Innovative Use of Cadavers in Perioperative Nursing Orientation.

The Periop 101 program administrator at a US Navy medical center worked with personnel in the facility's simulation and bioskills laboratories to develop an innovative perioperative nurse orientation curriculum that included the use of human cadavers during simulation activities. Participants were able to practice common perioperative nursing skills (eg, surgical skin antisepsis) on human cadavers rather than simulation manikins. The orientation program comprises two three-month phases. Participants were evaluated twice during phase 1: at the six-week mark and again six weeks later at the end of the phase. Using the Lasater Clinical Judgment Rubric, the administrator scored participants on their clinical judgment skills; results showed that mean scores increased for all learners between the two evaluation sessions. Practicing skills in a safe environment allows new staff members to learn without fear of causing accidental patient harm, and the additional use of cadavers further increased simulation fidelity and learner satisfaction.

An Innovative Simulation Curriculum to Train General Surgery Residents and Medical Students on Four Commonly Encountered Obstetric and Gynecologic Procedures.

INTRODUCTION: Lack of obstetric and gynecologic (OBGYN) procedure exposure during general surgery residency was recognized as a training gap for military general surgery residents by U.S. Navy trauma and general surgeons serving as simulation leads for the Naval Medical Center Portsmouth general surgery resident program. Program faculty requested the authors develop and implement a recurring simulation curriculum to address this training gap. The primary goal of the simulation curriculum was to increase exposure to and confidence in performing four commonly encountered OBGYN procedures in a deployed setting: spontaneous vaginal delivery (SVD), Bartholin's cyst incision and drainage with Word catheter placement, cesarean delivery, and total abdominal hysterectomy (TAH). We hypothesized that trainees exposed to the new simulation curriculum would demonstrate an increase in knowledge and confidence in these four commonly encountered OBGYN procedures. MATERIALS AND METHODS: The study utilized a pre- and postdesign to determine the efficacy of a newly developed simulation curriculum as measured by participants' knowledge and confidence levels. The annual curriculum was 4 hours in duration and included a targeted lecture followed by the administration of the four OBGYN simulation skills stations: SVD, Bartholin's, cesarean delivery, and total abdominal hysterectomy. Proctors for the simulation stations consisted of OBGYN teaching faculty who had at least 5 years of clinical teaching experience and were experienced simulation instructors. Precourse and postcourse knowledge and confidence were self-rated on a 5-point Likert scale. The learners rated the course using the Simulation Design Scale. Likert scale data were analyzed using the paired Wilcoxon rank sum test. Descriptive statistics were reported for the Simulation Design Scale. P < 0.05 was considered to be statistically significant. This project was classified as nonhuman subjects' research by the Naval Medical Center Portsmouth Institutional Review Board. RESULTS: Over the 2 years since curriculum implementation, 34 trainees participated in the curriculum; no trainees have had the curriculum twice. All trainees confirmed training gaps on baseline self-assessment of knowledge and confidence of all four OBGYN procedures with the most confidence reported for SVD (2.83 mean). Self-rated knowledge and confidence levels improved significantly in all four of the simulated procedures for all 34 participants (P < 0.001). Postcurricular surveys (82% response rate, 28/34) indicated a high satisfaction with all areas of the simulation training (4.74/5.0). CONCLUSIONS: The implemented curriculum increased general surgery trainees' knowledge and confidence in four commonly encountered OBGYN procedures and demonstrated a high level of learner satisfaction and sustainability. The curriculum exhibits high educational impact and could be a valuable adjunctive training for other non-OBGYN physicians who may need to provide OBGYN care in military environments.

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia.

Reduction/elimination of HIV-1 reservoirs that persist despite combination antiretroviral therapy (cART) will likely require induction of viral expression by residual infected cells and enhanced clearance of these cells. TLR7 agonists have potential to mediate these activities. We evaluated immunologic and virologic effects of repeated doses of the TLR7 agonist GS-9620 in SIV-infected rhesus macaques receiving cART, which was initiated at 13 days after infection and was continued for 75 weeks prior to GS-9620 administration. During cART, GS-9620 induced transient upregulation of IFN-stimulated genes in blood and tissues, increases in plasma cytokines, and changes in immune cell population activation and phenotypes but did not result in measurable increases in plasma viremia or viral RNA-to-viral DNA ratio in PBMCs or tissues nor decreases in viral DNA in PBMC or tissues. SIV-specific CD8+ T cell responses, negligible prior to GS-9620 treatment, were not measurably boosted by treatment; a second course of GS-9620 administration overlapping with later cART discontinuation was associated with increased CD8+ T cell responses during viral recrudescence. These results confirm and extend evidence for GS-9620-mediated enhancement of antiviral immune responses in SIV-infected macaques but suggest that GS-9620-mediated viral induction may depend critically on the timing of initiation and duration of cART and resulting characteristics of viral reservoirs.

In-situ Interprofessional Perinatal Drills: The Impact of a Structured Debrief on Maximizing Training While Sensing Patient Safety Threats.

Introduction In-situ interprofessional emergency team training improves participants' with confidence and knowledge and identifies latent safety threats. This study examined the impact of a structured debrief on an interprofessional perinatal team's ability to identify latent safety threats and assess competency in managing perinatal emergencies. It was hypothesized that latent safety threats would be reduced and checklist compliance would increase during subsequent in-situ perinatal team training. Methods Two in-situ training sessions were held six months apart. The perinatal emergency response team provided care for a standardized patient with preterm twin gestation. Each session included off-ward delivery and resuscitation of the first infant, transportation to appropriate inpatient units, cesarean delivery, and resuscitation of the second twin. Postpartum hemorrhage ensued, requiring massive transfusion protocol activation. Medical experts assessed team performance with critical action checklists. A structured debrief identified latent safety threats, developed action plans, and reviewed checklist compliance. Checklist compliance rates were analyzed using a z-ratio test. Results The first training session: seven teams (75 staff) completed 75% (292/391) critical action checklist items and identified 34 latent safety threats. Second training session: four teams (45 staff) completed 89% (94/106) critical action checklist items. Ten latent safety threats were mitigated during the second session. Utilizing a z-ratio, a significant difference was detected between the overall checklist compliance rates of the two sessions, z = -3.069, p = .002. Post-hoc power calculation was <10%. Conclusions In-situ interprofessional perinatal emergency team training is feasible, identifies latent patient safety threats, and may improve team competency.

Simulation Training for Operational Medicine Providers (STOMP): Impact of a Comprehensive Skills-Based Curriculum for Military General Medical Officers.

INTRODUCTION: A standardized training curriculum designed for general medical officers (GMO) titled Simulation Training for Operational Medicine Providers (STOMP) was recently developed to educate and improve GMOs' procedural skills through directed feedback prior to assuming duties in an operational environment. This study aimed to determine the impact this novel curriculum had on GMOs'confidence levels in 21 core privileges covering eight different subspecialties while stationed at Naval Medical Center Portsmouth (NMCP). MATERIALS AND METHODS: A cohort study from 2015 to 2017 was designed to address our specific aim to examine if the implementation of the STOMP curriculum increased GMOs' confidence levels. Fifty-seven participants enrolled in the study. The GMO case group completed the STOMP curriculum (n = 22), while the control or GMO self-study group (n = 35) did not complete the curriculum. Six months after starting clinical practice at NMCP, both groups completed an online survey that assessed their confidence level in performing each core privilege using a 5-point Likert scale. Scores were analyzed using a Wilcoxon Mann-Whitney test. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia IRB, protocol number: NMCP.2016.0010. RESULTS: Participants demonstrated a statistically significant increase in self-rated confidence scores (p < 0.05) in nine core privilege skills: punch biopsy, shave biopsy, excisional biopsy, removal of otic foreign body, removal of nasal foreign body, removal of ocular foreign body, tonometry, incision and drainage of a thrombosed hemorrhoid, and reduction of simple closed fractures and dislocations. CONCLUSIONS: These findings suggest that a novel and recently developed standardized simulation training curriculum entitled STOMP improves the confidence levels of early career physicians' in several primary care procedural skills and is an ideal adjunct to traditional lecture-based teaching prior to independent practice in a primary care environment.

Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV.

Human gammaherpesviruses are associated with malignancies in HIV infected individuals; in macaques used in non-human primate models of HIV infection, gammaherpesvirus infections also occur. Limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. We comprehensively examine all three-rhesus macaque gammaherpesviruses -Rhesus rhadinovirus (RRV), Rhesus Lymphocryptovirus (RLCV) and Retroperitoneal Fibromatosis Herpesvirus (RFHV) in macaques experimentally infected with Simian Immunodeficiency Virus or Simian Human Immunodeficiency Virus (SIV/SHIV) in studies spanning 15 years at the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research. We evaluated 18 animals with malignancies (16 lymphomas, one fibrosarcoma and one carcinoma) and 32 controls. We developed real time quantitative PCR assays for each gammaherpesvirus DNA viral load (VL) in malignant and non-tumor tissues; we also characterized the tumors using immunohistochemistry and in situ hybridization. Furthermore, we retrospectively quantified gammaherpesvirus DNA VL and SIV/SHIV RNA VL in longitudinally-collected PBMCs and plasma, respectively. One or more gammaherpesviruses were detected in 17 tumors; generally, one was predominant, and the relevant DNA VL in the tumor was very high compared to surrounding tissues. RLCV was predominant in tumors resembling diffuse large B cell lymphomas; in a Burkitt-like lymphoma, RRV was predominant; and in the fibrosarcoma, RFHV was predominant. Median RRV and RLCV PBMC DNA VL were significantly higher in cases than controls; SIV/SHIV VL and RLCV VL were independently associated with cancer. Local regressions showed that longitudinal VL patterns in cases and controls, from SIV infection to necropsy, differed for each gammaherpesvirus: while RFHV VL increased only slightly in all animals, RLCV and RRV VL increased significantly and continued to increase steeply in cases; in controls, VL flattened. In conclusion, the data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses.

Simulation Training for Operational Medicine Providers (STOMP): Design and Implementation of a Novel Comprehensive Skills-Based Curriculum for Military General Medical Officers.

Background: Fifty percent of graduating U.S. Navy post-graduate year (PGY)-1 physicians will practice in the operational environment before returning to residency training. However, current internship structure is less rotational and focuses more on specialty-specific training. Therefore, these physicians may not be fully prepared for this primary care role. Methods: Based on the U.S. Navy privileges for General Medical Officers, a comprehensive didactic and simulation curriculum was developed. Twenty-three procedural skill competencies (SK) and five validated standardized patient (SP) scenarios were identified. During the SK portion, learners reviewed instructional videos, read reference materials, and practiced with partial task trainers before small-group sessions with subject matter experts (SME). Separate SP round-robin sessions were conducted and feedback provided by SMEs and SPs. Learners demonstrated competency or were remediated. Results: One hundred and three PGY-1 trainees participated over 2 yr. All trainees met requirements during the SK phase. During the SP phase, seven learners required remediation. All learners ultimately met requirements for privileging. Conclusion: The Simulation Training for Operational Medicine Providers curriculum for future General Medical Officers is an effective tool for primary care skill training and credentialing. Plans for export to other Graduate Medical Education sites are underway and further evaluation of skills retention is warranted.

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy.

Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy.

Effect of suberoylanilide hydroxamic acid (SAHA) administration on the residual virus pool in a model of combination antiretroviral therapy-mediated suppression in SIVmac239-infected indian rhesus macaques.

Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4(+) T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches.

Persistence of viral reservoirs in multiple tissues after antiretroviral therapy suppression in a macaque RT-SHIV model.

Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood.

A macaque model of HIV-1 infection.

The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (Macaca nemestrina) lymphocytes. Importantly, infection of pig-tailed macaques with stHIV-1 results in acute viremia, approaching the levels observed in HIV-1-infected humans, and an ensuing persistent infection for several months. stHIV-1 replication was controlled thereafter, at least in part, by CD8+ T cells. We demonstrate the potential utility of this HIV-1-based animal model in a chemoprophylaxis experiment, by showing that a commonly used HIV-1 therapeutic regimen can provide apparently sterilizing protection from infection following a rigorous high-dose stHIV-1 challenge.

Evaluation of the safety, immunogenicity, and protective efficacy of whole inactivated simian immunodeficiency virus (SIV) vaccines with conformationally and functionally intact envelope glycoproteins.

A novel, general approach to chemical inactivation of retroviruses was used to produce inactivated simian immunodeficiency virus (SIV) particles with functional envelope glycoproteins. Inactivated virions of three different virus isolates (SIVmne E11S, SIVmac239, and SIVmac239 g4,5), prepared by treatment with 2,2'-dithiodipyridine (aldrithol-2, AT-2), were not detectably infectious, in vitro or in vivo. Immunization of pigtailed macaques with inactivated SIVmne E11S particles, without adjuvant, induced both humoral and cellular immune responses. Four of six animals immunized with the inactivated particles did not show measurable SIV RNA in plasma (<100 copy Eq/ml) following intravenous challenge with pathogenic, homologous virus (SIVmne E11S), compared to peak values of > or =10(6) copy Eq/ml in challenged SIV-naive control animals (p = 0.0001). Despite the absence of measurable viral RNA in plasma in these animals, culturable virus and viral DNA were initially detectable in blood and lymph node specimens; in contrast to control animals, SIV DNA could no longer be detected in PBMC by 10 weeks postchallenge in five of six SIV-immunized animals (p = 0.0001). However, vaccines did not resist a sequential rechallenge with the heterologous pathogenic virus SIVsm E660. AT-2-inactivated virus with functional envelope glycoproteins is a novel class of vaccine immunogen and was noninfectious, under conditions of rigorous in vivo challenge, and induced both binding and neutralizing antibody responses, along with cellular immune responses. Results suggest that immunization facilitated effective containment of pathogenic homologous challenge virus. With further optimization, AT-2-inactivated viral particles may be a useful class of immunogen in the development of a vaccine to prevent AIDS.