B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis.

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

Recombinant ADAMTS13 for Immune Thrombotic Thrombocytopenic Purpura.

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP.

A lithium-isotope perspective on the evolution of carbon and silicon cycles.

The evolution of the global carbon and silicon cycles is thought to have contributed to the long-term stability of Earth's climate1-3. Many questions remain, however, regarding the feedback mechanisms at play, and there are limited quantitative constraints on the sources and sinks of these elements in Earth's surface environments4-12. Here we argue that the lithium-isotope record can be used to track the processes controlling the long-term carbon and silicon cycles. By analysing more than 600 shallow-water marine carbonate samples from more than 100 stratigraphic units, we construct a new carbonate-based lithium-isotope record spanning the past 3 billion years. The data suggest an increase in the carbonate lithium-isotope values over time, which we propose was driven by long-term changes in the lithium-isotopic conditions of sea water, rather than by changes in the sedimentary alterations of older samples. Using a mass-balance modelling approach, we propose that the observed trend in lithium-isotope values reflects a transition from Precambrian carbon and silicon cycles to those characteristic of the modern. We speculate that this transition was linked to a gradual shift to a biologically controlled marine silicon cycle and the evolutionary radiation of land plants13,14.

Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease.

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

Two-million-year-old snapshots of atmospheric gases from Antarctic ice.

Over the past eight hundred thousand years, glacial-interglacial cycles oscillated with a period of one hundred thousand years ('100k world'1). Ice core and ocean sediment data have shown that atmospheric carbon dioxide, Antarctic temperature, deep ocean temperature, and global ice volume correlated strongly with each other in the 100k world2-6. Between about 2.8 and 1.2 million years ago, glacial cycles were smaller in magnitude and shorter in duration ('40k world'7). Proxy data from deep-sea sediments suggest that the variability of atmospheric carbon dioxide in the 40k world was also lower than in the 100k world8-10, but we do not have direct observations of atmospheric greenhouse gases from this period. Here we report the recovery of stratigraphically discontinuous ice more than two million years old from the Allan Hills Blue Ice Area, East Antarctica. Concentrations of carbon dioxide and methane in ice core samples older than two million years have been altered by respiration, but some younger samples are pristine. The recovered ice cores extend direct observations of atmospheric carbon dioxide, methane, and Antarctic temperature (based on the deuterium/hydrogen isotope ratio δDice, a proxy for regional temperature) into the 40k world. All climate properties before eight hundred thousand years ago fall within the envelope of observations from continuous deep Antarctic ice cores that characterize the 100k world. However, the lowest measured carbon dioxide and methane concentrations and Antarctic temperature in the 40k world are well above glacial values from the past eight hundred thousand years. Our results confirm that the amplitudes of glacial-interglacial variations in atmospheric greenhouse gases and Antarctic climate were reduced in the 40k world, and that the transition from the 40k to the 100k world was accompanied by a decline in minimum carbon dioxide concentrations during glacial maxima.

The origin of carbonate mud and implications for global climate.

Carbonate mud represents one of the most important geochemical archives for reconstructing ancient climatic, environmental, and evolutionary change from the rock record. Mud also represents a major sink in the global carbon cycle. Yet, there remains no consensus about how and where carbonate mud is formed. Here, we present stable isotope and trace-element data from carbonate constituents in the Bahamas, including ooids, corals, foraminifera, and algae. We use geochemical fingerprinting to demonstrate that carbonate mud cannot be sourced from the abrasion and mixture of any combination of these macroscopic grains. Instead, an inverse Bayesian mixing model requires the presence of an additional aragonite source. We posit that this source represents a direct seawater precipitate. We use geological and geochemical data to show that "whitings" are unlikely to be the dominant source of this precipitate and, instead, present a model for mud precipitation on the bank margins that can explain the geographical distribution, clumped-isotope thermometry, and stable isotope signature of carbonate mud. Next, we address the enigma of why mud and ooids are so abundant in the Bahamas, yet so rare in the rest of the world: Mediterranean outflow feeds the Bahamas with the most alkaline waters in the modern ocean (>99.7th-percentile). Such high alkalinity appears to be a prerequisite for the nonskeletal carbonate factory because, when Mediterranean outflow was reduced in the Miocene, Bahamian carbonate export ceased for 3-million-years. Finally, we show how shutting off and turning on the shallow carbonate factory can send ripples through the global climate system.

External validation of an artificial intelligence model for Gleason grading of prostate cancer on prostatectomy specimens.

OBJECTIVES: To externally validate the performance of the DeepDx Prostate artificial intelligence (AI) algorithm (Deep Bio Inc., Seoul, South Korea) for Gleason grading on whole-mount prostate histopathology, considering potential variations observed when applying AI models trained on biopsy samples to radical prostatectomy (RP) specimens due to inherent differences in tissue representation and sample size. MATERIALS AND METHODS: The commercially available DeepDx Prostate AI algorithm is an automated Gleason grading system that was previously trained using 1133 prostate core biopsy images and validated on 700 biopsy images from two institutions. We assessed the AI algorithm's performance, which outputs Gleason patterns (3, 4, or 5), on 500 1-mm2 tiles created from 150 whole-mount RP specimens from a third institution. These patterns were then grouped into grade groups (GGs) for comparison with expert pathologist assessments. The reference standard was the International Society of Urological Pathology GG as established by two experienced uropathologists with a third expert to adjudicate discordant cases. We defined the main metric as the agreement with the reference standard, using Cohen's kappa. RESULTS: The agreement between the two experienced pathologists in determining GGs at the tile level had a quadratically weighted Cohen's kappa of 0.94. The agreement between the AI algorithm and the reference standard in differentiating cancerous vs non-cancerous tissue had an unweighted Cohen's kappa of 0.91. Additionally, the AI algorithm's agreement with the reference standard in classifying tiles into GGs had a quadratically weighted Cohen's kappa of 0.89. In distinguishing cancerous vs non-cancerous tissue, the AI algorithm achieved a sensitivity of 0.997 and specificity of 0.88; in classifying GG ≥2 vs GG 1 and non-cancerous tissue, it demonstrated a sensitivity of 0.98 and specificity of 0.85. CONCLUSION: The DeepDx Prostate AI algorithm had excellent agreement with expert uropathologists and performance in cancer identification and grading on RP specimens, despite being trained on biopsy specimens from an entirely different patient population.

Cost analysis of care and blood transfusions in patients with Major Obstetric Haemorrhage in Ireland.

BACKGROUND AND OBJECTIVES: Obstetric haemorrhage is the leading cause of maternal morbidity and mortality worldwide. We aimed to estimate the economic cost of Major Obstetric Haemorrhage (MOH) and the cost of therapeutic blood components used in the management of MOH in Ireland. MATERIALS AND METHODS: We performed a nationwide cross-sectional study utilising top-down and bottom-up costing methods on women who experienced MOH during the years 2011-2013. Women with MOH were allocated to Diagnostic Related Groups (DRGs) based on the approach to MOH management (MOH group). The total number of blood components used for MOH treatment and the corresponding costs were recorded. A control group representative of a MOH-free maternity population was designed with predicted costs. All costs were expressed in Euro (€) using 2022 prices and the incremental cost of MOH to maternity costs was calculated. Cost contributions are expressed as percentages from the estimated total cost. RESULTS: A total of 447 MOH cases were suitable for sorting into DRGs. The estimated total cost of managing women who experienced MOH is approximately €3.2 million. The incremental cost of MOH is estimated as €1.87 million. The estimated total cost of blood components used in MOH management was €1.08 million and was based on an estimated total of 3997 products transfused. Red blood cell transfusions accounted for the highest contribution (20.22%) to MOH total cost estimates compared to other blood components. CONCLUSIONS: The total cost of caring for women with MOH in Ireland was approximately €3.2 million with blood component transfusions accounting for between one third and one half of the cost.

A modern scleractinian coral with a two-component calcite-aragonite skeleton.

One of the most conserved traits in the evolution of biomineralizing organisms is the taxon-specific selection of skeletal minerals. All modern scleractinian corals are thought to produce skeletons exclusively of the calcium-carbonate polymorph aragonite. Despite strong fluctuations in ocean chemistry (notably the Mg/Ca ratio), this feature is believed to be conserved throughout the coral fossil record, spanning more than 240 million years. Only one example, the Cretaceous scleractinian coral Coelosmilia (ca. 70 to 65 Ma), is thought to have produced a calcitic skeleton. Here, we report that the modern asymbiotic scleractinian coral Paraconotrochus antarcticus living in the Southern Ocean forms a two-component carbonate skeleton, with an inner structure made of high-Mg calcite and an outer structure composed of aragonite. P. antarcticus and Cretaceous Coelosmilia skeletons share a unique microstructure indicating a close phylogenetic relationship, consistent with the early divergence of P. antarcticus within the Vacatina (i.e., Robusta) clade, estimated to have occurred in the Mesozoic (ca. 116 Mya). Scleractinian corals thus join the group of marine organisms capable of forming bimineralic structures, which requires a highly controlled biomineralization mechanism; this capability dates back at least 100 My. Due to its relatively prolonged isolation, the Southern Ocean stands out as a repository for extant marine organisms with ancient traits.

Three Differing Methods of Treating Intraoperative Nondisplaced Calcar Fractures Demonstrate Similar Radiographic Stem Subsidence.

BACKGROUND: Several management strategies have been described to treat intraoperative calcar fractures during total hip arthroplasty (THA), including retaining the primary implant and utilizing cerclage cables (CCs) or switching the implant to one that bypasses the fracture and achieves diaphyseal fixation. However, the radiographic and clinical outcomes of these differing strategies have never been described and compared. METHODS: We retrospectively identified 50 patients who sustained an intraoperative calcar fracture out of 9,129 primary total hip arthroplasties (0.55%) performed by one of three surgeons between 2008 and 2022. Each of the three surgeons consistently employed a distinct strategy for the management of these fractures: retention of the primary metaphyseal-engaging implant and placement of CCs; exchange to a modular, tapered-fluted stem (MTF); or exchange to a fully-coated, diaphyseal-engaging stem (FC). Stem subsidence was then evaluated on standing anteroposterior pelvis radiographs at three months and one year postoperatively. Postoperative medical and surgical complication rates were evaluated. RESULTS: A total of fifteen patients were treated with CC, 15 with MTF, and 20 with FC. At three-month follow-up, mean stem subsidence was 0.43 ± 0.08 mm, 1.47 ± 0.36 mm, and 0.68 ± 0.39 mm for CC, MTF, and FC cohorts, respectively (P = .323). At one-year, mean stem subsidence was 0.70 ± 0.08 mm, 1.74 ± 0.69 mm, and 1.88 ± 0.90 mm for the CC, MTF, and FC cohorts, respectively (P = .485). Medical complications included 2 venous thromboembolic events (4%) within 90 days of surgery. There were 6 reoperations (12%); 3 (6%) for acute periprosthetic joint infection (all within the FC cohort); 2 (4%) for postoperative periprosthetic fractures (one fracture distal to the stem in the FC cohort and one fracture at the level of the stem in the MTF cohort), and 1 (2%) closed reduction for instability (within the CC cohort). CONCLUSIONS: The three described methods of managing intraoperative nondisplaced calcar fractures demonstrated little radiographic stem subsidence; however, the risk of reoperation was much higher than expected.

Outpatient Total Knee Arthroplasty Shows Decreasing Complication Burden From 2010 to 2020.

BACKGROUND: The number of total knee arthroplasties (TKAs) performed on an outpatient basis continues to increase. The purpose of this study was to compare complication rates over the last decade to evaluate trends in the safety of outpatient TKA. METHODS: Patients who underwent TKA from 2010 to 2020 from a large administrative claims database were retrospectively identified and stratified based on the year of surgery. Propensity-score matching was performed to match patients who were discharged within 24 hours of surgery to inpatients based on age, sex, comorbidity index, and year of surgery. Linear regression analyses were used to compare trends from 2010 to 2020. The 90-day adverse events in the early cohort (2010-2012) were compared to those in the late cohort (2018-2020) using multivariable regression analyses. Of the 547,137 patients in the sample, 28,951 outpatients (5.3%) were propensity matched to inpatients. RESULTS: The incidence of outpatient TKA increased from 2010 to 2018 (1.9 versus 13.8%, P < .001). Despite a similar complication rate early (24.1 versus 22.6%, P = .164), outpatient TKA had fewer complications at the end of the study period (13.7 versus 16.7%, P < .001). Multivariate analyses demonstrated that the risk of any complication after outpatient TKA was lower than inpatient from 2018 to 2020 (odds ratio, 0.78; 95% confidence interval, 0.71-0.84). CONCLUSIONS: Complications in both cohorts declined dramatically suggesting improvements in quality of care over time, with the greatest decline in patients undergoing outpatient surgery. These results suggest that outpatient TKA today is not higher risk for the patient than inpatient TKA. LEVEL OF EVIDENCE: Level III.

Invasive Gastrointestinal Endoscopy Following Total Joint Arthroplasty Increases the Risk for Periprosthetic Joint Infection.

BACKGROUND: The safety of postoperative colonoscopy and endoscopy following total joint arthroplasty (TJA) remains largely unknown. The objective of this study was to characterize the effect of gastrointestinal endoscopic procedures after TJA on the risk of postoperative periprosthetic joint infection (PJI). METHODS: Using a large national database, patients who underwent an endoscopic procedure (colonoscopy or esophagogastroduodenoscopy (EGD)) within 12 months after primary TJA were identified and matched in a 1:1 fashion based on procedure (primary total knee arthroplasty (TKA) versus total hip arthroplasty (THA)), age, sex, Charlson Comorbidity Index (CCI), and smoking status with patients who did not undergo endoscopy. A total of 142,055 patients who underwent endoscopy within 12 months following TJA (96,804 TKAs and 45,251 THAs) were identified and matched. The impact of timing of endoscopy relative to TJA on postoperative outcomes was assessed. Preoperative comorbidity profiles and 1-year complications were compared. Statistical analyses included Chi-squared tests and multivariate logistic regressions with outcomes considered significant at P < .05. RESULTS: Multivariate analyses revealed that endoscopy within 2 months following TKA and 1 month of THA was associated with a significantly increased odds of periprosthetic joint infection (odds ratio (OR): 1.29 [1.08-1.53]; P = .004; OR: 1.41 [1.01-1.90]; P = .033, respectively). Patients who underwent endoscopy greater than 2 months from the timing of their TKA and 1 month from THA were not at significantly greater risk of developing PJI. CONCLUSION: These data suggest that invasive endoscopic procedures should be delayed if possible by at least 2 months following TKA and 1 month following THA to minimize the risk of PJI.

The Effect of Segmentation Threshold on Computational Fluid Dynamic Analysis of Nasal Airflow.

BACKGROUND: The objective analysis of nasal airflow stands to benefit greatly from the adoption of computational fluid dynamic (CFD) methodologies. In this emerging field, no standards currently exist in regard to the ideal modeling parameters of the nasal airway. Such standards will be necessary for this tool to become clinically relevant. METHODS: Human nasal airways were modeled from a healthy control, segmented, and analyzed with an in-house immersed boundary method. The segmentation Hounsfield unit (HU) threshold was varied to measure its effect in relation to airflow velocity magnitude and pressure change. FINDINGS: Surface area and volume have a linear relationship to HU threshold, whereas CFD variables had a more complex relationship. INTERPRETATION: The HU threshold should be included in nasal airflow CFD analysis. Future work is required to determine the optimal segmentation threshold.

Estimating in vivo potassium distribution and fluxes with stable potassium isotopes.

Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow (n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet (P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.

Ionophore-mediated swelling of erythrocytes as a therapeutic mechanism in sickle cell disease.

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

The effect of rigid cells on blood viscosity: linking rheology and sickle cell anemia.

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

Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population.

BACKGROUND: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. METHODS: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. RESULTS: Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R- (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R- adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. CONCLUSION: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information.

High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension.

Sickle cell disease (SCD) is caused by a variant hemoglobin molecule that polymerizes inside red blood cells (RBCs) in reduced oxygen tension. Treatment development has been slow for this typically severe disease, but there is current optimism for curative gene transfer strategies to induce expression of fetal hemoglobin or other nonsickling hemoglobin isoforms. All SCD morbidity and mortality arise directly or indirectly from polymer formation in individual RBCs. Identifying patients at highest risk of complications and treatment candidates with the greatest curative potential therefore requires determining the amount of polymer in individual RBCs under controlled oxygen. Here, we report a semiquantitative measurement of hemoglobin polymer in single RBCs as a function of oxygen. The method takes advantage of the reduced oxygen affinity of hemoglobin polymer to infer polymer content for thousands of RBCs from their overall oxygen saturation. The method enables approaches for SCD treatment development and precision medicine.

COVID-19 Infection After Total Joint Arthroplasty Is Associated With Increased Complications.

BACKGROUND: The impact of a postoperative diagnosis of COVID-19 in patients undergoing total joint arthroplasty (TJA) remains unknown. The objective of this study is to characterize the effect of COVID-19 infection following TJA on perioperative complication rates. METHODS: The Mariner database was queried for patients undergoing total hip and total knee arthroplasty from January 2018 to April 2020. TJA patients who were diagnosed with COVID-19 within 90 days postoperatively were matched in a 1:3 fashion based on age, gender, iron deficiency anemia, payer status, and Charlson Comorbidity Index with patients who were not diagnosed with COVID-19. Preoperative comorbidity profiles and complications within 3 months of surgery were compared. Statistical analysis included chi-squared tests and multivariate logistic regression with outcomes considered significant at P < .05. RESULTS: Of the 239 COVID-19 positive patients, 132 (55.2%) underwent total hip arthroplasty. On multivariate analysis, COVID-19 diagnosis was associated with increased odds of deep vein thrombosis (odds ratio [OR] 4.86, 95% confidence interval [CI] 2.10-11.81, P < .001), pulmonary embolism (OR 6.27, 95% CI 2.57-16.71, P < .001), and all complications (OR 3.36, 95% CI 2.47-4.59, P < .001). Incidence of deep vein thrombosis/pulmonary embolism was greater the closer in time the COVID-19 diagnosis was to the surgical procedure (10.24 times at 1 month, 7.87 times at 2 months, and 1.42 times at 3 months; P < .001). A similar relationship was observed with all complications. CONCLUSION: Postoperative COVID-19 infection is associated with higher rates of cardiopulmonary complications, thromboembolic disease, renal injury, and urinary tract infections in patients undergoing hip and knee arthroplasty. COVID-19 infection earlier in the postoperative period is associated with a higher risk of complications.