Search

PURPOSE Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19– relapses and explore treatment variables associated with inferior survival. METHODS We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19–; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19– relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19– 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19– relapse is distinctly associated with decreased survival outcomes.

OBJECTIVE Intraoperative stimulation is used as a crucial adjunct in neurosurgical oncology, allowing for greater extent of resection while minimizing morbidity. However, limited data exist regarding the impact of cortical stimulation on the frequency of perioperative seizures in these patients. METHODS A retrospective chart review of patients undergoing awake craniotomy with electrocorticography data by a single surgeon at the authors’ institution between 2013 and 2020 was conducted. Eighty-three patients were identified, and electrocorticography, stimulation, and afterdischarge (AD)/seizure data were collected and analyzed. Stimulation characteristics (number, amplitude, density [stimulations per minute], composite score [amplitude × density], total and average stimulation duration, and number of positive stimulation sites) were analyzed for association with intraoperative seizures (ISs), ADs, and postoperative clinical seizures. RESULTS Total stimulation duration (p = 0.005), average stimulation duration (p = 0.010), and number of stimulations (p = 0.020) were found to significantly impact AD incidence. A total stimulation duration of more than 145 seconds (p = 0.04) and more than 60 total stimulations (p = 0.03) resulted in significantly higher rates of ADs. The total number of positive stimulation sites was associated with increased IS (p = 0.048). Lesions located within the insula (p = 0.027) were associated with increased incidence of ADs. Patients undergoing repeat awake craniotomy were more likely to experience IS (p = 0.013). Preoperative antiepileptic drug use, seizure history, and number of prior resections of any type showed no impact on the outcomes considered. The charge transferred to the cortex per second during mapping was significantly higher in the 10 seconds leading to AD than at any other time point examined in patients experiencing ADs, and was significantly higher than any time point in patients not experiencing ADs or ISs. Although the rate of transfer for patients experiencing ISs was highest in the 10 seconds prior to the seizure, it was not significantly different from those who did not experience an AD or IS. CONCLUSIONS The data suggest that intraoperative cortical stimulation is a safe and effective technique in maximizing extent of resection while minimizing neurological morbidity in patients undergoing awake craniotomies, and that surgeons may avoid ADs and ISs by minimizing duration and total number of stimulations and by decreasing the overall charge transferred to the cortex during mapping procedures.

ObjectiveDigital exposure notifications (DEN) systems were an emergency response to the coronavirus disease 2019 (COVID-19) pandemic, harnessing smartphone-based technology to enhance conventional pandemic response strategies such as contact tracing. We identify and describe performance measurement constructs relevant to the implementation of DEN tools: (1) reach (number of users enrolled in the intervention); (2) engagement (utilization of the intervention); and (3) effectiveness in preventing transmissions of COVID-19 (impact of the intervention). We also describe WA State’s experience utilizing these constructs to design data-driven evaluation approaches.MethodsWe conducted an environmental scan of DEN documentation and relevant publications. Participation in multidisciplinary collaborative environments facilitated shared learning. Compilation of available data sources and their relevance to implementation and operation workflows were synthesized to develop implementation evaluation constructs.ResultsWe identified 8 useful performance indicators within reach, engagement, and effectiveness constructs.DiscussionWe use implementation science to frame the evaluation of DEN tools by linking the theoretical constructs with the metrics available in the underlying disparate, deidentified, and aggregate data infrastructure. Our challenges in developing meaningful metrics include limited data science competencies in public health, validation of analytic methodologies in the complex and evolving pandemic environment, and the lack of integration with the public health infrastructure.ConclusionContinued collaboration and multidisciplinary consensus activities can improve the utility of DEN tools for future public health emergencies.

Objectives: Smartphone-based digital exposure notification (EN) tools were introduced during the COVID-19 pandemic to supplement strained case investigation and contact tracing efforts. We examined the influence of an EN tool implemented in Washington State, WA Notify, on user engagement in behaviors that protect against COVID-19 transmission. Methods: From January 25 through June 30, 2021, we administered 2 surveys to WA Notify users who received notification of a possible COVID-19 exposure. The initial survey, sent when users received a notification, focused on intent to engage in protective behaviors. The follow-up survey captured data on self-reported actual engagement in protective behaviors and contact by a public health contact tracer. Results: Of 1507 WA Notify users who completed the initial survey, 40.1% (n = 604) reported intending to seek COVID-19 testing and 67.1% (n = 1011) intended to watch for COVID-19 symptoms. Of 407 respondents to the follow-up survey, 57.5% (n = 234) reported getting tested and 84.3% (n = 343) reported watching for COVID-19 symptoms. Approximately 84% (n = 1266) of respondents to the initial survey received a notification from WA Notify before being reached by public health contact tracers; on follow-up, 42.5% (n = 173) of respondents reported never being contacted by public health. Conclusions: Our findings suggest that WA Notify users may initiate protective behaviors earlier than nonusers who will not know of an exposure until notified by public health or by a known contact. Digital EN tools may be a valuable addition to existing public health outbreak investigation and response activities.

OBJECTIVES In recent years, increased anti-immigrant hostility has trickled into school settings creating toxic climates for immigrant-origin (I-O) students (Rogers, School and society in the age of trump, 2019, UCLA's Institute for Democracy, Education, and Access). Through youth participatory action research (yPAR), this study qualitatively examined how a class of Emerging Bilingual (EB) students aimed to promote more inclusive learning environments by designing, implementing, and evaluating a school-wide program. Here, we consider how the students experienced growth in their civic development as well as how they contended with resistances encountered during the project. METHODS The current study took place at a majority I-O, northeastern high school and was led by an EB class (n = 20) and its teacher. Participants were as follows: on average 16.5 years; 60% female; and 65% Latinx, 30% Black, and 5% mixed-race (Black-Latino). Multiple data sources documenting the students' experiences were collected (including weekly student reflections and ethnographic field notes) and then thematically analyzed using open coding. RESULTS Participating students demonstrated civic development as evidenced through: growing confidence that the program could generate positive change; enhanced sense of connection toward their classmates; and increased commitment to future civic engagement. Nonetheless, some participants demonstrated initial trepidation in both disclosing their migration stories as well as the potential efficacy of engaging in the project. Furthermore, others were disappointed by the disinterest displayed by some of their peers and teachers. CONCLUSIONS Collaborative research can support I-O youths' civic development, though, the resistances encountered and engendered illuminate possible challenges to ensure its benefits. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

International audience; ObjectivesLupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN.MethodsWIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2–3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events.ResultsBetween 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI −1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups.ConclusionsNon-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares.Trial registration numberNCT01284725.

This study evaluates the effectiveness of the Veterans Crisis Line on immediate call outcomes (i.e., caller distress, suicidal ideation, and suicidal urgency) for veterans who provide identifying information.Coders rated pre- and post-distress, suicidal ideation, and suicidal urgency for 647 calls from 2019 veteran callers. Intraclass correlation coefficients examined inter-rater reliability. Multilevel generalized linear modeling examined pre-post changes.Inter-rater reliability was good for distress, excellent for suicidal ideation, and fair for urgency. Callers had 5 times greater odds of a reduction in distress (AOR=5.03, 95% CI=3.98, 6.49), almost 5 times greater odds of a reduction in suicidal ideation (AOR=4.92, 95% CI=3.49, 6.94), and 11 times greater odds of a reduction in suicidal urgency (AOR=11.01, 95% CI=2.72, 44.50) at the end of calls than at the beginning.Veterans Crisis Line callers who provide identifying information experience reductions in distress and suicidal ideation during the call. Research is needed to examine the reduction in suicidal urgency because of fair reliability, generalizability of results to other callers, post-call treatment contact and engagement, and risk for suicide attempts and death.

Intracranial hemorrhage (ICH) is considered an emergency that requires rapid medical or surgical management. Previous studies have used artificial intelligence to attempt to expedite the diagnosis of this pathology on neuroimaging. However, these studies have used local, institution-specific data for training of networks that limit deployment of across broader hospital networks or regions because of data biases.To demonstrate the creation of a neural network based on an openly available imaging data tested on data from our institution demonstrating a high-efficacy, institution-agnostic network.A data set was created from publicly available noncontrast computed tomography images of known ICH. These data were used to train a neural network using distinct windowing and augmentation. This network was then validated in 2 phases using cohort-based (phase 1) and longitudinal (phase 2) approaches.Our convolutional neural network was trained on 752 807 openly available slices, which included 112 762 slices containing intracranial hemorrhage. In phase 1, the final network performance for intracranial hemorrhage showed a receiver operating characteristic curve (AUC) of 0.99. At the inflection point, our model showed a sensitivity of 98% at a threshold specificity of 99%. In phase 2, we obtained an AUC of 0.98 after analysis of 726 scans with a negative predictive value of 99.70% (n = 726).We demonstrate an effective neural network trained on completely open data for screening ICH at an unrelated institution. This study demonstrates a proof of concept for screening networks for multiple sites while maintaining high efficacy.

Objective The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. Methods This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. Results Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. Conclusion We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.

Driving is a risky activity, and road users' behavior is one of the many factors that participate in increasing the risk of road-traffic crashes. Drivers must constantly adapt their behavior to the environment and control their vehicles, and must also anticipate the behavior of others, which may pose a threat to their own safety. Interactions between road users can therefore be stressful and elicit strong negative emotions. Psychological resources and vulnerabilities may be important in understanding how drivers perceive and respond to these driving interactions. The aim of this study was to investigate the role of empathy, self-compassion, personal distress, and alexithymia in both dangerous and prosocial driving behaviors.Our sample (N = 550) of French drivers was recruited via snowball sampling. The drivers filled in paper-and-pencil questionnaires including the Driver Behavior Questionnaire (DBQ), the French adaptation of the Toronto Empathy Questionnaire (Short-FTEQ), the Interpersonal Reactivity Index (IRI), the Self-Compassion Scale - Short Form (SCS-SF), and the Toronto Alexithymia Scale (TAS-20).After controlling for gender and age, regression analyses revealed that road traffic violations were positively predicted by alexithymia and negatively predicted by cognitive empathy; errors were positively predicted by alexithymia and personal distress, and prosocial driving was positively predicted by emotional and cognitive empathy. A two-step cluster analysis identified three groups of drivers: unsafe and psychologically vulnerable (n = 176), self-focused and less prosocial (n = 151), and safe and resourceful (n = 223).Empathy seems to promote safe driving behaviors. Moreover, cognitive empathy appears to safeguard drivers against deliberate violations, whereas psychological vulnerabilities seem to increase the probability of engaging in dangerous behaviors. Practical Applications: These results could open new research avenues for the prevention of dangerous driving behaviors and the promotion of road safety.

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various causes that may influence prognosis. Methods and results We extracted the electronic medical records for 2180 consecutive patients hospitalized between 2016 and 2019 for decompensated heart failure. Using a text mining algorithm looking for a left ventricular ejection fraction ≥50% and plasma brain natriuretic peptide level >100 pg/mL, we identified 928 HFpEF patients. We screened for a prevailing cause of HFpEF according to European guidelines and found that 418 (45.0%) patients had secondary HFpEF due to either myocardial (n = 125, 13.5%) or loading condition abnormalities (n = 293, 31.5%), while the remaining 510 (55.0%) patients had idiopathic HFpEF. We assessed the association between the causes of HFpEF and survival collected up to 31 December 2020 using Cox proportional hazards analysis. Even though patients with idiopathic HFpEF were older, frequently female, and had frequent co‐morbidities and a higher crude mortality rate compared with secondary HFpEF patients, their prognosis was similar after adjustment for age and sex. Unsupervised clustering analysis revealed three main phenogroups with different distribution of idiopathic vs. secondary HFpEF. The phenogroup with the highest proportion of idiopathic HFpEF (69%) had (i) an excess rate of non‐cardiac co‐morbidities including chronic obstructive pulmonary disease (31%) or obesity (41%) and (ii) a better prognosis compared with the two other phenogroups enriched with secondary HFpEF. Conclusions Aetiological classification provides clinical and prognostic information and may be useful to better decipher the clinical heterogeneity of HFpEF., Condensed abstract The identification of specific aetiologies was possible in almost half of patients with heart failure with preserved ejection fraction (HFpEF). Compared with patients with secondary HFpEF, patients with idiopathic HFpEF were older, frequently female, and had a higher proportion of co‐morbidities and high crude mortality rates, but their prognosis was similar after adjustment for age and sex. Unsupervised cluster analysis, however, indicated that idiopathic HFpEF patients were mostly grouped into separate cluster with a better prognosis. Aetiological classification provides clinical and prognostic information and may be useful to better decipher the clinical heterogeneity of HFpEF.

Abstract. Background: Communication campaigns offer a portable intervention to effectively reach and engage target populations at risk for suicide including US veterans. Few studies have evaluated such efforts, and still fewer have examined factors that contribute to failed suicide prevention messaging. Aims: We aimed to examine characteristics of suicide prevention messages and persuasive processes that may underlie failed communicative intervention with US veterans. Method: Telephone interviews were completed with veterans ( N = 33) from June to September 2016 using a semi-structured interview guide. Interview transcripts were coded by the authors with NVivo using a constant comparison analytic strategy. Results: Several reasons emerged for why suicide prevention messaging may fail to produce intended responses among veterans. Participants identified message features (e.g., language, images, messenger) and communication strategies that may diminish campaign effects. Limitations: Findings are not generalizable, are limited to participants who used VA healthcare and were not suicidal, and are subject to several biases. Conclusion: This work provides initial insights into barriers to effective message use with veterans.

Background Obesity in pregnancy is common, with more than 50% of pregnant women being overweight or obese. Obesity has been identified as an independent predictor of dysfunctional labor and is associated with increased risk of failed induction of labor resulting in cesarean section. Leptin, an adipokine, is secreted from adipose tissue under the control of the obesity gene. Concentrations of leptin increase with increasing percent body fat due to elevated leptin production from the adipose tissue of obese individuals. Interestingly, the placenta is also a major source of leptin production during pregnancy. Leptin has regulatory effects on neuronal tissue, vascular smooth muscle, and nonvascular smooth muscle systems. It has also been demonstrated that leptin has an inhibitory effect on myometrial contractility with both intensity and frequency of contractions decreased. These findings suggest that leptin may play an important role in dysfunctional labor and be associated with the outcome of induction of labor at term. Our aim is to determine whether maternal plasma leptin concentration is indicative of the outcome of induction of labor at term. We hypothesize that elevated maternal plasma leptin levels are associated with a failed term induction of labor resulting in a cesarean delivery. Methods In this case-control study, leptin was measured in 3rd trimester plasma samples. To analyze labor outcomes, 174 women were selected based on having undergone an induction of labor (IOL), (115 women with successful IOL and 59 women with a failed IOL). Plasma samples and clinical information were obtained from the UI Maternal Fetal Tissue Bank (IRB# 200910784). Maternal plasma leptin and total protein concentrations were measured using commercially available assays. Bivariate analyses and logistic regression models were constructed using regression identified clinically significant confounding variables. All variables were tested at significance level of 0.05. Results Women with failed IOL had higher maternal plasma leptin values (0.5 vs 0.3 pg, P = 0.01). These women were more likely to have obesity (mean BMI 32 vs 27 kg/m2, P = 0.0002) as well as require multiple induction methods (93% vs 73%, p = 0.008). Logistic regression showed Bishop score (OR 1.5, p P P = 0.010), use of multiple methods of induction (OR 0.22, P = 0.008) and leptin (OR 0.42, P = 0.017) were significantly associated with IOL outcome. Specifically, after controlling for BMI, Bishop Score, and preeclampsia, leptin was still predictive of a failed IOL with an odds ratio of 0.47 (P = 0.046). Finally, using leptin as a predictor for fetal outcomes, leptin was also associated with of fetal intolerance of labor, with an odds ratio of 2.3 (P = 0.027). This association remained but failed to meet statistical significance when controlling for successful (IOL) (OR 1.5, P = 0.50). Conclusions Maternal plasma leptin may be a useful tool for determining which women are likely to have a failed induction of labor and for counseling women about undertaking an induction of labor versus proceeding with cesarean delivery.

Background Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. Methods We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. Results We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. Conclusion These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.

High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.

International audience; Background and objectives Kidney impairment of ANCA-associated vasculitides can lead to kidney failure. Patients with kidney failure may suffer from vasculitis relapses but are also at high risk of infections and cardiovascular events, which questions the maintenance of immunosuppressive therapy. Design, setting, participants, & measurements Patients with ANCA-associated vasculitides initiating long-term dialysis between 2008 and 2012 in France registered in the national Renal Epidemiology and Information Network registry and paired with the National Health System database were included. We analyzed the proportion of patients in remission off immunosuppression over time and overall and event-free survival on dialysis (considering transplantation as a competing risk). We compared the incidence of vasculitis relapses, serious infections, cardiovascular events, and cancers before and after dialysis initiation. Results In total, 229 patients were included: 142 with granulomatous polyangiitis and 87 with microscopic polyangiitis. Mean follow-up after dialysis initiation was 4.6±2.7 years; 82 patients received a kidney transplant. The proportion of patients in remission off immunosuppression increased from 23% at dialysis initiation to 62% after 5 years. Overall survival rates on dialysis were 86%, 69%, and 62% at 1, 3, and 5 years, respectively. Main causes of death were infections (35%) and cardiovascular events (26%) but not vasculitis flares (6%). The incidence of vasculitis relapses decreased from 57 to seven episodes per 100 person-years before and after dialysis initiation ( P =0.05). Overall, during follow-up, 45% of patients experienced a serious infection and 45% had a cardiovascular event, whereas 13% experienced a vasculitis relapse. Conclusions The proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increases with time spent on dialysis. In this cohort, patients were far less likely to relapse from their vasculitis than to display serious infectious or cardiovascular events. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN03190321.mp3

ImportanceResults of randomized clinical trials have demonstrated rituximab’s noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)–associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3–positive AAV.ObjectiveTo compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients.Design, Setting, and ParticipantsThis comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022.ExposuresAt least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018.Main Outcomes and MeasuresThe primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity.ResultsAmong 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3–ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA–positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]).Conclusions and RelevanceIn this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

Objective Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort. Methods We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy. Results Sixty-three patients [27 women, median age 60 years (18–83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1–296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation. Conclusion Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.

Background Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail. Methods In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value. Results We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype. Conclusions Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.

OBJECTIVE: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy. METHODS: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy. RESULTS: The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure. CONCLUSION: Our results suggest potential for ASC-directed therapy in refractory lupus nephritis.

International audience; Background: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined.Methods: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being.Results: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS.Conclusions: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

Background The purpose of this study was to investigate allogenic immune responses following the transplantation of insulin-producing cells (IPCs) differentiated from human adipose tissue-derived stem cells (hAT-MSCs) into humanized mice. Methods hAT-MSCs were isolated from liposuction aspirates obtained from HLA-A2-negative healthy donors. These cells were expanded and differentiated into IPCs. HLA-A2-positive humanized mice (NOG-EXL) were divided into 4 groups: diabetic mice transplanted with IPCs, diabetic but nontransplanted mice, nondiabetic mice transplanted with IPCs and normal untreated mice. Three million differentiated cells were transplanted under the renal capsule. Animals were followed-up to determine their weight, glucose levels (2-h postprandial), and human and mouse insulin levels. The mice were euthanized 6–8 weeks posttransplant. The kidneys were explanted for immunohistochemical studies. Blood, spleen and bone marrow samples were obtained to determine the proportion of immune cell subsets (CD4+, CD8+, CD16+, CD19+ and CD69+), and the expression levels of HLA-ABC and HLA-DR. Results Following STZ induction, blood glucose levels increased sharply and were then normalized within 2 weeks after cell transplantation. In these animals, human insulin levels were measurable while mouse insulin levels were negligible throughout the observation period. Immunostaining of cell-bearing kidneys revealed sparse CD45+ cells. Immunolabeling and flow cytometry of blood, bone marrow and splenic samples obtained from the 3 groups of animals did not reveal a significant difference in the proportions of immune cell subsets or in the expression levels of HLA-ABC and HLA-DR. Conclusion Transplantation of IPCs derived from allogenic hAT-MSCs into humanized mice was followed by a muted allogenic immune response that did not interfere with the functionality of the engrafted cells. Our findings suggest that such allogenic cells could offer an opportunity for cell therapy for insulin-dependent diabetes without immunosuppression, encapsulation or gene manipulations. Graphical Abstract

The detection of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1/2) as tumor driver genes in chondromas and chondrosarcomas more than ten years ago was a first major step for better understanding the molecular carcinogenenesis of these rare mesenchymal tumors. Within the TCA cycle, wild-typ IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH mutations catalyze the production of a non-physiological metabolite, D-2hydroxyglutarate (D-2HG) from α-KG. D-2HG can inhibit the class of α-KG-dependent enzymes by binding competitively to its receptor. Important enzyme families, such as the Ten-Eleven Translocation (TET) family of 5-methylcytosine hydroxylases and the Jumonji family of histone lysine demethylases are α-KG dependent. Many of the TET and Jumonji family-dependent enzymes regulate epigenetic factors, such as DNA methylation, histone modification, and nucleosome remodeling, underscoring the central role of the epigenome in cancer development. When D-2HG acts with these enzymes instead α-KG their functions will be in disarray with heavily hypermethylated DNA and dysregulations in histone metylation. NcRNAs have increasingly been described as a cornerstone of cancer development. Therefore this review describes exemplarily the oncogenic functions of miRNAs in chondrosarcoma in more detail. Particularly in chondrosarcomas additional carcinogenic features are aquired by interactions of ncRNAs with α-KG-dependent epigenetic regulators. Distinct ncRNAs, miRNAs and lncRNAs alike, are involved in deregulating important cellular signalling pathways and thus contributing further to malignant transformation and development of malignant cellular traits in these rare mesenchymal tumors. This review specially empasizes the complex interactions between the world of ncRNAs and genetics and epigenetics.

Objective: Double-positive patients (DPPs), combining serum and/or histological findings for glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCAs), are rare and poorly described. This study aimed to compare characteristics between DPPs and ANCA-associated vasculitis (AAV) patients with severe renal involvement.Method: This retrospective multicentre study compared 33 DPPs and 45 AAV patients with severe renal involvement (serum creatinine > 300 μmol/L), all with biopsy-proven nephropathy.Results: All DPPs (including 18% exhibiting negative serum anti-GBM antibodies) presented severe acute kidney failure with histological GBM involvement. Compared to AAV patients, they had higher serum creatinine (719 vs 501 μmol/L; p = 0.006) and a higher proportion of patients requiring initial renal replacement therapy (82% vs 36%; p < 0.001). Berden classification differed significantly (p = 0.003), with more crescentic glomerulonephritis and fewer sclerotic lesions in DPPs. One-year renal survival was significantly lower in DPPs than in AAV patients (27% vs 64%; p < 0.0002). With comparable proportions of ANCA subtypes (two-thirds with anti-myeloperoxidase autoantibodies), numbers of extrarenal manifestations (mostly pulmonary in two-thirds), remission-inducing immunosuppressants, and median follow-ups (3 years) between groups, relapse rates were similar: 9.1% of DPPs and 10% of AAV patients.Conclusion: Although DPPs have features of both kinds of vasculitis, the anti-GBM component is the dominant phenotype, with more severe renal presentation and prognosis compared to AAV patients with severe renal failure. Simultaneous testing of both antibodies and systematically performed renal biopsy should be recommended in all rapidly progressing glomerulonephritis patients to recognize this difficult-to-treat, rare disease.

Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p

The standard of care for idiopathic normal pressure hydrocephalus (iNPH) is placement of a ventriculoperitoneal (VP) shunt. However, VP shunts require intracranial intervention and are associated with notable postoperative complications, with some groups reporting complication rates for VP shunts ranging from 17 to 33%, along with failure rates up to 17.7%. Lumboperitoneal (LP) shunts are an alternative for cerebrospinal fluid diversion that do not require intracranial surgery, thus providing utility in patients where intracranial surgery is not possible or preferred. Here we retrospectively reviewed our 25 patients with LP horizontal-vertical (LP-HV) shunts placement for initial treatment for iNPH from 2014 to 2019. All patients had preoperative gait dysfunction, 16 (64%) had urinary incontinence, and 21 (84%) exhibited cognitive insufficiency. Two weeks post-shunt placement, 23/25 (92%) patients demonstrated improvement in gait, 11/16 (68%) had improvement in incontinence, and 14/21 (66%) had improvement cognitive insufficiency. At six months or greater follow up 13/20 (65%) had improvement in gait, 7/15 (47%) showed improvement in incontinence, and 11/15 (73%) demonstrated improvement in cognitive function. Six patients (24%) required at least one revision of the LP shunt. Shunt malfunctions resulted from CSF leak in one patient, shunt catheter migration in two patients, peritoneal catheter pain in one patient, and clinical symptoms for overdrainage in two patients. Thus, we demonstrate that LP-HV shunt placement is safe and efficacious alternative to VP shunting for iNPH, resulting in notable symptomatic improvement and low risk of overdrainage, and may be considered for patients where cranial approaches should be avoided.

Two-thirds of veteran suicides are attributable to firearm injury. Although half of veterans who die by suicide are seen in primary care settings in the month prior to death, little is known about how to promote firearm safety within primary care. Describe veterans’ perspectives on discussing firearms storage safety (FSS) during primary care visits, and identify key strategies for primary care teams to use in discussing FSS with veterans at elevated risk for suicide. Qualitative analysis of transcripts and notes from four veteran focus groups and from individual semi-structured interviews with six veterans. Altogether, 68 veterans participated. Three of the groups were associated with one Veterans Health Administration facility. Groups were diverse in age, service era, and gender. The goals of the focus groups and interviews were to assess acceptance of FSS discussions during primary care visits, identify facilitators and barriers to conducting FSS discussions, and identify strategies for primary care teams to use to effectively conduct FSS discussions. Transcripts and meeting notes were analyzed using a grounded theory approach. There was general acceptance of having FSS discussions in primary care. Yet, most veterans did not support direct questioning about firearm ownership, which may trigger fears of having firearms taken away or limit access to firearms. Participants recommended primary care teams provide rationale for FSS discussions and be prepared to provide information on legal consequences of disclosing firearm ownership. Strategies suggested for primary care staff also included using a personalized, caring, and conversational approach rather than highly scripted or checklist approach, engaging veterans in a non-judgmental manner, and conveying respect for veterans’ knowledge of firearms. Discussing FSS with veterans in primary care settings is a promising upstream approach that can complement other suicide prevention efforts, but must be conducted in a veteran-centric manner.

The sociopolitical context for immigrant-origin (I-O) youth's civic development in the U.S. has dramatically shifted in the years following the 2016 election (e.g., heightened xenophobia). I-O children comprise 26% of young people in the U.S. and include those born outside the U.S. (first generation) and those with at least one parent born outside the U.S. (second generation). Using a qualitative approach, this study examined how I-O youth (N = 65, M = 16.22 years) experienced and engaged with the phenomena of the 2020 election season amidst recent economic, political, and social consequences from the pandemic and the current social movements against systemic racism. Findings expand our understanding of how I-O youth engage as political actors by examining the processes surrounding their sociopolitical development.

IntroductionPrognosis of lupus nephritis (LN) among patients of African descent living in Europe has been understudied.MethodsIn a retrospective study performed in two European university hospitals, we compared the prognosis of LN in patients of African descent or Caucasians. Remission was defined as a urine protein to creatinine (uP/C) ratio1 g/g, leading to a repeat kidney biopsy and/or immunosuppressive treatment change. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate≤60 mL/min/1.73 m2. Adherence was retrospectively assessed through medical files and/or hydroxychloroquine level measurements.Results52 patients of African descent and 85 Caucasian patients were included in this analysis. Class III and isolated class V LN were more common among patients of African descent. Time to first renal remission did not differ between ethnic subgroups. By contrast, patients of African descent suffered from earlier renal flares, CKD was more common and time to CKD was shorter after a flare. In a multivariate analysis, African ancestry was an independent risk factor for progression to CKD. We observed no significant difference in non-adherence to treatment between the two groups.ConclusionLN patients of African descent have worse renal outcomes, mainly explained by a higher rate of renal flare.

While neurosurgeons are experienced in treating penetrating brain injuries (PBIs) in civilian settings, much less is known about management and outcomes of PBIs in military settings.A systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Data extracted included surgical management, age, gender, location/type of injury, initial Glasgow Coma Scale (GCS) score, and outcomes. The primary outcomes were last reported Glasgow Outcome Score (GOS) and mortality. The secondary outcomes included central nervous system infections, seizures, and cerebrospinal fluid leak/fistula. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used for outcome analysis.Twelve studies with 1738 patients treated for PBIs in military settings were included. The weighted mean age was 27.8 years, 86.7% were male, and 64.3% underwent neurosurgical intervention. Most patients (64.3%) presented with a GCS score8, while 31.0% presented in a coma (GCS score8). Over a median last follow-up time of 9 months, 68.6% achieved a favorable (GOS = 4-5) outcome and 34.2% achieved a poor (GCS score = 1-3) outcome. The overall mortality was 18.0%. A meta-analysis was performed using 5 of 12 studies to evaluate the effect of the presenting GCS score on primary outcomes. Patients with an initial GCS score8 had statistically significant lower odds of a favorable (GOS = 4-5) outcome (OR: 0.03; 95% CI: 0.00-0.19; P: 0.000) and higher odds of mortality (OR: 28.46; 95% CI: 8.62-94; P: 0.000) than patients with an initial GCS score8. The pooled rates of central nervous system infection, seizures, and cerebrospinal fluid leak/fistula were 13.8%, 13.2%, and 5.4%, respectively.In this first systematic review and meta-analysis of outcomes following combat-related PBIs, a GCS score8 at presentation was found to be an important predictor of a favorable GOS and decreased mortality.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved forthis indication. Currently, patients receive a single dose of tisagenlecleucel across a wide doserange of 0.2 to 5.0× 106 and 0.1 to 2.5× 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7× 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300× 106 (n= 48 [27%]), 1.301 to 1.700× 106 (n= 46 [26%]), 1.701 to 2.400×106 (n= 43 [24%]), and 2.401 to 5.100× 106 (n= 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P= .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard totargeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

Background Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4. Methods Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures. Results High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4. Conclusion The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.

Objective To describe the main features at diagnosis and evolution over time of patients with localized granulomatosis with polyangiitis (L-GPA) compared with those of systemic GPA (S-GPA). Methods EULAR definitions of L-GPA, i.e. upper and/or lower respiratory tract involvement, and S-GPA were applied to patients from the French Vasculitis Study Group Registry. L-GPA and S-GPA patients’ characteristics at diagnosis and long-term outcomes were analysed and compared. Results Among the 795 Registry patients, 79 (10%) had L-GPA. Their main clinical manifestations were rhinitis, lung nodules, sinusitis and otitis. L-GPA vs S-GPA patients at diagnosis, respectively, were younger, more frequently had saddle nose deformity or subglottic stenosis and were less often PR3-ANCA–positive. L-GPA vs S-GPA induction therapy less frequently included CYC but more often a combination of MTX and glucocorticoids; 64% of MTX-treated patients experienced disease progression within 18 months post-diagnosis. L- and S-GPA patients’ estimated relapse-free–survival probabilities, relapse rates and refractory disease rates at each time point were comparable, but L-GPA patients had more frequent ENT and lung relapses, and higher overall survival rates (P Conclusions The relapse risks of L-GPA and S-GPA were similar, but relapse patterns differed and L-GPA overall survival rate was higher. About one-quarter of L-GPA patients developed S-GPA over time, but without end-stage organ involvement.

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness. ispartof: NATURE vol:605 issue:7911 pages:747-+ ispartof: location:England status: published

Pathogenic mutations of CYP24A1 lead to an impaired catabolism of vitamin D metabolites and should be considered in the differential diagnosis of hypercalcemia with low parathyroid hormone concentrations. Diagnosis is based on a reduced 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D ratio and confirmed by genetic analyses. Pregnancy is associated with an upregulation of the active vitamin D hormone calcitriol and may thus particularly trigger hypercalcemia in affected patients. We present a case report and a narrative review of pregnant women with CYP24A1 mutations (13 women with 29 pregnancies) outlining the laboratory and clinical characteristics during pregnancy and postpartum and the applied treatment approaches. In general, pregnancy triggered hypercalcemia in the affected women and obstetric complications were frequently reported. Conclusions on drugs to treat hypercalcemia during pregnancy are extremely limited and do not show clear evidence of efficacy. Strictly avoiding vitamin D supplementation seems to be effective in preventing or reducing the degree of hypercalcemia. Our case of a 24-year-old woman who presented with hypercalcemia in the 24th gestational week delivered a healthy baby and hypercalcemia resolved while breastfeeding. Pathogenic mutations of CYP24A1 mutations are rare but should be considered in the context of vitamin D supplementation during pregnancy.

BackgroundThe COVID-19 pandemic and the associated infection prevention and control measures had a negative impact on the mental health of many people. In the United Arab Emirates (UAE), infection control measures implemented after March 24th, 2020, placed necessary restrictions on people's freedom of movement.AimThis study aimed to assess the association between levels of daytime vs. nighttime outdoor activity and mental health among a sample of UAE residents during the lockdown period.MethodAn opportunity sample of 245 participants completed an online survey assessing levels of depression, somatic symptoms, daytime and nighttime activity levels.ResultsMultivariate logistic regression revealed that daytime activity, but not nighttime activity, was associated with a lower risk of clinically significant depressive and somatic symptomatology.ConclusionThe association of better mental health with daytime not nighttime outdoor activity could be possibly attributed to vitamin D, but further studies are needed to confirm this speculation.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range

Phenomenon: Because of its importance in residency selection, the United States Medical Licensing Examination Step 1 occupies a critical position in medical education, stimulating national debate about appropriate score use, equitable selection criteria, and the goals of undergraduate medical education. Yet, student perspectives on these issues and their implications for engagement with health systems science-related curricular content are relatively underexplored. Approach: We conducted an online survey of medical students at 19 American allopathic medical schools from March-July, 2019. Survey items were designed to elicit student opinions on the Step 1 examination and the impact of the examination on their engagement with new, non-test curricular content related to health systems science. Findings: A total of 2856 students participated in the survey, representing 23.5% of those invited. While 87% of students agreed that doing well on the Step 1 exam was their top priority, 56% disagreed that studying for Step 1 had a positive impact on engagement in the medical school curriculum. Eighty-two percent of students disagreed that Step 1 scores should be the top item residency programs use to offer interviews. When asked whether Step 1 results should be reported pass/fail with no numeric score, 55% of students agreed, while 33% disagreed. The majority of medical students agreed that health systems science topics were important but disagreed that studying for Step 1 helped learn this content. Students reported being more motivated to study a topic if it was on the exam, part of a course grade, prioritized by residency program directors, or if it would make them a better physician in the future. Insights: These results confirm the primacy of the United States Medical Licensing Examination Step 1 exam in preclinical medical education and demonstrate the need to balance the objectives of medical licensure and residency selection with the goals of the broader medical profession. The survey responses suggest several potential solutions to increase student engagement in health systems science curricula which may be especially important after Step 1 examination results are reported as pass/fail.