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.

Non-interferometric key recording applied to a joint transform cryptosystem.

In this Letter, we propose an opto-digital cryptosystem based on the joint transform correlator architecture without the need for a reference beam, phase-shifting techniques, or an additional window in the input plane. In this system, only two intensity recordings are necessary: the intensity of the key Fourier transform, and the joint power spectrum between the key and an arbitrary object in contact with a random phase mask. Combining them with the knowledge of their respective input modules, we implement a modified Gerchberg-Saxton algorithm to recover the phase associated with the encryption key. The validity of our approach is demonstrated by computer simulations and experimental results.

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.

National trends and outcomes of heart-kidney transplantation using hepatitis C positive donors.

BACKGROUND: This study evaluated the outcomes of combined heart-kidney transplantation in the United States using hepatitis C positive (HCV+) donors. METHODS: Adults undergoing combined heart-kidney transplantation from 2015 to 2020 were identified in the United Network for Organ Sharing registry. Patients were stratified by donor HCV status. Kaplan-Meier curves with multivariable Cox regression models were used for risk-adjustment in a propensity-matched cohort. RESULTS: A total of 950 patients underwent heart-kidney transplantation of which 7.8% (n = 75) used HCV+ donors; 68% (n = 51) were viremic and 32% (n = 24) were non-viremic donors. Unadjusted 1-year recipient survival was similar between HCV+ versus HCV- donors (84% vs 88%, respectively; P = .33). Risk-adjusted analysis in the propensity-matched cohort showed HCV+ donor use did not confer increased risk of 1-year mortality (hazard ratio .63, 95% CI .17-2.32; P = .49). Sub-group analysis showed viremic and non-viremic HCV+ donors had similar 1-year survival as well (84% vs 84%; P = .95). CONCLUSIONS: Compared with recipients of HCV- donor dual heart-kidney transplants, recipients of HCV+ organs had comparable 1-year survival and clinical outcomes after combined transplantation. Although future studies should evaluate other outcomes related to HCV+ donor use, this practice appears safe and should be expanded further in the heart-kidney transplant population.

The Quantitative Assessment of the Secreted IgG Repertoire after Recall to Evaluate the Quality of Immunizations.

One of the major goals of vaccination is to prepare the body to rapidly secrete specific Abs during an infection. Assessment of the vaccine quality is often difficult to perform, as simple measurements like Ab titer only partly correlate with protection. Similarly, these simple measurements are not always sensitive to changes in the preceding immunization scheme. Therefore, we introduce in this paper a new, to our knowledge, method to assay the quality of immunization schemes for mice: shortly after a recall with pure Ag, we analyze the frequencies of IgG-secreting cells (IgG-SCs) in the spleen, as well as for each cells, the Ag affinity of the secreted Abs. We observed that after recall, appearance of the IgG-SCs within the spleen of immunized mice was fast (<24 h) and this early response was free of naive IgG-SCs. We further confirmed that our phenotypic analysis of IgG-SCs after recall strongly correlated with the different employed immunization schemes. Additionally, a phenotypic comparison of IgG-SCs presented in the spleen during immunization or after recall revealed similarities but also significant differences. The developed approach introduced a novel (to our knowledge), quantitative, and functional highly resolved alternative to study the quality of immunizations.

Trends and outcomes following total artificial heart as bridge to transplant from the UNOS database.

INTRODUCTION: Bridge to transplantation (BTT) with a SynCardia Total Artificial Heart (TAH) has been gaining momentum as a therapy for patients with biventricular heart failure. Recent transplant waitlist and posttransplant outcomes with this strategy have not been comprehensively characterized. We reviewed the United Network for Organ Sharing (UNOS) database to examine BTT outcomes for the TAH system since approval. METHODS: Adult patients listed for heart transplantation in the UNOS system between 2004 and 2020 who underwent BTT therapy with a TAH were included in the study. Trends in utilization of TAH compared with other durable mechanical support strategies were examined. The primary outcome was 1-year survival following heart transplantation following BTT with TAH. Secondary outcomes included waitlist deterioration and risk factors for waitlist or posttransplant mortality. RESULTS: During the study 433 total patients underwent TAH implant as BTT therapy; 236 (54.4%) were listed with the TAH, while the remaining patients were upgraded to TAH support while on the waitlist. Waitlist mortality was 7.4%, with 375 patients (86.6%) ultimately being transplanted. Age, cerebrovascular disease, functional status, and ventilator dependence were risk factors for waitlist mortality. One-year survival following successful BTT was 80%. Risk factors for mortality following BTT included age, body mass index, and underlying diagnosis. CONCLUSIONS: Patients undergoing BTT with TAH demonstrate acceptable waitlist survival and good 1-year survival. While utilization initially increased as a BTT therapy, there has been a plateau in relative utilization. Individual patient and transplantation center factors deserve further investigation to determine the ideal population for this therapy.

Impact of ethnicity and race on outcomes after thoracic endovascular aortic repair.

INTRODUCTION: Thoracic endovascular aortic repair (TEVAR) became the standard of care for treating Type B aortic dissections and descending thoracic aortic aneurysms. We aimed to describe the racial/ethnic differences in TEVAR utilization and outcomes. METHODS: The National Inpatient Sample was reviewed for all TEVARs performed between 2010 and 2017 for Type B aortic dissection and descending thoracic aortic aneurysm (DTAA). We compared groups stratifying by their racial/ethnicity background in White, Black, Hispanic, and others. Mixed-effects logistic regression was performed to assess the relationship between race/ethnicity and the primary outcome, in-hospital mortality. RESULTS: A total of 25,260 admissions for TEVAR during 2010-2017 were identified. Of those, 52.74% (n = 13,322) were performed for aneurysm and 47.2% (n = 11,938) were performed for Type B dissection. 68.1% were White, 19.6% were Black, 5.7% Hispanic, and 6.5% were classified as others. White patients were the oldest (median age 71 years; p < .001), with TEVAR being performed electively more often for aortic aneurysm (58.8% vs. 34% vs. 48.3% vs. 48.2%; p < .001). In contrast, TEVAR was more likely urgent or emergent for Type B dissection in Black patients (65.6% vs. 41.1% vs. 51.6% vs. 51.7%; p < .001). Finally, the Black population showed a relative increase in the incidence rate of TEVAR over time. The adjusted multivariable model showed that race/ethnicity was not associated with in-hospital mortality. CONCLUSION: Although there is a differential distribution of thoracic indication and comorbidities between race/ethnicity in TEVAR, racial disparities do not appear to be associated with in-hospital mortality after adjusting for covariates.

Induction Immunosuppression and Renal Outcomes in Adult Heart Transplantation.

BACKGROUND: This study explores the use of induction therapy in orthotopic heart transplantation as it relates to preoperative renal function and evaluates the impact of its utilization on post-transplant outcomes. METHODS: We conducted a retrospective analysis using the United Network for Organ Sharing database from 2000 to 2018 evaluating the initiation of de novo dialysis after transplantation. We examined the relationship between induction immunosuppression and pre-transplant estimated glomerular filtration rate with post-transplant outcomes, accounting for inter-center variability through a mixed-effects logistic regression model. RESULTS: In total, 16,201 patients were included with a median age of 57 y (interquartile range 47, 63); 26% were women (n = 4222) and 28% (n = 4552) had a history of diabetes mellitus. The median estimated glomerular filtration rate (eGFR) was 67.5 mL/min (interquartile range 53.1, 86.7); 51.2% (n = 3068) of the recipients with eGFR < 60 received induction therapy compared to 42.5% (n = 4336) within the eGFR ≥ 60 group (P < 0.001). Adjusted multivariable analysis found that induction therapy was associated with de novo dialysis (odds ratio 1.25, 95% confidence interval 1.10-1.43, P < 0.001), with the most significant effect on patients with eGFR ≥ 60. Although significant, there was a weak correlation between center-level induction utilization and mean eGFR (r = -0.2, P < 0.001). CONCLUSION: In this analysis, the use of induction immunosuppression in orthotopic heart transplantation varied widely between centers and did not correlate strongly with pre-transplant eGFR. In addition, its utilization did not mitigate the risk of renal replacement therapy after transplantation and in fact was associated with increased risk even after adjusting for confounders most notably in patients with eGFR ≥ 60.

A mortality risk score for septuagenarians undergoing orthotopic heart transplantation.

BACKGROUND: With septuagenarians undergoing orthotopic heart transplantation (OHT) more frequently, we aimed to develop a risk score for 1-year mortality in this population. METHODS: Septuagenarian OHT recipients were identified from the UNOS registry between 1987 and 2018. The primary outcome was 1-year post-OHT mortality. Patients were randomly divided into derivation and validation cohorts. Associated covariates were entered into a multivariable logistic regression model. A risk score was created using the magnitudes of the odds ratios from the derivation cohort, and its 1-year post-OHT mortality prediction capacity was tested in the validation cohort. RESULTS: A total of 1156 septuagenarians were included, and they were randomly divided into derivation (66.7%, n = 771) and validation (33.3%, n = 385) cohorts. An 11-point risk score incorporating 4 variables was created, which included mechanical ventilation, serum bilirubin, serum creatinine, and donor age. The predicted 1-year mortality ranged from 4.2% (0 points) to 48.1% (11-points) (p < .001). After cross-validation, the c-index was 0.67 with a Brier score of 0.10. Risk scores above 3 points portended a survival disadvantage at 1-year follow-up (p < .001). CONCLUSIONS: This 11-point risk score for septuagenarians is predictive of mortality within 1-year of OHT and has potential utilization in improving recipient evaluation and selection of elderly patients.

EHealth to empower patients with musculoskeletal pain in rural Australia (EMPoweR) a randomised clinical trial: study protocol.

BACKGROUND: Low back pain (LBP) and knee osteoarthritis (OA) are major contributors to disability worldwide. These conditions result in a significant burden at both individual and societal levels. Engagement in regular physical activity and exercise programs are known to improve physical function in both chronic LBP and knee OA populations. For people residing in rural areas, musculoskeletal conditions are often more frequent and disabling compared to urban populations, which could be the result of reduced access to appropriate health services and resources in rural settings. EHealth is an innovative solution to help provide equitable access to treatment for people with musculoskeletal pain living in rural settings. METHODS/DESIGN: We will conduct a randomised clinical trial investigating the effects of an eHealth intervention compared to usual care, for people with chronic non-specific LBP or knee OA in rural Australia. We will recruit 156 participants with non-specific chronic LBP or knee OA. Following the completion of baseline questionnaires, participants will be randomly allocated to either the eHealth intervention group, involving a tailored physical activity and progressive resistance exercise program remotely delivered by a physiotherapist (n = 78), or usual care (n = 78) involving referral to a range of care practices in the community. Outcomes will be measured at baseline, 3 and 6 months post-randomisation. The primary outcome will be physical function assessed by the Patient-Specific Functional Scale (PSFS). Secondary outcomes include pain intensity, physical activity levels, activity limitations, quality of life, pain coping. We will also collect process evaluation data such as recruitment rate, attendance and adherence, follow-up rate, participants' opinions and any barriers encountered throughout the trial. DISCUSSION: The findings from this trial will establish the effectiveness of eHealth-delivered interventions that are known to be beneficial for people with LBP and knee OA when delivered in person. As a result, this trial will help to inform health care policy and clinical practice in Australia and beyond for those living in non-urban areas. TRIAL REGISTRATION: This study was prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN12618001494224 ) registered 09.05.2018.

Pre-implant right ventricular free wall strain predicts post-LVAD right heart failure.

BACKGROUND: The aim of this study is to evaluate the predictive utility of preoperative right ventricular (RV) global longitudinal strain (GLS) and free wall strain (FWS) on outcomes following left ventricular assist devices (LVADs) implantation. METHODS: Preoperative transthoracic echocardiograms were retrospectively reviewed in adults undergoing continuous-flow LVAD implantation between 2004 and 2018 at a single center. Patients undergoing pump exchange were excluded. RV GLS and FWS were calculated using commercially available software with the apical four-chamber view. The primary outcome was RV failure as defined by the Interagency Registry for Mechanically Assisted Circulatory Support within 1-year post-LVAD insertion. RESULTS: A total of 333 patients underwent continuous-flow LVAD implantation during the study period and 137 had adequate preoperative studies for RV strain evaluation. RV FWS was found to be a significant predictor of postoperative RV failure in univariate analysis (odds ratio [OR] = 1.12, p = .03), and this finding persisted after risk adjustment in multivariable analysis (OR = 1.14, p = .04). Using the optimal cutoff value of -5.64%, the c-index of FWS in predicting RV failure was 0.65. RV GLS was not associated with post-LVAD RV failure (OR = 1.07, p = .29). PCWP was the only additional significant predictor of RV failure using multivariable analysis (OR = 0.90, p = .02). CONCLUSION: Pre-implant RV FWS is predictive of RV failure in the first postoperative year after LVAD implantation.

Changes in multiorgan heart transplants following the 2018 allocation policy change.

BACKGROUND: This study evaluated the impact of the heart allocation policy change in 2018 on the characteristics and outcomes of multiorgan transplants involving heart allografts. METHODS: Adults undergoing multiorgan heart transplantation from 2010 to 2020 were identified from the United Network for Organ Sharing (UNOS) registry. Transplants were stratified into occurring before versus after the October 2018 heart allocation change. The primary outcome was 1-year survival following transplantation. A Cox proportional hazards model was used to evaluate the risk-adjusted effect of the allocation policy change on outcomes between cohorts. RESULTS: A total of 1832 patients underwent multiorgan heart transplantation during the study period with 245 (13.37%) undergoing heart-lung transplantation, 244 (13.32%) undergoing heart-liver transplantation, and 1343 (73.31%) undergoing heart-kidney transplantation. There was a higher utilization of temporary MCSDs as well as longer ischemic times for all three types of transplantation following the policy change. Heart-lung and heart-liver recipients had a similar 1-year survival before and after the policy change (each p > .05). Renal failure requiring dialysis (29.5% vs. 39.4%, p = .001) as well as 1-year survival (88% vs. 82%; log-rank p = .01) were worse in the heart-kidney cohort after the organ allocation system modification. CONCLUSIONS: This study demonstrates similar trends in multiorgan transplants as has been observed in isolated heart transplants following the allocation change, including more frequent utilization of temporary mechanical support and longer ischemic times. Although outcomes have remained comparable in the new allocation era with heart-lung and heart-liver transplants, heart-kidney recipients have a worse 1-year survival following the change.

Nationwide variability in the use of induction immunosuppression for adult heart transplantation.

BACKGROUND: Institutional factors have been shown to impact outcomes following orthotopic heart transplantation (OHT). This study evaluated center variability in the utilization of induction therapy for OHT and its implications on clinical outcomes. METHODS: Adult OHT patients between 2010 and 2018 were identified from the United Network for Organ Sharing registry. Transplant centers were stratified based on their rates of induction therapy utilization. Mixed-effects logistic regression models were created with drug-treated rejection within 1 year as primary endpoint and individual centers as a random parameter. Risk-adjusted Cox regression was used to evaluate patient-level mortality outcomes. RESULTS: In 17,524 OHTs performed at 100 centers, induction therapy was utilized in 48.6% (n = 8411) with substantial variability between centers (interquartile range, 21.4%-79.1%). There were 36, 30, and 34 centers in the low (<29%), intermediate (29%-66%), and high (>67%) induction utilization terciles groups, respectively. Induction therapy did not account for the observed variability in the treated rejection rate at 1 year among centers after adjusting for donor and recipient factors (p = .20). No differences were observed in postoperative outcomes among induction utilization centers groups (all, p > .05). Furthermore, there was a weak correlation between the percentage of induction therapy utilization at the center-level and recipients found to have moderate (r = .03) or high (r = .04) baseline risks for acute rejection at 1 year. CONCLUSIONS: This analysis demonstrates that there is substantial variability in the use of induction therapy among OHT centers. In addition, there was a minimal correlation with baseline recipient risk or 1-year rejection rates, suggesting a need for better-standardized practices for induction therapy use in OHT.

Periodized Aerobic Interval Training Modifies Geometric Indices of Heart Rate Variability in Metabolic Syndrome.

Background: Metabolic syndrome (MetS) influences the autonomic modulation, increasing the risk of cardiovascular events, which demands the identification of effective treatments for this population. Considering this, the study has the objective of evaluating the effects of periodized aerobic interval training (AIT) on geometrical methods of heart rate variability (HRV) on individuals with MetS. Methods: 52 individuals with MetS were considered for analysis. They were divided into two groups: aerobic interval training group (AITG; n = 26) and control group (CG; n = 26). The AITG performed 16 weeks of periodized AIT. For HRV analysis, the heart rate was recorded beat-by-beat at the beginning and the end of the AIT program and geometrical methods were used for analysis. Results: significant increase was observed for triangular index (RRtri, -1.25 ± 0.58 vs. 1.41 ± 0.57), standard deviation of distances from diagonal to points (SD1, -0.13 ± 1.52 vs. 4.34 ± 1.49), and standard deviation of distances from points to lines (SD2, -2.14 ± 3.59 vs. 11.23 ± 3.52) on AITG compared to CG. Significant differences were not observed for triangular interpolation of normal heartbeats interval histogram (TINN, -4.05 ± 17.38 vs. 25.52 ± 17.03) and SD1/SD2 ratio (0.03 ± 0.02 vs. 0.00 ± 0.02). Qualitative analysis of the Poincaré plot identified increase on dispersion of both short and long-term intervals between successive heartbeats (RR interval) on AITG after the AIT program. Conclusion: geometric indices of HRV suggest an increase in cardiac autonomic modulation in individuals with MetS after 16 weeks of periodized AIT.

High-Intensity Intermittent Exercise and Autonomic Modulation: Effects of Different Volume Sessions.

The aim of this study was to compare heart rate variability (HRV) recovery after 2 sessions of high-intensity intermittent exercise at different volumes (1.25 km [HIIE1.25] and 2.5 km [HIIE2.5]). 13 participants determined their maximal aerobic speed (MAS) and completed 2 HIIE (1:1 at 100% MAS) trials. The heart rate was recorded before and after each session. HRV indicators were calculated according to time (RMSSD and SDNN) and frequency (LF, HF and LF/HF ratio) domains. SDNN and RMSSD presented effect of test (F=20.97; p<0.01 and F=21.00; p<0.01, respectively) and moment (F=6.76; p<0.01 and F=12.30; p<0.01, respectively), without interaction. Even though we did not find an interaction effect for any HRV variables, the HIIE2.5 presented a delay of only 5 min in HRV recovery, when compared to HIIE1.25. However, the effects of the test (SDNN, RMSSD, LF-log, and HF-log) indicate higher autonomic stress during the entire recovery period. These findings may indicate that exercise volume interferes with HRV recovery. If so, physically active subjects may choose a lower volume exercise (i. e., HIIE1.25) in order to promote similar physical fitness adaptations with lower loading on autonomic modulation.

Genome-level determination of Plasmodium falciparum blood-stage targets of malarial clinical immunity in the Peruvian Amazon.

BACKGROUND: Persons with blood-stage Plasmodium falciparum parasitemia in the absence of symptoms are considered to be clinically immune. We hypothesized that asymptomatic subjects with P. falciparum parasitemia would differentially recognize a subset of P. falciparum proteins on a genomic scale. METHODS AND FINDINGS: Compared with symptomatic subjects, sera from clinically immune, asymptomatically infected individuals differentially recognized 51 P. falciparum proteins, including the established vaccine candidate PfMSP1. Novel, hitherto unstudied hypothetical proteins and other proteins not previously recognized as potential vaccine candidates were also differentially recognized. Genes encoding the proteins differentially recognized by the Peruvian clinically immune individuals exhibited a significant enrichment of nonsynonymous nucleotide variation, an observation consistent with these genes undergoing immune selection. CONCLUSIONS: A limited set of P. falciparum protein antigens was associated with the development of naturally acquired clinical immunity in the low-transmission setting of the Peruvian Amazon. These results imply that, even in a low-transmission setting, an asexual blood-stage vaccine designed to reduce clinical malaria symptoms will likely need to contain large numbers of often-polymorphic proteins, a finding at odds with many current efforts in the design of vaccines against asexual blood-stage P. falciparum.

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.

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.