformational entropy of the CAG repeats, combined with stable CCG base pairs, creates a stick-slip behavior that explains the aggregation propensity of expHTT mRNA.

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study.

BACKGROUND: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. METHODS: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. FINDINGS: Insomnia was associated with higher risk of endometrioid EOC (OR = 1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR = 0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR = 1.45, 95% CI 1.13-1.87) and HGSOC (OR = 1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR = 2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. INTERPRETATION: This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.

BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.

MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.

PURPOSE: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context. EXPERIMENTAL DESIGN: Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed exvivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry. RESULTS: We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs. CONCLUSIONS: Our study supports the concept that MYC represents an Achilles' heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.

Results of Randomized Controlled Trials of Platelet-Rich Plasma in Lower-Extremity Tendinopathy Are Not Influenced by Industry Sponsorship.

PURPOSE: To determine whether industry affiliation influences the results of randomized controlled trials (RCTs) studying the use of platelet-rich plasma (PRP) for the treatment of patellar or Achilles tendinopathy. METHODS: The PubMed, Scopus, Cochrane, and MEDLINE databases were searched in July 2023 for RCTs investigating PRP for the treatment of patellar or Achilles tendinopathy published between 2009 and July 2023. Industry affiliation was determined by analyzing each study's funding or conflict-of-interest section. Author disclosures were searched in the American Academy of Orthopaedic Surgeons disclosure database and the Centers for Medicare & Medicaid Services open payments database. An industry-affiliated (IA) designation was given if an author had a relevant disclosure or if the company that funded the study manufactured PRP. Otherwise, a non-industry-affiliated (NIA) designation was given. Fisher exact analysis was used to determine whether PRP had a favorable effect, no significant effect, or an unfavorable effect on outcome. RESULTS: Analysis was performed on 22 studies (10 IA and 12 NIA), with 17 studies (77.3%) reporting a conflict of interest or funding for the research, 4 (18.2%) reporting no conflict of interest, and 1 (4.5%) with no reporting. Of the 22 included studies, 8 (36.4%) reported favorable outcomes regarding PRP use and 14 (63.6%) reported no significant effect. Favorable outcomes were found in 4 of the 10 IA studies (40.0%), whereas no significant effect was reported in 6 (60.0%). The 12 NIA studies included 4 (33.3%) with favorable results and 8 (66.7%) with no significant effect. The comparison between industry affiliation and results reported was not statistically significant (P > .999). CONCLUSIONS: The results of RCTs evaluating the use of PRP in lower-extremity tendinopathy were not influenced by industry sponsorship. CLINICAL RELEVANCE: Most biomedical research is funded through industry sponsorship. Although this relation is necessary as technologies are developed, it is important to scrutinize studies for evidence of industry bias to understand how this bias may be affecting study results published in the literature.

Molecular templating of layered halide perovskite nanowires.

Layered metal-halide perovskites, or two-dimensional perovskites, can be synthesized in solution, and their optical and electronic properties can be tuned by changing their composition. We report a molecular templating method that restricted crystal growth along all crystallographic directions except for [110] and promoted one-dimensional growth. Our approach is widely applicable to synthesize a range of high-quality layered perovskite nanowires with large aspect ratios and tunable organic-inorganic chemical compositions. These nanowires form exceptionally well-defined and flexible cavities that exhibited a wide range of unusual optical properties beyond those of conventional perovskite nanowires. We observed anisotropic emission polarization, low-loss waveguiding (below 3 decibels per millimeter), and efficient low-threshold light amplification (below 20 microjoules per square centimeter).

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Minimizing Structural Heterogeneity in DNA Self-Assembled Dye Templating via DNA Origami-Tuned Conformations.

With recent advances in DNA-templated dye aggregation for leveraging and engineering molecular excitons, a need exists for minimizing structural heterogeneity. Holliday Junction complexes (HJ) are commonly used to covalently template dye aggregates on their core; however, the global conformation of HJ is detrimentally dynamic. Here, the global conformation of the HJ is selectively tuned by restricting its position and orientation by using a sheet-like DNA origami construct (DOC) physisorbed on glass. The HJ arms are fixed with four different designed interduplex angles (IDAs). Atomic force microscopy confirmed that the HJs are bound to the surface of DOC with tuned IDAs. Dye orientation distributions were determined by combining dipole imaging and super-resolution microscopy. All IDAs led to dye orientations having dispersed distributions along planes perpendicular to the HJ plane, suggesting that stacking occurred between the dye and the neighboring DNA bases. The dye-base stacking interpretation was supported by increasing the size of the core cavity. The narrowest IDA minimizes structural heterogeneity and suggests dye intercalation. A strong correlation is found between the IDA and the orientation of the dye along the HJ plane. These results show that the HJ imposes restrictions on the dye and that the dye-DNA interactions are always present regardless of global conformation. The implications of our results are discussed for the scalability of dye aggregates using DNA self-assembly. Our methodology provides an avenue for the solid-supported single-molecule characterization of molecular assemblies templated on biomolecules─such as DNA and protein templates involved in light-harvesting and catalysis─with tuned conformations and restricted in position and orientation.

Central cone design demonstrates greater micromotion compared to keel design in cementless tibial baseplates: A biomechanical analysis.

PURPOSE: The purpose of this study was to compare micromotion of two new cementless tibial baseplates to a cementless design with well-published clinical success. METHODS: Three cementless tibial baseplate designs (fixed-bearing [FB] with keel and cruciform pegs, rotating-platform with porous central cone and pegs, FB with cruciform keel and scalloped pegs) were evaluated on sawbone models. Loading was applied to the baseplate at a rate of 1 Hz for 10,000 cycles, which represents 6-8 weeks of stair descent. This time frame also represents the approximate time length for the induction of biologic fixation of cementless implants. Compressive and shear micromotion at the sawbone-implant interface were measured. RESULTS: At the end of the loading protocol, the central cone rotating-platform design exhibited greater micromotion at the anterior (p < 0.001), posterior (p < 0.001) and medial locations (p = 0.049) compared to the other two implants. The central cone design also exhibited greater translational micromotion in the sagittal plane at the medial (p = 0.001) and lateral locations (p = 0.034) and in the coronal plane anteriorly (p = 0.007). CONCLUSION: The cementless central cone rotating-platform baseplate demonstrated greater vertical and translational micromotion compared to the two FB baseplates with a keel underloading. This may indicate lower initial mechanical stability in implants without a keel, which possibly affects osseointegration. The implication of this is yet unknown and requires further long-term clinical follow-up to correlate these laboratory findings. LEVEL OF EVIDENCE: V (biomechanical study).

Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study.

BACKGROUND: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.