Objectives
Adverse childhood experiences (ACEs) can detrimentally impact perinatal mental health, birth outcomes, and parenting behaviors. Proximal psychosocial stressors also increase risks to ...perinatal health and wellbeing. Additional research on effective perinatal mental health programs is needed, especially for individuals and families with historical and concurrent adversity, and those with moderate to severe symptoms.
Methods
The Mother-Baby Day Hospital at Hennepin County Medical Center provides trauma-informed, multi-generation treatment for perinatal women. Data were collected from patients between January 2016 and September 2019. Self-reported depression, anxiety, and maternal functioning assessments were administered pre- and post-treatment. Patients completed the ACE questionnaire and indicators of current psychosocial stressors (i.e., food insecurity, housing insecurity, and social support) at intake. A series of bivariate tests and hierarchical regression models examined relationships among variables, including whether distal and proximal adversity predicted post-treatment symptoms.
Results
159 Perinatal patients consented to research and completed the ACEs questionnaire at first admission. High proportions of patients reported 4+ ACEs and current psychosocial stressors. Effect sizes for associations between ACEs, psychosocial stressors, and self-report symptoms were small to moderate. Individuals with food or housing insecurity entered treatment with higher anxiety. In regression models, the most robust predictors of post-treatment symptoms were pre-treatment symptoms. Effects of ACEs on post-treatment depression and food insecurity on post-treatment maternal functioning approached the adjusted significance cut-off (
p
< .01).
Conclusions for Practice
Current psychosocial stressors and ACEs did not substantially limit post-treatment depression, anxiety, and maternal functioning outcomes. High prevalence of ACEs and psychosocial stressors highlight the need for trauma-informed, multi-generation treatments to improve maternal mental health and parenting capacity.
Infection with Respiratory Syncytial Virus (RSV) causes both upper and lower respiratory tract disease in humans, leading to significant morbidity and mortality in both young children and older ...adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. During the infection process, the type I viral fusion (F) glycoprotein on the surface of the RSV particle rearranges from a metastable prefusion conformation to a highly stable postfusion form. In people naturally infected with RSV, most potent neutralizing antibodies are directed to the prefusion form of the F protein. Therefore, an engineered RSV F protein stabilized in the prefusion conformation (DS-Cav1) is an attractive vaccine candidate. Long-term stability at 4°C or higher is a desirable attribute for a commercial subunit vaccine antigen. To assess the stability of DS-Cav1, we developed assays using D25, an antibody which recognizes the prefusion F-specific antigenic site Ø, and a novel antibody 4D7, which was found to bind antigenic site I on the postfusion form of RSV F. Biophysical analysis indicated that, upon long-term storage at 4°C, DS-Cav1 undergoes a conformational change, adopting alternate structures that concomitantly lose the site Ø epitope and gain the ability to bind 4D7.
The surface glycoprotein hemagglutinin (HA) of influenza virus is the primary target for the design of an effective universal influenza vaccine as it is capable of eliciting broadly cross-reactive ...antibodies against different HA subtypes. Several monoclonal antibodies targeting the stem region of HA that are able to neutralize various subtypes of influenza virus have been isolated in the recent past. Designing a stable, HA stem immunogen that attains a native-like conformation and can elicit such antibodies has been a challenge. We describe the affinity maturation of a previously designed stem immunogen (H1HA6) by random mutagenesis, followed by selection using yeast surface display. The affinity-matured mutant protein (H1HA6P2), upon bacterial expression, attained a stable, native-like, trimeric conformation without any heterologous trimerization motif and showed a significant improvement in thermal stability and binding to several stem specific, conformation-sensitive, broadly neutralizing antibodies (bnAbs) relative to H1HA6. These results point to an effective strategy for the design of stabilized HA stem immunogens that can be tested for their protective ability.
Mapping conformational changes of α‐synuclein (α‐syn) from soluble, unstructured monomers to β‐sheet‐ rich aggregates is crucial towards understanding amyloid formation. Raman microspectroscopy is ...now used to spatially resolve conformational heterogeneity of amyloid aggregates and monitor amyloid formation of segmentally 13C‐labeled α‐syn in real‐time. As the 13C‐isotope shifts the amide‐I stretching frequency to lower energy, the ligated construct, 13C1–8612CS87C–140‐α‐syn, exhibits two distinct bands allowing for simultaneous detection of secondary structural changes in N‐terminal 1–86 and C‐terminal 87–140 residues. The disordered‐to‐β‐sheet conformational change is first observed for the N‐terminal followed by the C‐terminal region. Finally, Raman spectroscopic changes occurred prior to Thioflavin T fluorescence enhancement, indicating that the amide‐I band is a superior probe of amyloid formation.
Two peaks are better than one: Native chemical ligation was used to segmentally label α‐synuclein with 13C. This labeling results in two spectroscopically distinct amide‐I bands that independently report on region‐specific conformational changes of the protein backbone. The N‐terminal region was seen to adopt a β‐sheet structure first in the formation of amyloid.
Mapping conformational changes of α-synuclein (α-syn) from soluble, unstructured monomers to β-sheet- rich aggregates is crucial towards understanding amyloid formation. Raman microspectroscopy is ...now used to spatially resolve conformational heterogeneity of amyloid aggregates and monitor amyloid formation of segmentally
C-labeled α-syn in real-time. As the
C-isotope shifts the amide-I stretching frequency to lower energy, the ligated construct,
C
C
-α-syn, exhibits two distinct bands allowing for simultaneous detection of secondary structural changes in N-terminal 1-86 and C-terminal 87-140 residues. The disordered-to-β-sheet conformational change is first observed for the N-terminal followed by the C-terminal region. Finally, Raman spectroscopic changes occurred prior to Thioflavin T fluorescence enhancement, indicating that the amide-I band is a superior probe of amyloid formation.
The RSV Fusion (F) protein is a target for neutralizing antibody responses and is a focus for vaccine discovery; however, the process of RSV entry requires F to adopt a metastable prefusion form and ...transition to a more stable postfusion form, which displays less potent neutralizing epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, which may allow conformational transitions similar to those observed during natural infection to occur. Here we evaluate a panel of chemically modified mRNA vaccines expressing different forms of the RSV F protein, including secreted, membrane associated, prefusion-stabilized, and non-stabilized structures, for conformation, immunogenicity, protection, and safety in rodent models. Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion- and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifts the immune response toward prefusion-specific epitopes, but does not impact neutralizing antibody titer. mRNA vaccine candidates expressing either prefusion stabilized or native forms of RSV F protein elicit robust neutralizing antibody responses in both mice and cotton rats, similar to levels observed with a comparable dose of adjuvanted prefusion stabilized RSV F protein. In contrast to the protein subunit vaccine, mRNA-based vaccines elicited robust CD4+ and CD8+ T-cell responses in mice, highlighting a potential advantage of the technology for vaccines requiring a cellular immune response for efficacy.
To explore the correlation between health-illness transition (HIT) experiences and distress among patients with pancreatic cancer.
55 patients with a diagnosis of pancreatic cancer receiving ...chemotherapy at a tertiary cancer center in New York.
A prospective correlational study was performed to explore the frequency, extent, and management of HITs. HITs were evaluated using the Measurement of Transitions in Cancer Scale, and distress was measured with the National Comprehensive Cancer Network Distress Thermometer.
All patients experienced at least one HIT. The extent of HITs decreased over time. Patients reported that they managed HITs moderately well. There was a significant correlation between unmanaged HITs and distress. As distress increased, the extent of the physical and emotional HITs increased and management worsened.
HITs are ubiquitous among patients diagnosed with pancreatic cancer. Associated distress inhibits management. Nurses are well suited to assess for potential HITs and to support self-management of HITs.
The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter ...retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL
There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We ...assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.
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