Programmable protein arrays for immunoprofiling HPV-associated cancers.

Over 600,000 cancers each year are attributed to the human papillomavirus (HPV), including cervical, anogenital and oropharyngeal cancers (OPC). A key challenge in understanding HPV immunobiology is the diversity of oncogenic HPV types and the need for multiplexed display of HPV antigens to measure antibody responses. We have generated custom HPV protein microarrays displaying 98 proteins as C-terminal GST fusion proteins, representing eight antigens of two low-risk HPV types (HPV6 and 11) and ten oncogenic high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52 and 58). We demonstrate robust and reproducible protein expression of 96/98 of the antigens using a human cell lysate expression system. The target epitopes and specificities of four monoclonal antibodies were identified. Using sera from ten patients with newly diagnosed OPC and ten controls, we demonstrate specific IgG seroreactivity to HPV16 E1, E2, and E7 (a fold increase of 1.52, 2.19 and 1.35 in cases vs. controls, respectively, all p < 0.005), confirming our prior data on an ELISA platform. We also detect HPV52 E7 Abs in serum from a patient with cervical cancer. The HPV protein array has potential for rapid identification of serologic responses to 12 HPV types.

A Systematic Review of the Department of Veterans Affairs Mental Health-Care Access Interventions for Veterans With PTSD.

INTRODUCTION: Access to mental health care has been a priority area for the U.S. Department of Veterans Affairs (DVA) for decades. Access for veterans with PTSD is essential because untreated PTSD is associated with numerous adverse outcomes. Although interventions have been developed to improve access to DVA mental health care, the impact of these interventions on access for veterans with untreated PTSD has not been examined comprehensively, limiting guidance on appropriate implementation. MATERIALS AND METHODS: We conducted a systematic review of PubMed and PTSDpubs between May 2019 and January 2022 to identify DVA access interventions for veterans with PTSD not engaged in DVA mental health care. We identified 17 interventions and 29 manuscripts reporting quantitative access outcomes. We categorized interventions into four major categories: Primary care mental health integration, other national initiatives, telemental health, and direct outreach. We evaluated five outcome domains: Binary attendance, number of sessions attended, wait time, number of patients seen, and care initiation. We assessed the risk of bias using the Cochrane Collaboration criteria. RESULTS: Across articles, binary attendance generally improved, whereas the impact on the number of sessions attended was equivocal. Overall, the number of patients seen increased compared to control participants and retrospective data. The few articles that examined care initiation had mixed results. Only one article examined the impact on wait time. CONCLUSIONS: Access interventions for veterans with PTSD demonstrated varied success across interventions and outcomes. The national initiatives-particularly primary care mental health integration -were successful across several outcomes; telemental health demonstrated promise in improving access; and the success of direct outreach varied across interventions. Confidence in these findings is tempered by potential bias among studies. Limited literature on how these interventions impact relevant preattendance barriers, along with incomplete data on how many perform nationally, suggests that additional work is needed to ensure that these interventions increase access for veterans with PTSD nationwide.

Does screening for PTSD lead to VA mental health care? Identifying the spectrum of initial VA screening actions.

Despite the active posttraumatic stress disorder (PTSD) screening program in Department of Veterans Affairs (VA) primary care clinics and the availability of empirically supported treatments for PTSD at VA, many veterans for whom screening suggests treatment may be indicated do not gain access to VA-based mental health care. To determine where we may be losing veterans to follow-up, we need to begin by identifying the initial action taken in response to a positive PTSD screen in primary care. Using VA administrative data and chart review, we identified the spectrum of initial actions taken after veterans screened positive for PTSD in VA primary care clinics nationwide between October 2017 and September 2018 (N = 41,570). We collapsed actions into those that could lead to VA-based mental health care (e.g., consult placed to a VA mental health clinic) versus not (e.g., veteran declined care), and then examined the association between these categories of actions and contextual- and individual-level variables. More than 61% of veterans with positive PTSD screens had evidence that an initial action toward VA-based mental health care was taken. Urban-dwelling and female veterans were significantly more likely to have evidence of these initial actions, whereas White and Vietnam-era veterans were significantly less likely to have this evidence. Our findings suggest that most veterans screening positive for PTSD in VA primary care clinics have evidence of initial actions taken toward VA-based mental health care; however, a substantial minority do not, making them unlikely to receive follow-up care. Findings highlight the potential benefit of targeted primary care-based access interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

How Are Emerging Data Translated Into Clinical Practice? A Mixed Methods Investigation of Coronavirus Disease 2019 Institutional Treatment Protocols.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was minimal data to guide treatment, and we lacked understanding of how clinicians translated this limited evidence base for potential therapeutics to bedside care. Our objective was to systematically determine how emerging data about COVID-19 treatments was implemented by analyzing institutional treatment protocols. METHODS: Treatment protocols from North American healthcare facilities and recommendations from guideline-issuing bodies were collected. Qualitative data on treatment regimens and their applications were extracted using an adapted National Institutes of Health/US Food and Drug Administration experimental therapeutics framework. Structured data on risk factor and severity of illness scoring systems were extracted and analyzed using descriptive statistics. RESULTS: We extracted data from 105 independent protocols. Guideline-issuing organizations published recommendations after the initial peak of the pandemic in many regions and generally recommended clinical trial referral, with limited additional guidance. Facility-specific protocols favored offering some treatment (96.8%, N = 92 of 95), most commonly, hydroxychloroquine (90.5%), followed by remdesivir and interleukin-6 inhibitors. Recommendation for clinical trial enrollment was limited largely to academic medical centers (19 of 52 vs 9 of 43 community/Veterans Affairs [VA]), which were more likely to have access to research studies. Other themes identified included urgent protocol development, plans for rapid updates, contradictory statements, and entirely missing sections, with section headings but no content other than "in process." CONCLUSIONS: In the COVID-19 pandemic, emerging information was rapidly implemented by institutions into clinical practice and, unlike recommendations from guideline-issuing bodies, heavily favored administering some form of therapy. Understanding how and why evidence is translated into clinical care is critical to improve processes for other emerging diseases.

Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine.

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.