The transition into adolescence involves a number of changes that for many adolescents result in increased negative affect and internalizing symptoms, especially for females. In the current study we ...examined the direct and indirect effects of emotional awareness on internalizing symptoms by exploring the extent to which certain emotion regulation strategies influence this relationship. Participants were 123 female adolescents aged 13–16 years (
M
= 14.51 years) who completed measures of emotional awareness, emotion regulation (emotional reappraisal and expressive suppression), and symptoms of depression and social anxiety. Two multiple indirect effect models were conducted including both reappraisal and suppression (one for each of the dependent variables, depression and social anxiety) via the bootstrapping method. Results found that reappraisal accounted for the effect of emotional awareness on depressive symptoms but suppression accounted for the effect of emotional awareness on social anxiety symptoms. Results suggest that emotion regulation strategies play an important role in determining depressive and social anxiety symptoms and are associated with an adolescent’s level of emotional awareness.
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the ...high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.
Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or ...agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.
Purpose
The Hennepin Healthcare Mother-Baby Day Hospital is a partial hospital program for pregnant and postpartum women with moderate to severe psychiatric illness. Based in an urban safety net ...hospital, the Day Hospital provides trauma-informed, multigenerational, group-based therapy and psychiatric care. This report describes the program and preliminary data regarding maternal mental health and functioning at treatment entry and discharge.
Methods
Data include information on pregnant and postpartum women who were admitted to the Day Hospital between April 2013 and September 2019 and completed at least 4 days of treatment. We describe patient demographics and changes in mental health and maternal functioning.
Results
328 women consented to participation in research, representing 364 unique admissions. Primary diagnoses included major depression (55.6%;
n
= 202); generalized anxiety (36.4%;
n
= 132); bipolar spectrum (28%;
n
= 102); and trauma-related disorders (20.6%;
n
= 75). Patients reported significant improvements (
p
< 0.001) in self-report scales assessing depression, anxiety, and maternal functioning.
Conclusions
A mother-baby day hospital based in an urban safety net hospital is effective in improving mental health and parenting functioning in perinatal women with moderate to severe psychiatric illness. The high acuity and prevalence of comorbid depression, anxiety, bipolar spectrum, and trauma-related disorders support the need for trauma-informed, multigenerational approaches that address perinatal mental health and attachment-based parenting support.
CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector ...cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.
Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data ...to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies.
This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS 95%CI was measured using Kaplan–Meier Analysis and Log–Rank test.
Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.12.4–7.8 months) compared to LDHlowLM-patients (median OS: 15.38.9-NA months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.817.9-NA months (vs 13.110.8–18.5, P = 0.02) in the overall population and 30.319.93-NA months (vs 14.18.69-NA, P = 0.0013) in patients with melanoma.
LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need.
•A baseline machine learning-derived signature predicted survival on immunotherapy.•LDHhi (elevated serum LDH) and LM+ (liver metastasis) forecasted short survival.•LDHlow LM-forecasted longer survival with immunotherapy than other systemic therapies.•LDH LM status could guide clinical decision making for advanced cancer patients.
Purpose To estimate the prevalence of sperm banking among adolescent males newly diagnosed with cancer and to identify factors associated with banking outcomes. Patients and Methods A prospective, ...single-group, observational study design was used to test the contribution of sociodemographic, medical, psychological/health belief, communication, and developmental factors to fertility preservation outcomes. At-risk adolescent males (N = 146; age 13.00 to 21.99 years; Tanner stage ≥ 3), their parents, and medical providers from eight leading pediatric oncology centers across the United States and Canada completed self-report questionnaires within 1 week of treatment initiation. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% CIs for specified banking outcomes (collection attempt v no attempt and successful completion of banking v no banking). Results Among adolescents (mean age, 16.49 years; standard deviation, 2.02 years), 53.4% (78 of 146) made a collection attempt, with 43.8% (64 of 146) successfully banking sperm (82.1% of attempters). The overall attempt model revealed adolescent consultation with a fertility specialist (OR, 29.96; 95% CI, 2.48 to 361.41; P = .007), parent recommendation to bank (OR, 12.30; 95% CI, 2.01 to 75.94; P = .007), and higher Tanner stage (OR, 5.42; 95% CI, 1.75 to 16.78; P = .003) were associated with an increased likelihood of a collection attempt. Adolescent history of masturbation (OR, 5.99; 95% CI, 1.25 to 28.50; P = .025), banking self-efficacy (OR, 1.23; 95% CI, 1.05 to 1.45; P = .012), and parent (OR, 4.62; 95% CI, 1.46 to 14.73; P = .010) or medical team (OR, 4.26; 95% CI, 1.45 to 12.43; P = .008) recommendation to bank were associated with increased likelihood of sperm banking completion. Conclusion Although findings suggest that banking is underutilized, modifiable adolescent, parent, and provider factors associated with banking outcomes were identified and should be targeted in future intervention efforts.
α-Synuclein (α-Syn) is a presynaptic protein that is accumulated in its amyloid form in the brains of Parkinson's patients. Although its biological function remains unclear, α-syn has been suggested ...to bind to synaptic vesicles and facilitate neurotransmitter release. Recently, studies have found that α-syn induces membrane tubulation, highlighting a potential mechanism for α-syn to stabilize highly curved membrane structures which could have both functional and dysfunctional consequences. To understand how membrane remodeling by α-syn affects amyloid formation, we have studied the α-syn aggregation process in the presence of phosphatidylglycerol (PG) micellar tubules, which were the first reported example of membrane tubulation by α-syn. Aggregation kinetics, β-sheet content, and macroscopic protein-lipid structures were observed by Thioflavin T fluorescence, circular dichroism spectroscopy and transmission electron microscopy, respectively. Collectively, the presence of PG micellar tubules formed at a stochiometric (L/P = 1) ratio was found to stimulate α-syn fibril formation. Moreover, transmission electron microscopy and solid-state nuclear magnetic resonance spectroscopy revealed the co-assembly of PG and α-syn into fibril structures. However, isolated micellar tubules do not form fibrils by themselves, suggesting an important role of free α-syn monomers during amyloid formation. In contrast, fibrils did not form in the presence of excess PG lipids (≥L/P = 50), where most of the α-syn molecules are in a membrane-bound α-helical form. Our results provide new mechanistic insights into how membrane tubules modulate α-syn amyloid formation and support a pivotal role of protein–lipid interaction in the dysfunction of α-syn.
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•α-Syn remodels anionic PG, PA, and PS membranes into micellar tubules.•Effect of POPG on α-syn amyloid formation was probed by CD, ThT fluorescence, and TEM.•POPG micellar tubules shorten the lag phase and enhanced β-sheet formation.•POPG micellar tubules are co-assembled into α-syn fibrils.•POPG micellar tubes do not to convert into amyloids in the absence of free α-syn.
The sensitivity and resolution of single-molecule fluorescence imaging in biology are mainly limited by two known weaknesses of fluorescent proteins: label brightness and photostability. In this ...work, we use patterned gold substrates to achieve plasmon-enhanced emission from intrinsically fluorescent proteins in living pathogenic bacteria cells. By coupling membrane-bound single fluorescent protein fusions to the virulence regulator TcpP in living Vibrio cholerae bacteria to extracellular gold nanotriangle arrays, we use plasmonics to improve our measurements of this important question in pathogenesis: how does V. cholerae produce its deadly toxin? Based on a simple experimental geometry, we observe a 1.3× enhancement in the rate of emission and a 1.4× enhancement in the number of photons detected prior to photobleaching. Furthermore, by enhancing both the rate of emission and the total number of photons detected from single-molecule fluorescent probes in live cells, we show that plasmon-enhanced fluorescence is a biocompatible, generalizable path to directly improve the resolution and trajectory lengths of single molecules in live cells.
Chikungunya virus-like particles (VLPs) have potential to be used as a prophylactic vaccine based on testing in multiple animal models and are currently being evaluated for human use in a Phase I ...clinical trial. The current method for producing these enveloped alphavirus VLPs by transient gene expression in mammalian cells presents challenges for scalable and robust industrial manufacturing, so the insect cell baculovirus expression vector system was evaluated as an alternative expression technology. Subsequent to recombinant baculovirus infection of Sf21 cells in standard culture media (pH 6.2-6.4), properly processed Chikungunya structural proteins were detected and assembled capsids were observed. However, an increase in culture pH to 6.6-6.8 was necessary to produce detectable concentrations of assembled VLPs. Since this elevated production pH exceeds the optimum for growth medium stability and Sf21 culture, medium modifications were made and a novel insect cell variant (SfBasic) was derived by exposure of Sf21 to elevated culture pH for a prolonged period of time. The high-pH adapted SfBasic insect cell line described herein is capable of maintaining normal cell growth into the typical mammalian cell culture pH range of 7.0-7.2 and produces 11-fold higher Chikungunya VLP yields relative to the parental Sf21 cell line. After scale-up into stirred tank bioreactors, SfBasic derived VLPs were chromatographically purified and shown to be similar in size and structure to a VLP standard derived from transient gene expression in HEK293 cells. Total serum anti-Chikungunya IgG and neutralizing titers from guinea pigs vaccinated with SfBasic derived VLPs or HEK293 derived VLPs were not significantly different with respect to production method, suggesting that this adapted insect cell line and production process could be useful for manufacturing Chikungunya VLPs for use as a vaccine. The adaptation of Sf21 to produce high levels of recombinant protein and VLPs in an elevated pH range may also have applications for other pH-sensitive protein or VLP targets.
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