Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer.

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs.

Patients' opinions on participation in patient-centered outcomes research in community pharmacies: A qualitative study.

BACKGROUND: Patient-centered outcomes research (PCOR) often brings patient voices, thoughts, and opinions into the research process, allowing patients to have a say in the research process from project inception to dissemination of results. Community pharmacy teams are well-situated to engage patients in their own health and in research, given their trusting relationships with patients and access in communities. OBJECTIVE: To gather patients' opinions on participation in PCOR at their local community pharmacy. METHODS: Four regional focus groups representing western, central, northeastern, and southeastern Pennsylvania were conducted. A single community pharmacy in each region recruited patients to participate in each focus group. A focus group discussion guide was developed and reviewed by a Stakeholder Advisory Board that consisted patients, pharmacists, and researchers. Questions focused on patients' relationships with their pharmacy and pharmacist, perceptions of research occurring at their local pharmacy, and patient engagement methods. Focus group sessions were audio-recorded, transcribed verbatim, and independently coded by 2 investigators. Coding discrepancies were reconciled through discussion, and a qualitative inductive thematic analysis was conducted by the research team. RESULTS: A total of 44 patients participated in one of 4 focus groups. Patients provided insights into what would make them more likely to participate in PCOR at their local community pharmacy. Four themes emerged from the discussions: (1) Understanding the impact to one's health or community affects participation; (2) Patients prefer to schedule research activities at times outside of prescription pick-up or drop-off; (3) Trusted relationships can be leveraged for recruitment; and (4) Face-to-face engagement is preferred for participant recruitment. CONCLUSION: Patients want to engage in research in a way that is respectful of their time and matters to them. Strong patient-pharmacist relationships are essential for patient engagement in and acceptance of PCOR opportunities in community pharmacies. Community pharmacies may be rich locations to engage patients in PCOR.

Infrahuman madness: Mental health nursing and the discursive production of alterity.

By examining an exemplar sample of mental health nursing educational policies and related legislation, in this article, we trace the discursive production of madness as an "othered" identity category. We engage in a critical discourse analysis of mental health nursing education in Canada, drawing on provincial and federal policies and legislation as the main sources of data. Theoretically framed by critical posthumanism and mad studies, this article outlines how the mad subjectivity becomes decontextualized out of its identity-based understanding and recontextualized as an inferior category of "the human," circulating within discourses of pedagogy, economics, law, and psychiatry. The article maps the intertextual nexus of the discourse of mental health nursing education, making visible the complex, the arbitrary, and the sometimes-contradictory nature of the discipline's grappling with identity-based mental health concepts. We close with several implications for nursing policy, education, and practice.

Investigation of metal mobility in gold and silver mine tailings by single-step and sequential extractions.

Metal leachate from mine tailings has the potential to release toxic metals into the surrounding environment. A single-step extraction procedure mimicking rainwater and a three-step BCR sequential extraction procedure (acid, reducing and oxidizing conditions) were applied to gold (GMT) and silver (SMT) mine tailings. Major (Al, Ca, Fe, Mg, and Mn) and trace metals were monitored to better understand the mobility and geochemistry of these metals when exposed to various environmental leaching conditions. Rainwater extraction released only small quantities of metals, while the three-step BCR extraction was more effective in mobilizing metals from the tailings. Under the acidic conditions of BCR step 1, Ca, Mg, Cd, Cu, and Mn were released in high concentrations. The dissolution of Fe, Ca, and Mg were dominant along with Pb in step 2 (reducing conditions). In step 3 (oxidizing conditions), Fe was the most dominant species together with Co, Cu, Ni, and Se. A high fraction of Al, Be, Cr, Li, Mo, Sb, Tl, and V remained in the residue. From SMT, larger quantities of As, Ca, Cd, and Zn were released compared to GMT. The BCR extraction could be applied to tailings to predict the potential release of toxic metals from mine wastes; however, excessive amounts of Ca and Fe in the tailings could cause carry-overs and incomplete extraction and carry-overs, resulting in a misinterpretation of results.

Giant Cell Tumor of Bone: Effect of Longer Dosing Intervals of Denosumab on Tumor Control and Bone-related Complications.

BACKGROUND: Denosumab is an effective treatment for giant cell tumor of the bone (GCTB) but can cause clinically significant adverse effects. Current approved dosing is every 4 weeks after 3 weekly loading doses. We assessed whether alternative, longer dosing intervals are associated with differences in efficacy or bone toxicity. METHODS: Single institution retrospective chart review was conducted on patients with GCTB over 18 years old who received at least 1 year of standard denosumab dosing. Patients identified using a free-text search engine with keywords "giant cell tumor" and "denosumab" from January 1998 to August 2020. RESULTS: Approximately 37 patients with GCTB (19F, 18M) were identified with median age of 37 years (range 22-73). Dosing interval was increased in 38% (n = 14), with the most common final dosing interval 12 weeks (n = 8). Six patients (16%) had bone complications: osteonecrosis of the jaw (n =5), atypical fracture (n = 1), and nonhealing dental wounds (n = 2). All patients with bone complications were on the monthly dosing schedule, but there was no statistically significant difference compared to longer dosing intervals (P = .22). No statistically significant difference in median PFS was noted (P = .97). However, 5-year PFS was superior in patients treated with less frequent versus standard dosing of denosumab (P = .036). CONCLUSIONS: Increasing the interval of denosumab dosing for GCTB provided similar tumor control compared to standard dosing and lower absolute number of bone toxicity events. Larger studies are needed to better define the optimal interval of denosumab administration and the effect on efficacy, toxicity, and associated healthcare expense.

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.

Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.

Teleoncology for Veterans: High Patient Satisfaction Coupled With Positive Financial and Environmental Impacts.

PURPOSE: There was rapid adoption of teleoncology care in the Veterans Health Administration during the COVID-19 pandemic. One third of 9 million Veterans Health Administration enrolled Veterans live in rural areas. Although digital solutions can expand capacity, enhance care access, and reduce financial burden, they may also exacerbate rural-urban health disparities. Careful evaluation of patients' perceptions and policy tradeoffs are necessary to optimize teleoncology postpandemic. METHODS: Patients with ≥ 1 teleoncology visit with medical, surgical, or radiation oncology between March 2020 and June 2020 were identified retrospectively. Validated, Likert-type survey assessing patient satisfaction was developed. Follow-up survey was conducted on patients with ≥ 1 teleoncology visit from August 2020 to January 2021. Travel distance, time, cost, and carbon dioxide emissions were calculated based on zip codes. RESULTS: A hundred surveys were completed (response rate, 62%). Patients overall were satisfied with teleoncology (83% Agree or Strongly Agree) but felt less satisfied than in-person visits (47% Agree or Strongly Agree). Audiovisual component improved patient perception of involvement in care, ability to self-manage health or medical needs, and comparability to in-person visits. Follow-up survey demonstrated similar satisfaction. Total travel-related savings are as follows: 86,470 miles, 84,374 minutes, $49,720 US dollars, and 35.5 metric tons of carbon dioxide. CONCLUSION: Veterans are broadly satisfied with teleoncology. Audiovisual capabilities are critical to satisfaction. This is challenging for rural populations with lack of technology access. Patients experienced financial and time savings, and society benefitted from reduced carbon emissions. Continued optimization is needed to enhance patient experience and address secondary effects.

It's not 'just a tube of blood': principles of protocol development, sample collection, staffing and budget considerations for blood-based biomarkers in immunotherapy studies.

Immunotherapy for cancer is now a standard pillar in the armamentarium of treatments for many cancers. Immune checkpoint inhibitors, in particular, have resulted in significant therapeutic benefit and prolongation of survival in solid organ cancers, such as melanoma and lung cancer. However, the extent of benefit is not uniform. There are several groups studying predictors of benefit from these therapies. Recently, there has been a burgeoning interest in studying predictive biomarkers from the blood. These markers include circulating tumor DNA, circulating tumor cells, lymphocyte subpopulations, exosomes and metabolites to name a few. The logistics involved in such biomarker work are complex and rigorous with potential to impact a given study. Such pre-analytic components include development of a rigorous protocol, standard operating procedures for collection and storage of various blood components, ethics of patient consent, personnel involved as well as budget considerations. In this primer, we lay out representative aspects of each of the aforementioned components as a guide to blood-based biomarker research for immunotherapy studies in cancer.

Telehealth for Cancer Care in Veterans: Opportunities and Challenges Revealed by COVID.

The Veterans Health Administration system is one of the largest integrated health care providers in the United States, delivering medical care to > 9 million veterans. Barriers to delivering efficient health care include geographical limitations as well as long wait times. Telehealth has been used as a solution by many different health care services. However, it has not been as widely used in cancer care. In 2018, the US Department of Veterans Affairs (VA) Pittsburgh Healthcare System expanded the use of telehealth to provide antineoplastic therapies to rural patients by creating a clinical video telehealth clinic of the Virtual Cancer Care Network. This allows oncologists located at the tertiary center to virtually deliver care to remote sites. The recent COVID-19 pandemic forced oncologists across the VA system to adopt telehealth to provide continuity of care. On the basis of our review and personal experience, we have outlined opportunities for telehealth to play a role in every step of the cancer care journey from diagnosis to therapy to surveillance to clinical trials for medical, surgical, and radiation oncology. There are many advantages, such as decreased travel time and potential cost savings; however, there continues to be challenges with veterans having access to devices and the Internet as well as understanding how to use telehealth equipment. The lessons learned from this assessment of the VA telehealth system for cancer care can be adopted and integrated into other health systems. In the future, there needs to be evaluation of how telehealth can be further incorporated into oncology, satisfaction of veterans using telehealth services, overcoming telehealth barriers, and defining metrics of success.

3D Printed Hydrogel-Based Sensors for Quantifying UV Exposure.

Exposure to excessive ultraviolet (UV) radiation can have detrimental effects on human health. Inexpensive easy-to-use sensors for monitoring UV radiation can allow broad-scale assessment of UV exposure, but their implementation requires technology that enables rapid and affordable manufacturing of these sensors on a large scale. Herein, we report a novel three-dimensional (3D) printing procedure and printable ink composition that produce robust, flexible, and wearable UV sensors. To fabricate the sensors, a color-changing hydrogel ink was first developed from which standalone constructs were 3D printed. The ink contains alginate, gelatin, photoactive titanium dioxide nanoparticles, and dyes (methyl orange, methylene blue, and malachite green) in which the nanoparticles are used to initiate photocatalytic degradation of dyes, leading to discoloration of the dye. The sensors resemble a color-changing tattoo that loses color upon exposure to UV. The viscosity and ink composition were optimized to achieve printability and tune the mechanical properties (e.g., modulus, hardness) of the sensors. The optimized procedure enabled the one-step fabrication of mechanically stable sensors that can effectively measure outdoor sun exposure by quantifying the decrease in color, visible to the naked eye. Apart from being used as wearable sensors, these sensors have the potential to be used along with UV-based workspace sterilizing devices to ensure that surfaces have been efficiently exposed to UV. The sensors are inexpensive, stable, extremely robust, biodegradable, and easy to use. The tunability, biocompatibility, and printability of the ink offer excellent potential for developing advanced 3D printing methods that, in addition to UV sensors, can be applied more broadly to fabricate other sensing technologies for a variety of other applications.

Nitric oxide signaling via cGMP-stimulated phosphodiesterase in striatal neurons.

Nitric oxide (NO) acts in the nervous system to activate guanylyl cyclase and increase cGMP. One target for cGMP appears to be the cGMP-stimulated phosphodiesterase (PDE2A), which is widely expressed in the brain and provides a molecular mechanism for NO to regulate cAMP levels. We have found that PDE2A is highly expressed in the medium spiny neurons of the striatum, which project to the pallidum and substantia nigra. These cells express dopamine-stimulated adenylyl cyclase, and we have found that increases in cAMP in these neurons, produced by activation of the D1-type dopamine receptor, are dramatically enhanced by the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the PDE2A-selective inhibitor erythro-p-(2-hydroxyl-3-nonyl)adenine (EHNA). These results indicate that PDE2A plays a major role in regulating dopamine-stimulated cAMP production in striatal neurons. EHNA also enhances NO-induced increases in striatal cGMP. In addition, dopamine appears to act via another receptor, activated by the agonist SKF83959, to increase striatal cGMP in a NO-dependent manner. Together, these observations indicate that striatal NO producing interneurons can act via the PDE2A in the medium spiny neurons to regulate the cAMP response to dopamine stimulation.