Maternal Perspective of Inpatient Methadone Initiation: Opportunities to Increase Retention in Treatment.

OBJECTIVES: Recent trends demonstrate increases in the rates of opioid use among pregnant and parenting women. Treatment for pregnant people with opioid use disorder (OUD) includes medications for OUD, like methadone, as well as comprehensive support services. Still, inpatient treatment engagement is suboptimal and treatment drop out is common. There is little research examining the maternal perspective of the inpatient methadone initiation experience. The primary aim of this qualitative methods study was to explore patient experience and perspective of the inpatient methadone initiation period. METHODS: All participants were recruited from a single urban university affiliated hospital and OUD treatment program. Data were collected from 30 maternal participants in OUD treatment about their inpatient methadone initiation experience while pregnant using semistructured interviews. Thematic analyses were conducted using an inductive approach after an iterative process of code development and application among a multidisciplinary team of 3 coders. Validity was accounted for through 2 participant feedback interviews and study team review and discussion of findings. RESULTS: Four themes emerged from the maternal interview data: (1) Barriers to Inpatient Methadone Initiation, (2) Facilitators to Inpatient Methadone Initiation, (3) Transition From Hospital Inpatient to Outpatient or Residential OUD Treatment Services, and (4) Opportunities for Enhanced Clinical Support. CONCLUSION: Maternal participants reported multiple barriers and facilitators to inpatient care during methadone initiation, highlighting opportunities for improvement to effectively engage pregnant individuals in treatment.

Host CD3+ T-cells can significantly modulate phage treatment effects on bacterial bioburden in mouse models.

Wound healing is a complex system including such key players as host, microbe, and treatments. However, little is known about their dynamic interactions. Here we explored the interplay between: (1) bacterial bioburden and host immune responses, (2) bacterial bioburden and wound size, and (3) treatments and wound size, using murine models and various treatment modalities: Phosphate buffer saline (PBS or vehicle, negative control), doxycycline, and two doses of A. baumannii phage mixtures. We uncovered that the interplay between bacterial bioburden and host immune system may be bidirectional, and that there is an interaction between host CD3+ T-cells and phage dosage, which significantly impacts bacterial bioburden. Furthermore, the bacterial bioburden and wound size association is significantly modulated by the host CD3+ T-cells. When the host CD3+ T-cells (x on log10 scale) are in the appropriate range (1.35 < x < = 1.5), we observed a strong association between colony forming units (CFU) and wound size, indicating a hallmark of wound healing. On the basis of the findings and our previous work, we proposed an integrated parallel systems biology model.

Food Insecurity and Psychological Distress Amongst Parenting Women in Treatment for Opioid Use: Identifying Barriers to Nutritional Equity and Implications for Future Intervention Research.

PURPOSE: To describe the prevalence of food insecurity among pregnant and parenting women with opioid use disorder (OUD), its association with psychosocial health, and their experience with the Special Supplemental Nutrition Program for Women Infant Child (WIC) program. DESIGN: This cross-sectional study collected survey data through REDCAP. SETTING: The study was conducted at a single, urban, opioid treatment program. SUBJECTS: A total of 91 female participants (≥18 years of age and receiving OUD treatment services) were approached about the study and all consented. MEASURES: Measures included: US Household Short Form Food Security Survey, Patient Health Questionnaire 4(PHQ4), Perceived Stress Scale (PSS), and a demographics and food behavior survey. ANALYSIS: Descriptive analyses (frequency, means) described data and Chi-Square, Fischer's exact, t-tests were used to compare data between food security groups. RESULTS: Participants were on average 34 years old, Caucasian (68%), and non-Hispanic (87%). Most reported low (32%) to very low (33%) food security. Pearson correlation analyses indicate a strong positive linear relationship between Food Security Score and PHQ4 Total (P = .0002), PHQ4 Depression (P = .0003), PHQ4 Anxiety (P = .0009), and PSS Total (P < .0001). Only 38% felt the foods available in WIC supported their breastfeeding. Limitations include a single site and recall bias. CONCLUSIONS: Significant nutritional inequity in families affected by maternal substance use exists, with potential for adverse maternal and child development related implications.

Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma.

The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.

Comprehensive and compassionate responses for opioid use disorder among pregnant and parenting women.

Pregnant and parenting women with opioid use disorder face multiple challenges to recovery. Trauma histories, poverty, stigma and discrimination, and lack of access to treatment intersect to marginalise this population. It is important that pregnant and parenting women with opioid use disorder receive comprehensive care to improve their health, the health of their child(ren), and prevent the intergenerational transmission of opioid and other substance use disorders. For nearly 50 years the Maternal Addiction Treatment, Education, and Research program has provided an evolving and expanding range of comprehensive services for treating opioid and other substance use disorders in this population. In this review the rationale for, and processes by which, key components of a comprehensive approach are discussed. These components include patient navigation for access to care, low-barrier medications for opioid use disorder, effective trauma-responsive therapy, prenatal and well-child healthcare, and other support services that make it possible for pregnant and parenting women to engage in treatment and improve the health of the entire family. Additionally, a method for supporting staff to build resilience and reduce fatigue and burnout is discussed. These components comprise an effective model of care for pregnant and parenting women with opioid and other substance use disorders.

The use of mindfulness dialogue for life in substance use disorder treatment in the time of COVID-19.

Effective communication is critical for therapeutic work with individuals, for the interdisciplinary team, and for leadership in a substance use disorder (SUD) treatment program. Prior to the COVID-19 pandemic, over a two-year period Thomas Jefferson University's Maternal Addiction Treatment, Education and Research (MATER) program, an SUD treatment program serving pregnant and parenting women living in an urban environment, implemented Mindfulness Dialogue for Life (MDfL) to deepen communication, encourage courageous conversations, bring more compassion to staff and patients, and improve trust among leadership. MDfL focuses on three stages-connecting, exploring, and discovering-and it uses mindfulness practices to enhance communication. Here we describe our efforts to implement MDfL on a virtual platform and how the COVID-19 pandemic affected staff's work experience, as identified during their MDfL sessions.

Identification of Differential Tumor Subtypes of T1 Bladder Cancer.

Stage T1 bladder cancers have the highest progression and recurrence rates of all non-muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, and identified five consensus subtypes of T1 tumors treated with repeat transurethral resection (reTUR) and induction and maintenance BCG. The T1-LumGU subtype was associated with carcinoma in situ (CIS; six/13, 46% of all CIS), had high E2F1 and EZH2 expression, and was enriched in E2F target and G2M checkpoint hallmarks. The T1-Inflam subtype was inflamed and infiltrated with immune cells. While most T1 tumors were classified as luminal papillary, the T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes had the most recurrences (14/30 within 24 mo), the highest median MYC expression, and, when combined, had significantly worse recurrence-free survival than the other three subtypes. T1-Early had five (38%) recurrences within the first 6 mo of BCG, and repressed IFN-α and IFN-γ hallmarks and inflammation. We developed a single-patient T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future research will be necessary to validate the proposed T1 subtypes and to determine if therapies can be individualized for each subtype. PATIENT SUMMARY: We identified and characterized expression subtypes of high-grade stage T1 bladder cancer that are biologically heterogeneous and have variable responses to bacillus Calmette-Guérin treatment. We validated the subtypes and describe a single-patient classifier.

Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma.

Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

Genomic and Therapeutic Landscape of Non-muscle-invasive Bladder Cancer.

Non-muscle-invasive bladder cancer (NMIBC) is heterogeneous, but current diagnostic and treatment strategies rely primarily on clinical parameters, lacking individualization to tumor and host genetics and biology. The heterogeneity of NMIBCs is derived from mutations, mutation signatures, chromosomal loss, and disruption of molecular pathways, which ultimately affects tumor progression, recurrence, and responsiveness to intravesical and systemic chemotherapy. Although research is still underway, advances in sequencing technology, insight into differential bacillus Calmette-Guérin responses, and new investigational treatment targets will soon offer clinicians new, precision-based tools to risk stratify and determine treatment regimens for future patients with bladder cancer.