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We document that an SEC investigation of an underwriter imposes indirect penalties on the underwriter and its past clients, particularly IPO clients. Targeted underwriters experience large declines in IPO market share and increased regulatory scrutiny and client risk after an SEC investigation is announced. Stock prices of clients decline significantly. We attribute these effects to a sudden deterioration in the value of the underwriter's reputation capital, suggesting that the general assumption in prior IPO research that underwriter reputation is stationary may be inappropriate. Our results also suggest that the SEC's power to institute investigations should be considered when designing optimal securities regulation.

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

The COVID-19 pandemic and resulting lockdown had a pro- found impact worldwide, making it a highly valenced event. Prior research has indicated that during such highly valenced events, individuals’ internal states tend to synchronize, which could potentially lead to synchronized facial behaviors. To test this hypothesis, this study utilized a between-subject experimental design to examine whether individuals exhibited more synchronized facial behaviors during lockdown periods compared to the post-lockdown period, using a naturalistic viewing approach and OpenFace to extract facial action units. Our results indicated that individuals tend to exhibit more synchronized facial behaviors, particularly those associated with negative emotions, during the lockdown than post-lockdown period. Our machine-learning model accurately classified participants into their respective groups, with weights closely aligned with expressions of sadness and fear. No significant between-group differences in personality traits and behavioral tendencies were found, indicating that between-group differences in facial synchrony cannot be solely attributed to basic group differences. Our findings offer novel insights that could inform future research into the mechanisms and implications of synchronized facial behaviors as a potential collective response to external stressors.

Supplementary Movie S3 from Development and Characterization of a Novel In vivo Model of Carcinoid Syndrome

Purpose: Carcinoid syndrome, characterized by flushing, diarrhea, and valvular heart disease, can occur following carcinoid tumor metastasis to the liver and systemic release of bioactive hormones into the systemic circulation. Treatment of this devastating disease is hampered by the lack of an in vivo model that recapitulates the clinical syndrome.Experimental Design: Here, we have injected BON cells, a novel human carcinoid cell line established in our laboratory, into the spleens of athymic nude mice to establish liver metastases.Results: The majority of mice injected intrasplenically with BON cells developed significant increases in plasma serotonin and urine 5-hydroxyindoleacetic acid, and several mice exhibited mesenteric fibrosis, diarrhea, and fibrotic cardiac valvular disease reminiscent of carcinoid syndrome by both echocardiographic and histopathologic evaluation. Mice pretreated with octreotide, a long-acting somatostatin analogue, or bevacizumab, a vascular endothelial growth factor inhibitor, developed fewer liver metastases and manifestations of carcinoid syndrome, including valvular heart disease.Conclusion: We have provided an important in vivo model to further delineate novel treatment modalities for carcinoid syndrome that will also be useful to elucidate the factors contributing to the sequelae of carcinoid disease (e.g., mesenteric fibrosis and valvular heart disease).

Supplementary Figure 1. Summary of study enrollment by dose level and disease cohort. All patients were evaluated for safety and anti-tumor activity. Supplementary Table 1. Enrollment. Supplementary Table 2. Treatment-emergent adverse events occurring in at least 10% of patients treated with pinatuzumab vedotin by pooled dose cohorts and histology. Supplementary Table 3. Incidence of treatment-emergent peripheral neuropathy (PN) among patients with prior PN and/or prior vinca alkaloid treatment. Supplementary Figure 2. Cycle 1 and 3 mean ({plus minus} SD) serum/plasma concentration-time curves for total antibody, conjugate (evaluated as acMMAE), and MMAE following 2.4-mg/kg dose per cycle for every three-week cycle of single-agent pinatuzumab vedotin in B-cell lymphoma patients. Supplementary Table 4. Mean (SD) values for selected serum/plasma PK parameters of total antibody, conjugate (evaluated as acMMAE) and unconjugated MMAE following Cycle 1 doses of pinatuzumab vedotin in PK-evaluable CLL patients. Supplementary Table 5. Tabulation of demographic/clinical features for r/r NHL (combined DLBCL and iNHL) patients with and without PFS events.

Purpose: Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167–76. ©2016 AACR.

Refugee women often share histories of forced displacement, economic hardship, or gender-based violence and may face common barriers to reproductive health care access after resettlement in high-income countries. This Critical Interpretive Synthesis integrates the available data on contraceptive care for refugee women after resettlement. The review examined shared aspects of the refugee experience that impact women's access to high-quality contraceptive care and transcend the particularities of specific health systems or countries of origin. These include possible shifts in gendered norms and fertility preferences after resettlement, prior experiences with contraception in home countries, refugee camps, and other sites of first-asylum, and negative experiences with health care providers after resettlement (i.e., communication barriers or experiencing discrimination). Our findings demonstrate the need for further methodologically-rigorous research in the field of refugee reproductive health, specifically in relation to evidence-based approaches to training interpreters and providers in contraceptive care for refugees and on male partners and their influence on contraceptive use.

The Covid-19 pandemic lockdown had led to unusually mas- sive social isolation that lasted for months around the world. In order to compensate for the poverty of social life, individ- uals are likely to shift their attention from their regular social world to their inner imaginative world during this lockdown pe- riod. Thus, the purpose of this study is to investigate whether intersubject similarity in individuals’ imaginative abilities (i.e., fantasy tendency) is associated with their similarity in affective ratings of the videos they watched, and whether this associa- tion is enhanced during the pandemic lockdown period. We recruited one lockdown group and two post-lockdown groups to test the above hypothesis. During the experiment, partici- pants were asked to watch a series of videos covering a wide range of topics, and then they were asked to complete several affective appraisal ratings (e.g., liking or feeling of resonance) of each video. We then used intersubject representational similar- ity analysis (ISRSA) to map the intersubject similarity in their fantasy tendency onto their similarity in the affective appraisal ratings. Our results showed that those who were more simi- lar in their fantasy scores also showed more similarity in their affective appraisals of videos. Most importantly, this fantasy- appraisal association was particularly strong in the lockdown group, but rather weak in the post-lockdown groups. Our find- ings suggest that individual differences in their imaginative abil- ities would become a crucial factor influencing how individuals appraise their inner world during social isolation. The current study may provide an example for policymakers on how to as- sess the impact of social isolation as we may face another wave of pandemics in the future.

Alcohol use disorder (AUD) is a complex genetic disorder characterized by problems arising from excessive alcohol consumption. Identifying functional genetic variations that contribute to risk for AUD is a major goal. Alternative splicing of RNA mediates the flow of genetic information from DNA to gene expression and expands proteome diversity. We asked whether alternative splicing could be a risk factor for AUD. Herein, we used a Mendelian randomization (MR)-based approach to identify skipped exons (the dominant splicing event in brain) that contribute to AUD risk. Genotypes and RNA-seq data from the CommonMind Consortium were used as the training dataset to develop predictive models linking individual genotypes to exon skipping in the prefrontal cortex. We applied these models to data from the Collaborative Studies on Genetics of Alcoholism to examine the association between the imputed cis-regulated splicing outcome and the AUD-related traits. We identified 27 exon skipping events that were predicted to affect AUD risk; six of these were replicated in the Australian Twin-family Study of Alcohol Use Disorder. Their host genes are DRC1, ELOVL7, LINC00665, NSUN4, SRRM2 and TBC1D5. The genes downstream of these splicing events are enriched in neuroimmune pathways. The MR-inferred impacts of the ELOVL7 skipped exon on AUD risk was further supported in four additional large-scale genome-wide association studies. Additionally, this exon contributed to changes of grey matter volumes in multiple brain regions, including the visual cortex known to be involved in AUD. In conclusion, this study provides strong evidence that RNA alternative splicing impacts the susceptibility to AUD and adds new information on AUD-relevant genes and pathways. Our framework is also applicable to other types of splicing events and to other complex genetic disorders.

Chimeric antigen receptor (CAR) T-cell therapy revolutionized treatment for many patients with aggressive relapsed or refractory large B-cell lymphoma (LBCL) Treatment can be complicated by clinically evident cytokine release syndrome (CRS), which is characterized by the development of fevers, hypoxia, and hypotension and can be life-threatening. Most patients treated with CAR T cells develop CRS, which is thought to represent an immune phenomenon. It was previously unknown if patients who do not develop CRS have reduced CAR T-cell activity and therefore are likely to have worse outcomes. We conducted a multicenter retrospective analysis that included 352 adult patients treated at eight academic medical centers within the United States who received axicabtagene ciloleucel or tisagenlecleucel for treatment of LBCL. Outcomes of interest included progression free survival, overall survival, complete response rate, and overall response rate. Of the included patients, 262 (74.4%) developed CRS. There was no significant difference in progression free (p=0.99) or overall survival (p=0.16) between patients who developed CRS and those who did not. Peak ferritin during treatment >5000 and lactate dehydrogenase greater than the institutional upper limit of normal prior to lymphodepleting chemotherapy were associated in multivariate analysis with significantly worse progression free and overall survival. There was no significant difference in complete response or overall response rate between patients who did and did not develop CRS. In this retrospective analysis, we report that patients who develop CRS have similar clinical outcomes compared to patients without CRS treated with commercial anti-CD19 CAR T cells.

While the concept of ‘transit insecurity’ may seem self-explanatory, the phrase is not widely used in the current lexicon of city planning, public discourse, or in policy research. The term also lacks a widely accepted definition, scale, or metric of assessment. This scoping review will provide a definition, and explore metrics that demonstrate the extent to which a person or community is transit insecure. To arrive at this definition and set of metrics, a systematic search was conducted in three electronic databases for studies pertaining to transit insecurity. Articles were screened and assessed based on inclusion/exclusion criteria. Over 200 articles were initially identified and after review, a total of 15 articles were included in the final analysis, ranging in publication from 2005 to 2020. There were four factors found to affect transit insecurities: income level; travel distance; duration; and accessibility. By examining the impact of transit insecurity we hope to shed light on these problems and assist in proposing and studying solutions to transit insecurity.

PURPOSE OF REVIEW Given recent national attention to the role of racism in perpetuating racial inequities in society and health, this review provides a timely and relevant summary of key measures of systemic racism in kidney transplantation. More specifically, the review identifies current and promising interventions, whereas highlighting the need for more sustainable and impactful interventions. RECENT FINDINGS Racial disparities persist in kidney transplantation. Black and Hispanic individuals are less likely to receive a kidney transplant than non-Hispanic Whites despite disproportionately higher rates of kidney failure. Studies demonstrate that socioeconomic factors do not fully explain existing racial disparities in transplantation. Systemic racism at all levels, individual, interpersonal, institutional, and structural, is at the core of racial disparities, and current interventions are insufficient in mitigating their effects. Thus, targeted and sustainable interventions must be implemented to mitigate systemic racism in kidney transplantation. SUMMARY Systemic racism in all its forms continues to influence disparities at all stages of kidney transplantation. This paper highlights recent findings that shed light on how racism contributes to racial disparities in kidney transplantation. Using these findings to identify targets and strategies for mitigation, relevant interventions and policies that show promise are detailed.