Cancer Treatment Decision-Making for People Living With HIV: Physician-Reported Barriers, Facilitators, and Recommendations.

BACKGROUND: Compared with the general cancer population, people living with HIV (PLWH) and cancer are less likely to receive treatment and have significantly elevated cancer-specific mortality for many common cancer types. Physician recommendations drive the cancer therapy that patients receive, yet there is limited information assessing how cancer treatment decisions are made for people living with HIV and cancer. We sought to understand oncologist decision-making in PLWH and cancer by eliciting barriers, facilitators, and recommendations for enhancing care delivery. SETTING: Participants were recruited between May 2019 and May 2021 from one academic medical center in the western United States (n = 13), another in the southeastern United States (n = 7), and community practices nationwide (n = 5). METHODS: Using an inductive qualitative approach, we conducted in-depth interviews with 25 oncologists from two academic medical centers and community practices. RESULTS: Facilitators of cancer care delivery included readily available information regarding HIV status and stage, interdepartmental communication, and antiviral therapy adherence. Barriers included a lack of formal education on HIV malignancies, perceptions of decreased life expectancy, fear of inadvertent disclosure, and drug-drug interactions. Recommendations included improved provider communication, patient social and mental health resources, and continuing education opportunities. CONCLUSION: The study revealed drivers of cancer treatment decision-making, highlighting physician-reported barriers and facilitators, and recommendations to support treatment decision-making. This is the first known study examining oncologists' perceptions of caring for PLWH. Given that cancer is a leading cause of death among PLWH, there is an urgent need to improve care and outcomes.

Women's Health Provider Perspectives on Reproductive Services Provision in the Veterans Health Administration.

OBJECTIVES: Women veterans are a fast-growing population in the Veterans Health Administration (VHA), and ensuring reproductive service availability is a VHA priority. As such, we sought to explore barriers and facilitators to VHA reproductive service provision across a catchment area from women's health providers' perspectives. METHODS: We performed a mixed-methods study, including semistructured, qualitative provider interviews with a quantitative survey on training, comfort, and knowledge of reproductive services. All women's health providers and their support staff from the Salt Lake City Veterans Affairs Medical Center and nine VHA community-based outpatient clinics were asked to participate. We conducted qualitative interviews and knowledge surveys with providers and staff to explore training, care processes, and improvement opportunities in reproductive service provision. We completed descriptive analyses of all of the quantitative data and used an open, iterative process to analyze provider interviews for emergent themes. RESULTS: We interviewed 15 providers (7 advanced practice nurses, 4 registered nurses, and 4 physicians) across nine sites (50% response rate). The commonly identified barriers included provider training and staffing, scheduling/referral processes, inconsistent services/supplies, and lack of veteran awareness of reproductive services. Facilitators included prior non-VHA reproductive health experience among providers, invested support staff, and the integrated VHA health system. CONCLUSIONS: Addressing barriers to VHA reproductive healthcare provision may overcome reproductive service variations related to clinic location and improve reproductive health outcomes for women veterans.

Improving Cancer Care for People Living With HIV: A Qualitative Study of Provider Knowledge, Attitudes, and Practice.

PURPOSE: Cancer is now the leading cause of non-AIDS death in the US population with HIV. People living with HIV (PLWH) are known to have lower cancer treatment rates and worse cancer outcomes. Disparate cancer treatment is driven by health system, patient, and clinician factors. Little attention has been given to the factors oncologists consider when making cancer treatment recommendations to PLWH. This study sought to examine oncologists' knowledge, attitudes, and practices that influence cancer treatment decision-making. METHODS AND MATERIALS: This study used qualitative methods to explore oncologists' treatment decision-making processes for PLWH and cancer. The sample included 25 radiation, medical, and surgical oncologists from 2 academic centers and 5 community practices. The interview domains were developed from the Andersen Healthcare Utilization Model, the Health Belief Model, and the PEN-3 Model, as well as our prior survey research. RESULTS: This study describes elements of cancer treatment decision-making for PLWH. Oncologists highlighted the need for formal HIV education to support cancer treatment. One main concern with patient-provider interactions pertained to maintaining patient confidentiality during clinical encounters. Lastly, the importance of multidisciplinary care among health care providers allowed oncologists to facilitate both cancer care and logistical support. CONCLUSIONS: As cancer becomes an increasingly common cause of death among PLWH, it is critical to understand the drivers of the observed disparities in cancer treatment. To our knowledge, this is the first qualitative study to describe oncologists' knowledge, attitudes, and practices toward patients who have a comorbid diagnosis of HIV and cancer. Several themes for future interventions emerge, including HIV training for cancer care providers, fostering interdisciplinary collaboration, enhancing HIV education for oncology learners and clinicians, and minimizing implicit bias.

Determinants of Risk-Aligned Bladder Cancer Surveillance-Mixed-Methods Evaluation Using the Tailored Implementation for Chronic Diseases Framework.

PURPOSE: For many patients with cancer, the frequency of surveillance after primary treatment depends on the risk for cancer recurrence or progression. Lack of risk-aligned surveillance means too many unnecessary surveillance procedures for low-risk patients and not enough for high-risk patients. Using bladder cancer as an example, we examined whether practice determinants differ between Department of Veterans Affairs sites where risk-aligned surveillance was more (risk-aligned sites) or less common (need improvement sites). METHODS: We used our prior quantitative data to identify two risk-aligned sites and four need improvement sites. We performed semistructured interviews with 40 Veterans Affairs staff guided by the Tailored Implementation for Chronic Diseases framework that were deductively coded. We integrated quantitative data (risk-aligned site v need improvement site) and qualitative data from interviews, cross-tabulating salient determinants by site type. RESULTS: There were 14 participants from risk-aligned sites and 26 participants from need improvement sites. Irrespective of site type, we found a lack of knowledge on guideline recommendations. Additional salient determinants at need improvement sites were a lack of resources ("the next available without overbooking is probably seven to eight weeks out") and an absence of routines to incorporate risk-aligned surveillance ("I have my own guidelines that I've been using for 35 years"). CONCLUSION: Knowledge, resources, and lack of routines were salient barriers to risk-aligned bladder cancer surveillance. Implementation strategies addressing knowledge and resources can likely contribute to more risk-aligned surveillance. In addition, reminders for providers to incorporate risk into their surveillance plans may improve their routines.

Selective Synthesis of 2,2,4,4-Tetrasilylpentasilane.

A new structural isomer of nonasilane, 2,2,4,4-tetrasilylpentasilane or (H3Si)3SiSiH2Si(SiH3)3, is formed in disproportionational condensation of neopentasilane. This reaction can be catalyzed by a freshly cleaned borosilicate surface, and the catalyzed reaction can have over 85% selectivity for this branched nonasilane near 100 °C. A synthetic method has been developed from this catalytic reaction for making 98 wt % 2,2,4,4-tetrasilylpentasilane. The high-purity 2,2,4,4-tetrasilylpentasilane has a workable shelf life in 316 stainless steel containers.

Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice.

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKß and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

Hollow Cathode Plasma-Enhanced Atomic Layer Deposition of Silicon Nitride Using Pentachlorodisilane.

In this work, a novel chlorodisilane precursor, pentachlorodisilane (PCDS, HSi2Cl5), was investigated for the growth of silicon nitride (SiN x) via hollow cathode plasma-enhanced atomic layer deposition (PEALD). A well-defined self-limiting growth behavior was successfully demonstrated over the growth temperature range of 270-360 °C. At identical process conditions, PCDS not only demonstrated approximately >20% higher growth per cycle than that of a commercially available chlorodisilane precursor, hexachlorodisilane (Si2Cl6), but also delivered a better or at least comparable film quality determined by characterizing the refractive index, wet etch rate, and density of the films. The composition of the SiN x films grown at 360 °C using PCDS, as determined by X-ray photoelectron spectroscopy, showed low O content (∼2 at. %) and Cl content (<1 at. %; below the detection limit). Fourier transform infrared spectroscopy spectra suggested that N-H bonds were the dominant hydrogen-containing bonds in the SiN x films without a significant amount of Si-H bonds originating from the precursor molecules. The possible surface reaction pathways of the PEALD SiN x using PCDS on the surface terminated with amine groups (-NH2 and -NH-) are proposed. The PEALD SiN x films grown using PCDS also exhibited a leakage current density as low as 1-2 nA/cm2 at 2 MV/cm and a breakdown electric field as high as ∼12 MV/cm.

Draft Genome Sequence of Gephyronic Acid Producer Cystobacter violaceus Strain Cb vi76.

A draft genome sequence of Cystobacter violaceus strain Cb vi76, which produces the eukaryotic protein synthesis inhibitor gephyronic acid, has been obtained. The genome contains numerous predicted secondary metabolite clusters, including the gephyronic acid biosynthetic pathway. This genome will contribute to the investigation of secondary metabolism in other Cystobacter strains.

Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document.

BACKGROUND: There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making. METHODS: The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document. RESULTS: Recommendations were developed for "using available data" and "future clinical studies". The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. CONCLUSION: The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design.

Elucidation of gephyronic acid biosynthetic pathway revealed unexpected SAM-dependent methylations.

Gephyronic acid, a cytostatic polyketide produced by the myxobacterium Cystobacter violaceus Cb vi76, exhibits potent and selective eukaryotic protein synthesis inhibition. Next-generation sequencing of the C. violaceus genome revealed five type I polyketide synthases and post-PKS tailoring enzymes including an O-methyltransferase and a cytochrome P450 monooxygenase. Seven methyltransferase (MT) domains embedded within the PKS subunits were found to install the methyl branches throughout the gephyronic acid skeleton. A rare loading domain from the GNAT superfamily also contains an embedded MT domain that catalyzes the in situ production of an isobutyryl starter unit. Phylogenetic analysis identified new motifs that distinguish MT domains located in PKS pathways with in cis acyltransferase (AT) domains from MT domains located in PKS pathways with trans AT enzymes. The identification of the gene cluster sets the stage for the generation of a heterologous expression system, which will allow further investigation of selective eukaryotic protein synthesis inhibitors through the generation of gephyronic acid analogues.

Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration.

INTRODUCTION: The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis. METHODS: We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays. RESULTS: Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes. CONCLUSIONS: These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis.

Evolution of polyketides: post-PKS processing in the formation of spiroketals.

It is now well recognized that natural products have directly or indirectly contributed to the discovery and development of as much as 75% of our current treatments for cancer and infectious disease as well as other indications. It cannot be overemphasized that new sources of chemical diversity are essential to the discovery of the next generation of chemotherapeutic agents. Characterization of the polyketide gene clusters responsible for the production of the spirangienes A and B provided detailed information regarding the biochemistry of myxobacterial secondary metabolism as well as significant insights into the evolution of post-PKS enzymes. The implications of these findings, coupled with additional examples, suggest that putative PKS products represent a new source of chemical diversity with chemotherapeutic potential and are thus worthy of further investigation.