Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer.

Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Barriers and facilitators to implementing evidence-based integrated HIV and behavioral health care: perspectives from seven federal ending the HIV epidemic jurisdictions.

The federal Ending the HIV Epidemic (EHE) initiative was created to reduce new US HIV infections, largely through pre-exposure prophylaxis and HIV treatments that reduce HIV transmissibility to zero. Behavioral health disorders (mental health and substance use) remain significant barriers to achieving EHE goals. Addressing behavioral health (BH) disorders within HIV primary care settings has been promoted as a critical EHE strategy. Implementation of efficacious HIV-BH care integration and its impact on HIV-related health outcomes is not well documented. In a federally-funded, exploratory phase implementation science study, we used the Collective Impact Framework to engage partners in seven EHE jurisdictions about the feasibility, acceptability, and sustainability of implementing HIV-BH integration interventions within local HIV settings. Partners concluded that full integration will remain the exception unless health systems invest in collaborative practice, professional training, appropriate health technology, and inter-system communication. Partners supported smaller incremental improvements including transdiagnostic approaches to reinforce each team member's sense of value in the shared endeavor. This early phase implementation science study identified research and implementation gaps that are critical to fill to end the HIV epidemic. Both the Collective Impact Framework and implementation science show promise for guiding future implementation of evidence-based HIV-BH intervention integration.

Interventions for Integrating Behavioral Health into HIV Settings for US Adults: A Narrative Review of Systematic Reviews and Meta-analyses, 2010-2020.

Mental health and substance use disorders can negatively affect physical health, illness management, care access, and quality of life. These behavioral health conditions are prevalent and undertreated among people with HIV and may worsen outcomes along the entire HIV Care Continuum. This narrative review of tested interventions for integrating care for HIV and behavioral health disorders summarizes and contextualizes findings from systematic reviews and meta-analyses conducted in the past decade. We sought to identify gaps in research that hinder implementing evidence-based integrated care approaches. Using terms from the Substance Abuse and Mental Health Services Administration-Health Resources & Services Administration standard framework for integrated health care, we searched PubMed and PsycInfo to identify peer-reviewed systematic reviews or meta-analyses of intervention studies to integrate behavioral health and HIV published between 2010 and 2020. Among 23 studies identified, only reviews and meta-analyses that described interventions from the United States designed to integrate BH services into HIV settings for adults were retained, leaving six studies for narrative review by the study team. Demonstrated benefits from the relatively small literature on integrated care interventions include improved patient- and service-level outcomes, particularly for in-person case management and outreach interventions. Needed are systems-level integration interventions with assessments of long-term outcomes on behavioral health symptoms, HIV viral suppression, HIV transmission rates, and mortality. HIV, primary care, and other providers must include behavioral health as a part of overall healthcare and must play a central role in behavioral health care delivery. Research is needed to guide their way.

Observed humidity trends in dry regions contradict climate models.

Arid and semi-arid regions of the world are particularly vulnerable to greenhouse gas-driven hydroclimate change. Climate models are our primary tool for projecting the future hydroclimate that society in these regions must adapt to, but here, we present a concerning discrepancy between observed and model-based historical hydroclimate trends. Over the arid/semi-arid regions of the world, the predominant signal in all model simulations is an increase in atmospheric water vapor, on average, over the last four decades, in association with the increased water vapor-holding capacity of a warmer atmosphere. In observations, this increase in atmospheric water vapor has not happened, suggesting that the availability of moisture to satisfy the increased atmospheric demand is lower in reality than in models in arid/semi-arid regions. This discrepancy is most clear in locations that are arid/semi-arid year round, but it is also apparent in more humid regions during the most arid months of the year. It indicates a major gap in our understanding and modeling capabilities which could have severe implications for hydroclimate projections, including fire hazard, moving forward.

A Systematic Review of Intervention Studies That Address HIV-Related Stigmas Among US Healthcare Workers and Health Systems: Applying a Theory-Based Ontology to Link Intervention Types, Techniques, and Mechanisms of Action to Potential Effectiveness.

BACKGROUND: To end the HIV epidemic, we need to better understand how to address HIV-related stigmas in healthcare settings, specifically the common theoretical bases across interventions so that we can generalize about their potential effectiveness. PURPOSE: We describe theory-based components of stigma interventions by identifying their functions/types, techniques, and purported mechanisms of change. METHODS: This systematic review examined studies published by April 2021. We applied a transtheoretical ontology developed by the Human Behaviour Change Project, consisting of 9 intervention types (ITs), 93 behavior change techniques (BCTs), and 26 mechanisms of action (MOAs). We coded the frequency and calculated the potential effectiveness of each IT, BCT, and MOA. We evaluated study quality with a 10-item adapted tool. RESULTS: Among the nine highest quality studies, indicated by the use of an experimental design, the highest potentially effective IT was "Persuasion" (i.e. using communication to induce emotions and/or stimulate action; 66.7%, 4/6 studies). The highest potentially effective BCTs were "Behavioral practice/rehearsal" (i.e. to increase habit and skill) and "Salience of consequences" (i.e. to make consequences of behavior more memorable; each 100%, 3/3 studies). The highest potentially effective MOAs were "Knowledge" (i.e. awareness) and "Beliefs about capabilities" (i.e. self-efficacy; each 67%, 2/3 studies). CONCLUSIONS: By applying a behavior change ontology across studies, we synthesized theory-based findings on stigma interventions. Interventions typically combined more than one IT, BCT, and MOA. Practitioners and researchers can use our findings to better understand and select theory-based components of interventions, including areas for further evaluation, to expedite ending the HIV epidemic.

Efficacy of a Dual-Epitope Dendritic Cell Vaccine as Part of Combined Immunotherapy for HER2-Expressing Breast Tumors.

Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.

Sexual health services in urban, suburban, and rural outpatient mental healthcare settings in New York: findings from a survey of practices and gaps.

We surveyed all licensed outpatient mental health programs in New York to examine sexual health services and training needs of providers. Gaps were found in processes for assessing whether patients were sexually active, engaging in sexual risk behaviours, and in need of HIV testing and pre-exposure prophylaxis. Significant differences between urban, suburban, and rural settings statewide were found in how the following sexual health services were delivered: education; on-site sexually transmitted infection screenings; and condom distribution and barriers to distribution. Staff training in sexual health services delivery is critically needed for optimal sexual health and recovery of patients in community mental healthcare.

Predictors of Developmental and Adaptive Behaviour Outcomes in Response to Early Intensive Behavioural Intervention and the Early Start Denver Model.

Many autistic children require support to meet their learning needs. Given the heterogeneity within the autism spectrum it is plausible that different types of support might be better suited to different children. However, knowledge on what interventions work best for which children is limited. We examined the outcomes of autistic preschool-aged children receiving one of two community early intervention approaches. Our main objective was to understand which baseline child characteristics might be associated with the degree of individual response to intervention-whether prognostically (i.e., irrespective of intervention received) or predictively (i.e., specifically in the context of one or other EI approach). Participants comprised two matched groups of preschool-aged autistic children receiving either Group-based Early Start Denver Model (G-ESDM; n = 42) delivered in a 1:3-4 staff:child ratio or an Early Intensive Behavioural Intervention (EIBI; n = 40) delivered in combination of 1:1 and 1:2 staff:child ratio. Over an approximate one-year follow-up period, children in both groups made significant gains in Developmental Quotient (DQ) scores, and trend-level gains in adaptive behaviour composite scores. Higher attention to a playful adult measured via an eye-tracking task was prognostically indicative of better verbal DQ and adaptive behaviour outcomes for the cohort overall. Moderation analyses indicated a single predictive effect-of pre-program sustained attention for subsequent NVDQ outcomes specific to those children receiving G-ESDM. These findings suggest that fine-grained measures of learning skills offer promise towards the selection and tailoring of intervention approaches to meet individual children's learning needs.

A systematic review of multimodal prehabilitation in breast cancer.

PURPOSE: Breast cancer is the most prevalent malignancy in women. Prehabilitation may offer improvements in physical and psychological wellbeing among participants prior to treatment. This systematic review aimed to determine the efficacy of prehabilitation in participants diagnosed with breast cancer. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Studies exploring the impact of prehabilitation in participants with breast cancer were included. Studies were assessed independently according to pre-eligibility criteria, with data extraction and methodological quality assessed in parallel. RESULTS: 3184 records were identified according to our search criteria, and 14 articles were included. Articles comprised of quantitative randomised controlled trials (n = 7), quantitative non-randomised studies (n = 5), a qualitative study (n = 1), and a mixed-method study (n = 1). The majority of selected studies completed exercise programs (n = 4) or had exercise components (n = 2), with two focusing on upper-limb exercise. Five articles reported complementary and alternative therapies (n = 5). Two articles reported smoking cessation (n = 2), with a single study reporting multi-modal prehabilitation (n = 1). Mostly, prehabilitation improved outcomes including physical function, quality of life, and psychosocial variables (P < 0.05). The qualitative data identified preferences for multimodal prehabilitation, compared to unimodal with  an interest in receiving support for longer. CONCLUSIONS: Prehabilitation for patients with breast cancer is an emerging research area that appears to improve outcomes, however, ensuring that adequate intervention timeframes, follow-up, and population groups should be considered for future investigations. IMPLICATIONS FOR CANCER SURVIVORS: The implementation of prehabilitation interventions for individuals diagnosed with breast cancer should be utilised by multidisciplinary teams to provide holistic care to patients as it has the potential to improve outcomes across the cancer care trajectory.

A potential syndemic effect associated with symptoms of depression among men who have sex with men.

INTRODUCTION: Globally, depression rates are high among men who have sex with men (MSM). Multiple factors may interact synergistically to increase this risk. This analysis assessed the prevalence of symptoms of depression among MSM in Brazil and synergistic effects of several factors. METHODS: Cross-sectional study conducted in 12 cities using respondent-driven sampling. Sociodemographic and behavioral characteristics were collected. The PHQ-9 was used to screen for depression. Having moderate-severe depressive symptoms was compared to none-mild using logistic regression. The syndemic factor was a composite of hazardous alcohol use, sexual violence, and discrimination due to sexual orientation. Those with one to three of these factors were compared to those with none. RESULTS: The weighted prevalence of moderate-severe depressive symptoms was 24.9% (95%CI = 21.8-28.8) and 16.2%, 22.9%, 46.0% and 51.0% when none, one, two, or three syndemic factors were present, respectively, indicating a dose-response effect. Perception of HIV risk, high level of HIV knowledge, known HIV infection, and health self-rated as poor or very poor were also associated with depressive symptoms. CONCLUSION: The prevalence of moderate-severe depressive symptoms among MSM in Brazil is high, and selected factors act synergistically in increasing their prevalence. Public health policies should consider holistic depression prevention and treatment interventions for this population.

A potential syndemic effect associated with symptoms of depression among men who have sex with men

Introduction: Globally, depression rates are high among men who have sex with men (MSM). Multiple factors may interact synergistically to increase this risk. This analysis assessed the prevalence of symptoms of depression among MSM in Brazil and synergistic effects of several factors. Methods: Cross-sectional study conducted in 12 cities using respondent-driven sampling. Sociodemographic and behavioral characteristics were collected. The PHQ-9 was used to screen for depression. Having moderate-severe depressive symptoms was compared to none-mild using logistic regression. The syndemic factor was a composite of hazardous alcohol use, sexual violence, and discrimination due to sexual orientation. Those with one to three of these factors were compared to those with none. Results: The weighted prevalence of moderate-severe depressive symptoms was 24.9% (95%CI = 21.8-28.8) and 16.2%, 22.9%, 46.0% and 51.0% when none, one, two, or three syndemic factors were present, respectively, indicating a dose-response effect. Perception of HIV risk, high level of HIV knowledge, known HIV infection, and health self-rated as poor or very poor were also associated with depressive symptoms. Conclusion: The prevalence of moderate-severe depressive symptoms among MSM in Brazil is high, and selected factors act synergistically in increasing their prevalence. Public health policies should consider holistic depression prevention and treatment interventions for this population.

Reducing Intersecting Stigmas in HIV Service Organizations: An Implementation Science Model.

BACKGROUND: HIV-related and intersectional stigmas are key barriers for service delivery, but best practices are nascent for addressing them in high-resource and high-burden contexts such as New York City (NYC). The Stigma Reduction and Resilience (STAR) implementation science (IS) Mapping Project in 2020 identified untested stigma reduction efforts in HIV organizations, highlighting the need for an IS framework. SETTING: Organizations providing HIV prevention and/or care in NYC. METHODS: An interagency team determined that IS provides a structured approach for addressing identified gaps in stigma reduction efforts, but defining existing IS concepts and adapting IS frameworks were necessary to facilitate its use. The Implementation Research Logic Model was adapted to empower HIV organizations to use IS to implement stigma reduction. RESULTS: Questions, definitions, and tips were developed to guide, strengthen, and simplify the application of IS within HIV organizations to improve the reduction of HIV and intersecting stigmas. The resulting Stigma Reduction Logic Model incorporates tools for implementers who synthesize each component of the logic model (intervention, determinants, implementation strategies, mechanisms, and outcomes), including a menu of options for selecting stigma reduction interventions and implementation determinants, a checklist to assess organizational readiness for stigma reduction, and an IS terminology guide applied for stigma reduction. CONCLUSIONS: Stigma reduction initiatives and research can use this model to enable implementers, researchers, and HIV organization stakeholders to use the methodology of IS to build consensus for, systematically plan, implement, and evaluate stigma reduction activities relevant to the HIV epidemic. The next step is testing the model's utility.

Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer.

PURPOSE: Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab. PATIENTS AND METHODS: 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations. RESULTS: Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (-3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT). CONCLUSIONS: Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.

Growing impact of wildfire on western US water supply.

Streamflow often increases after fire, but the persistence of this effect and its importance to present and future regional water resources are unclear. This paper addresses these knowledge gaps for the western United States (WUS), where annual forest fire area increased by more than 1,100% during 1984 to 2020. Among 72 forested basins across the WUS that burned between 1984 and 2019, the multibasin mean streamflow was significantly elevated by 0.19 SDs (P < 0.01) for an average of 6 water years postfire, compared to the range of results expected from climate alone. Significance is assessed by comparing prefire and postfire streamflow responses to climate and also to streamflow among 107 control basins that experienced little to no wildfire during the study period. The streamflow response scales with fire extent: among the 29 basins where >20% of forest area burned in a year, streamflow over the first 6 water years postfire increased by a multibasin average of 0.38 SDs, or 30%. Postfire streamflow increases were significant in all four seasons. Historical fire-climate relationships combined with climate model projections suggest that 2021 to 2050 will see repeated years when climate is more fire-conducive than in 2020, the year currently holding the modern record for WUS forest area burned. These findings center on relatively small, minimally managed basins, but our results suggest that burned areas will grow enough over the next 3 decades to enhance streamflow at regional scales. Wildfire is an emerging driver of runoff change that will increasingly alter climate impacts on water supplies and runoff-related risks.

HIV and Intersectional Stigma Reduction Among Organizations Providing HIV Services in New York City: A Mixed-Methods Implementation Science Project.

Stigma remains a pervasive barrier to Ending the HIV Epidemic (EHE) in New York City (NYC). As part of an EHE implementation science planning process, we mapped multi-level HIV-related stigma-reduction activities, assessed their evidence base, and characterized barriers and facilitators. We interviewed and surveyed a convenience sample of 27 HIV prevention and/or treatment services organizations in NYC, March-August, 2020, using an embedded mixed-methods design. The greatest facilitators of stigma reduction included integration of health services, hiring staff who represent the community, and trainings. Intersecting stigmas were primarily addressed through the integration of HIV with mental health and substance use services. Barriers were multilevel, with organizational structure and capacity most challenging. A strong base of stigma-reduction activities was utilized by organizations, but intersectional frameworks and formal evaluation of activities' impact on stigma were lacking. Effectiveness-implementation hybrid research designs are needed to evaluate and increase the uptake of effective stigma-reduction approaches in NYC.

Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. SIGNIFICANCE: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.

Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922).

BACKGROUND: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. METHODS: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). RESULTS: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. CONCLUSION: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.

The RESPECT study: a feasibility randomised controlled trial of a sexual health promotion intervention for people with serious mental illness in community mental health services in the UK.

BACKGROUND: People with serious mental illness (SMI) have sexual health needs but there is little evidence to inform effective interventions to address them. In fact, there are few studies that have addressed this topic for people with SMI outside USA and Brazil. Therefore, the aim of the study was to establish the acceptability and feasibility of a trial of a sexual health promotion intervention for people with SMI in the UK. METHOD: The RESPECT study was a two-armed randomised controlled, open feasibility trial (RCT) comparing Sexual health promotion intervention (3 individual sessions of 1 h) (I) or treatment as usual (TAU) for adults aged 18 or over, with SMI, within community mental health services in four UK cities. The main outcome of interest was the percentage who consented to participate, and retained in each arm of the trial, retention for the intervention, and completeness of data collection. A nested qualitative study obtained the views of participants regarding the acceptability of the study using individual telephone interviews conducted by lived experience researchers. RESULTS: Of a target sample of 100, a total of 72 people were enrolled in the trial over 12 months. Recruitment in the initial months was low and so an extension was granted. However this extension meant that the later recruited participants would only be followed up to the 3 month point. There was good retention in the intervention and the study as a whole; 77.8% of those allocated to intervention (n = 28) received it. At three months, 81.9% (30 I; 29 TAU) and at 6 months, 76.3% (13 I and 16 TAU) completed the follow-up data collection. No adverse events were reported. There was good completeness of the data. The sexual health outcomes for the intervention group changed in favour of the intervention. Based on analysis of the qualitative interviews, the methods of recruitment, the quality of the participant information, the data collection, and the intervention were deemed to be acceptable to the participants (n = 22). CONCLUSIONS: The target of 100 participants was not achieved within the study's timescale. However, effective strategies were identified that improved recruitment in the final few months. Retention rates and completeness of data in both groups indicate that it is acceptable and feasible to undertake a study promoting sexual health for people with SMI. A fully powered RCT is required to establish effectiveness of the intervention in adoption of safer sex. STUDY REGISTRATION: ISRCTN Registry ISRCTN15747739 prospectively registered 5th July 2016.