High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.

BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.

The Burden of Major Complications on Failure-to-Rescue After Surgery for Acute Type A Aortic Dissections: An analysis of over 19,000 patients.

INTRODUCTION: The relationship between the number and type of postoperative complications and mortality in the setting for surgery for Type A Aortic Dissection (ATAAD) remains underexplored despite the critical role in the Failure-to-Rescue (FTR) metric. METHODS: Retrospective study using data from the Society of Thoracic Surgeons Adult Cardiac Surgical Database, encompassing ATAAD surgeries between January 2018 and December 2022. Patients were categorized based on the number of major complications. The primary outcome was FTR. We employed Multilevel Regression and Classification and Regression Tree models. RESULTS: We included 19,243 patients, with a median age of 61 years and 33.3% were women. Regarding complications, 47.7% of patients had none, 20.2% had one, 12.7% had two, and 19.4% experienced three or more. The most common complications were prolonged mechanical ventilation (30.3%), unplanned reoperations (19.5%), and renal failure (17.2%). Cardiac arrest was observed in 7.1% of cases. FTR increased from 13% in patients with one complication to over 30% in those with four or more. Cardiac arrest (aOR 10.9) and renal failure (aOR 5.3) showed the highest odds for mortality, followed by limb ischemia (aOR 2.7), stroke (aOR 2.6), and gastrointestinal complications (aOR 2.4). Hospitals in the top performance quartile consistently showed lower FTR rates across all levels of complication. CONCLUSION: The study validates a dose-response association between postoperative complications and mortality for ATAAD. Top-performing hospitals consistently show lower FTR rates independently of the number of complications. Further research should focus on the timing of complications and interventions to reduce the burden of complications.

Global prevalence of musculoskeletal pain in rural and urban populations. A systematic review with meta-analysis. Musculoskeletal pain in rural and urban populations.

INTRODUCTION: To systematically compare the global prevalence of musculoskeletal pain and care-seeking in rural and urban populations. METHODS: A systematic review with meta-analysis of observational studies reporting a direct comparison of rural and urban populations was conducted worldwide and included back, knee, hip, shoulder, neck pain and a broad diagnosis of 'musculoskeletal pain'. A search strategy combining terms related to 'prevalence', 'musculoskeletal pain' and 'rural' was used on the following databases: MEDLINE, Embase, CINAHL, Scopus, and rural and remote health from their inception to 1 June 2022. Random-effects meta-analysis was used to pool the data. Results were presented as odds ratios (OR) along with 95% confidence intervals (95% CI). RESULTS: A total of 42 studies from 24 countries were included with a total population of 489 439 participants. The quality scores for the included studies, using the modified Newcastle Ottawa Scale tool, showed an average score of 0.78/1, which represents an overall good quality. The pooled analysis showed statistically greater odds of hip (OR = 1.62, 95% CI = 1.23-2.15), shoulder (OR = 1.42, 95% CI = 1.06-1.90) and overall musculoskeletal pain (OR = 1.26, 95% CI = 1.08-1.47) in rural populations compared to urban populations. Although the odds of seeking treatment were higher in rural populations this relationship was not statistically significant (OR = 0.76, 95% CI = 0.55-1.03). CONCLUSION: Very low-certainty evidence suggests that musculoskeletal, hip and shoulder pain are more prevalent in rural than urban areas, although neck, back and knee pain, along with care-seeking, showed no significant difference between these populations. Strategies aimed to reduce the burden of musculoskeletal pain should consider the specific needs and limited access to quality evidence-based care for musculoskeletal pain of rural populations.

The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination.

The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19-) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.

Invasion of spontaneous germinal centers by naive B cells is rapid and persistent.

In autoreactive germinal centers (GC) initiated by a single rogue B cell clone, wild-type B cells expand and give rise to clones that target other autoantigens, known as epitope spreading. The chronic, progressive nature of epitope spreading calls for early interventions to limit autoimmune pathologies, but the kinetics and molecular requirements for wild-type B cell invasion and participation in GC remain largely unknown. With parabiosis and adoptive transfer approaches in a murine model of systemic lupus erythematosus, we demonstrate that wild-type B cells join existing GCs rapidly, clonally expand, persist, and contribute to autoantibody production and diversification. The invasion of autoreactive GCs by wild-type B cells required TLR7, B cell receptor specificity, antigen presentation, and type I interferon signaling. The adoptive transfer model provides a tool for identifying early events in the breaking of B cell tolerance in autoimmunity.

The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination.

The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19 - ) and non-LLPC (CD19 + ) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.

Lupus-associated innate receptors drive extrafollicular evolution of autoreactive B cells.

In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). CD21loCD11c+ B cells, associated with aging, infection, and autoimmunity, are contributors to autoreactive EF ASCs but have an obscure developmental trajectory. To study EF kinetics of autoreactive B cell in tissue, we adoptively transferred WT and gene knockout B cell populations into the 564Igi mice - an autoreactive host enriched with autoantigens and T cell help. Time-stamped analyses revealed TLR7 dependence in early escape of peripheral B cell tolerance and establishment of a pre-ASC division program. We propose CD21lo cells as precursors to EF ASCs due to their elevated TLR7 sensitivity and proliferative nature. Blocking receptor function reversed CD21 loss and reduced effector cell generation, portraying CD21 as a differentiation initiator and a possible target for autoreactive B cell suppression. Repertoire analysis further delineated proto-autoreactive B cell selection and receptor evolution toward self-reactivity. This work elucidates receptor and clonal dynamics in EF development of autoreactive B cells, and establishes modular, native systems to probe mechanisms of autoreactivity.

The association between musculoskeletal pain during pregnancy and pregnancy outcomes: A systematic review and meta-analyses.

OBJECTIVE: To systematically investigate the association between musculoskeletal pain during pregnancy and birth outcomes including caesarean section, newborn birthweight, newborn birth length, and gestational age at birth. METHODS: Medline, Embase, Web of Science, Cinahl and Scopus were systematically searched to identify eligible studies. Odds ratios, mean differences, and confidence intervals were used to describe results. Risk of Bias was assessed using the Newcastle-Ottawa Scale for observational studies. GRADE (The Grading of Recommendation Assessment, Development, and Evaluation) was used to assess the quality of each outcome. RESULTS: Seven studies were included with a total population of 85,991 participants. There is low- quality evidence that pregnant women with musculoskeletal pain had 1.59 greater odds to experience delivery by caesarean section compared to those without musculoskeletal pain ([OR] 1.59, 95 % confidence interval [CI] 1.09 to 2.31). Both newborn birth weight (Mean Difference [MD] 77.79 g, 95 % [CI] -23.09 to 178.67) and newborn birth length ([MD] 0.55 cm, 95 % [CI] -0.47 to 1.56) were not affected by musculoskeletal pain, with very low-quality and low-quality evidence, respectively. There was moderate evidence that pregnant women with musculoskeletal pain had shorter gestational age (weeks), although the effect was small and possibly not clinically relevant ([MD] -0.41, 95 % [CI] -0.41 to -0.07). CONCLUSION: Pregnant women experiencing musculoskeletal pain are at greater odds of delivering their babies via caesarean than those without musculoskeletal pain, however, musculoskeletal pain during pregnancy does not appear to affect newborn birth weight, length, or gestational age at birth.

Optimizing Surgical Selection for Transposition With Left Ventricular Outflow Tract Obstruction.

BACKGROUND: Studies that have assessed the Rastelli and Nikaidoh operations for transposition of the great arteries (TGA) with obstructed left ventricular outflow tract obstruction (LVOTO) have not fully evaluated the anatomic drivers that may contribute to surgical selection. We present our procedural selection process for optimizing outcomes of complex TGA in the modern era. METHODS: This is a single-center, retrospective study that included pediatric patients who underwent either a Nikaidoh or Rastelli operation for the treatment of TGA-LVOTO, congenitally corrected TGA-LVOTO, or double-outlet right ventricle TGA type-LVOTO from June 2004 to June 2021. RESULTS: There were 34 patients stratified by Nikaidoh (n = 16) or Rastelli (n = 18) operation. The incidence of all postoperative complications and mortality was low, and the incidence of complications between the groups was similar. Patients were more likely to have undergone a Nikaidoh than a Rastelli if they had a pulmonary annulus >5 mm (87.5% vs 11.1%), anteriorly/posteriorly oriented great vessels (88% vs 8%), remote (80% vs 11%) or restrictive (75% vs 6%) ventricular septal defect, and right ventricular hypoplasia (50% vs 0%; all, P < .05). The resulting rates of reoperation were similar between the groups (44.0% vs 37.5%; P = .24) and largely composed of conduit replacements in the Rastelli patients and valvular repairs or replacements in the Nikaidoh group. Rates of catheter-based interventions were also similar. CONCLUSIONS: These findings suggest that for the optimal treatment of conotruncal anomalies with discordant ventriculoarterial connections, procedural selection should be based on pathoanatomic criteria that can ensure patients undergo the operation most suited to their anatomy.

Effectiveness of an eHealth-Delivered Program to Empower People With Musculoskeletal Pain in Rural Australia: A Randomized Controlled Trial.

OBJECTIVE: Our objective was to evaluate the effectiveness of a three-month physiotherapist-delivered eHealth physical activity program compared with usual care to improve function in adults with low back pain or knee osteoarthritis in rural Australia. METHODS: This was a parallel, two-group, pragmatic, superiority, randomized controlled trial involving three- and six-month posttreatment follow-ups. There was a total of 156 adults with chronic nonspecific low back pain (n = 97) or knee osteoarthritis (n = 59) from rural Australia. The intervention involved an eHealth physical activity and an exercise program that included five to eight teleconsultations with a physiotherapist (primary time point three months) or usual care (eg, general practitioner, physiotherapy, and pain medication). The primary outcome was the Patient-Specific Functional Scale (0-30), with a three-point difference between groups being considered the minimum clinically important difference. RESULTS: Participants receiving the eHealth intervention (n = 78) reported significantly greater and clinically worthwhile improvements in function (mean between-group difference 3.6; 95% confidence interval [CI] 1.3-5.9) compared to participants receiving usual care (n = 78). Small but statistically significantly greater improvements in disability (7.2 of 100; 95% CI 2.1-12.3) and quality of life (4.5 of 100; 95% CI 0.0-9.0) also favored the eHealth group. No clinical or statistical differences between groups were found for the secondary outcomes of pain, coping skills, and physical activity levels. CONCLUSION: A physiotherapist-delivered eHealth intervention is effective and provides clinically meaningful improvements in function compared to usual care for people with musculoskeletal pain in rural communities. These findings highlight the potential for eHealth-based programs to improve access to evidence-based exercise interventions for people with musculoskeletal pain in rural communities.

Long-term sex-based outcomes after surgery for acute type A aortic dissection: Meta-analysis of reconstructed time-to-event data.

BACKGROUND: The influence of sex on outcomes of surgery for acute type A aortic dissection remains incompletely characterized. We sought to evaluate post-procedural survival in the follow-up of females versus males. METHODS: We carried out a systematic review with meta-analysis of Kaplan-Meier-derived time-to-event data from studies published by June 2023 in the following databases: PubMed/MEDLINE, EMBASE, Web of Science and CENTRAL/CCTR (Cochrane Controlled Trials Register). RESULTS: Twelve studies met our eligibility criteria, including 11,696 patients (3753 females; 7943 males). The mean age ranged from 41.2 to 72.6 years with low prevalence of bicuspid aortic valve (ranging from 0.0% to 12.0%) and connective tissue disorders (ranging from 0.8% to 7.3%). We found a considerable prevalence of coronary artery disease (ranging from 12.1% to 21.1%) and malperfusion (ranging from 20.0% to 46.3%). At 10 years, females undergoing surgery had a significantly higher risk of all-cause mortality compared with males (HR 1.25, 95%CI 1.14-1.38, P â€‹< â€‹0.001). CONCLUSION: In the follow-up of patients undergoing surgery for type A aortic dissection, females presented poorer overall survival in comparison with males.

Double outlet right ventricle.

This review article addresses the history, morphology, anatomy, medical management, and different surgical options for patients with double outlet right ventricle.

Volume-failure-to-rescue relationship in acute type A aortic dissections: An analysis of The Society of Thoracic Surgeons Database.

OBJECTIVE: To determine the relationship between volume of cases and failure-to-rescue (FTR) rate after surgery for acute type A aortic dissection (ATAAD) across the United States. METHODS: The Society of Thoracic Surgeons adult cardiac surgery database was used to review outcomes of surgery after ATAAD between June 2017 and December 2021. Mixed-effect models and restricted cubic splines were used to determine the risk-adjusted relationships between ATAAD average volume and FTR rate. FTR calculation was based on deaths associated with the following complications: venous thromboembolism/deep venous thrombosis, stroke, renal failure, mechanical ventilation >48 hours, sepsis, gastrointestinal complications, cardiopulmonary resuscitation, and unplanned reoperation. RESULTS: In total, 18,192 patients underwent surgery for ATAAD in 832 centers. The included hospitals' median volume was 2.2 cases/year (interquartile range [IQR], 0.9-5.8). Quartiles' distribution was 615 centers in the first (1.3 cases/year, IQR, 0.4-2.9); 123 centers in the second (8 cases/year, IQR, 6.7-10.2); 66 centers in the third (15.6 cases/year, IQR, 14.2-18); and 28 centers in the fourth quartile (29.3 cases/year, IQR, 28.8-46.0). Fourth-quartile hospitals performed more extensive procedures. Overall complication, mortality, and FTR rates were 52.6%, 14.2%, and 21.7%, respectively. Risk-adjusted analysis demonstrated increased odds of FTR when the average volume was fewer than 10 cases per year. CONCLUSIONS: Although high-volume centers performed more complex procedures than low-volume centers, their operative mortality was lower, perhaps reflecting their ability to rescue patients and mitigate complications. An average of fewer than 10 cases per year at an institution is associated with increased odds of failure to rescue patients after ATAAD repair.

Pulmonary Homograft vs Handmade Polytetrafluoroethylene-Valved Conduits After the Ross Procedure.

BACKGROUND: This study aimed to longitudinally compare expanded polytetrafluoroethylene (ePTFE)-valved conduits vs pulmonary homograft (PH) conduits after right ventricular outflow tract reconstruction in the Ross procedure. METHODS: Patients undergoing a Ross procedure from June 2004 to December 2021 were identified. Echocardiographic data, catheter-based interventions, or conduit replacements, as well as time to first reintervention or replacement, were comparatively assessed between handmade ePTFE-valved conduits and PH conduits. RESULTS: A total of 90 patients were identified. The median age and weight were 13.8 years (interquartile range [IQR], 8.08-17.80 years) and 48.3 kg (IQR, 26.8-68.7 kg), respectively. There were 66% (n = 60) ePTFE-valved conduits and 33% (n = 30) PHs. The median size was 22 mm (IQR, 18-24 mm) for ePTFE-valved conduits and 25 mm (IQR, 23-26 mm) for PH conduits (P < .001). Conduit type had no differential effect in the gradient evolution or the odds of presenting with severe regurgitation in the last follow-up echocardiogram. Of the 26 first reinterventions, 81% were catheter-based interventions, without statistically significant differences between the groups (69% PH vs 83% ePTFE). The overall surgical conduit replacement rate was 15% (n = 14), and it was higher in the homograft group (30% vs 8%; P = .008). However, conduit type was not associated with an increased hazard for reintervention or reoperation after adjusting for covariates. CONCLUSIONS: Right ventricular outflow tract reconstruction using handmade ePTFE-valved conduits after a Ross procedure provides encouraging midterm results, without a differential effect in hemodynamic performance or valve function compared with PH conduits. These results are reassuring about the use of handmade valved conduits in pediatric and young adult patients. Longer follow-up of tricuspid conduits will complement valve competency assessment.

Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers.

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here, we used fate-mapping reporter mice and single-cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody-secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.

Long-Term Outcomes of Patients With Carotid and Aortic Body Tumors.

Chemodectomas are tumors derived from parasympathetic nonchromaffin cells and are often found in the aortic and carotid bodies. They are generally benign but can cause mass-effect symptoms and have local or distant spread. Surgical excision has been the main curative treatment strategy. The National Cancer Database was reviewed to study all patients with carotid or aortic body tumors from 2004 to 2015. Demographic data, tumor characteristics, treatment strategies, and patient outcomes were examined, split by tumor location. Kaplan-Meier survival estimates were generated for both locations. In total, 248 patients were examined, with 151 having a tumor in the carotid body and 97 having a tumor in the aortic body. Many variables were similar between both tumor locations. However, aortic body tumors were larger than those in the carotid body (477.80 ± 477.58 mm vs 320.64 ± 436.53 mm, p = 0.008). More regional lymph nodes were positive in aortic body tumors (65.52 ± 45.73 vs 35.46 ± 46.44, p <0.001). There were more distant metastases at the time of diagnosis in carotid body tumors (p = 0.003). Chemotherapy was used more for aortic body tumors (p = 0.001); surgery was used more for carotid body tumors (p <0.001). There are slight differences in tumor characteristics and response to treatment. Surgical resection is the cornerstone of management, and radiation can often be considered. In conclusion, chemodectomas are generally benign but can present with metastasis and compressive symptoms that make understanding their physiology and treatment important.

Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model.

Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in the pathogenesis of SLE and its associated neuropsychiatric symptoms (NPSLE). However, it remains unclear how type 1 interferon signaling in the central nervous system (CNS) might result in neuropsychiatric sequelae. In this study, we validate an NPSLE mouse model and find an elevated peripheral type 1 interferon signature alongside clinically relevant NPSLE symptoms such as anxiety and fatigue. Unbiased single-nucleus sequencing of the hindbrain and hippocampus revealed that interferon-stimulated genes (ISGs) were among the most highly upregulated genes in both regions and that gene pathways involved in cellular interaction and neuronal development were generally repressed among astrocytes, oligodendrocytes, and neurons. Using image-based spatial transcriptomics, we found that the type 1 interferon signature is enriched as spatially distinct patches within the brain parenchyma of these mice. Our results suggest that type 1 interferon in the CNS may play an important mechanistic role in mediating NPSLE behavioral phenotypes by repressing general cellular communication pathways, and that type 1 interferon signaling modulators are a potential therapeutic option for NPSLE.

A Readmission Risk Score for Transcatheter Aortic Valve Replacement: An Analysis of 200,000 Patients.

OBJECTIVE: The objective of this study was to leverage a national database of TAVR procedures to create a risk model for 30-day readmissions. METHODS: The National Readmissions Database was reviewed for all TAVR procedures from 2011 to 2018. Previous ICD coding paradigms created comorbidity and complication variables from the index admission. Univariate analysis included any variables with a P-value of ≤0.2. A bootstrapped mixed-effects logistic regression was run using the hospital ID as a random effect variable. By bootstrapping, a more robust estimate of the variables' effect can be generated, reducing the risk of model overfitting. The odds ratio of variables with a P-value <0.1 was turned into a risk score following the Johnson scoring method. A mixed-effect logistic regression was run using the total risk score, and a calibration plot of the observed to expected readmission was generated. RESULTS: A total of 237,507 TAVRs were identified, with an in-hospital mortality of 2.2 %. A total of 17.4 % % of TAVR patients were readmitted within 30 days. The median age was 82 with 46 % of the population being women. The risk score values ranged from -3 to 37 corresponding to a predicted readmission risk between 4.6 % and 80.4 %, respectively. Discharge to a short-term facility and being a resident of the hospital state were the most significant predictors of readmission. The calibration plot shows good agreement between the observed and expected readmission rates with an underestimation at higher probabilities. CONCLUSION: The readmission risk model agrees with the observed readmissions throughout the study period. The most significant risk factors were being a resident of the hospital state and discharge to a short-term facility. This suggests that using this risk score in conjunction with enhanced post-operative care in these patients could reduce readmissions and associated hospital costs, improving outcomes.