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BACKGROUND: CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB-IV melanoma. METHODS: Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. RESULTS: Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3â5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8- T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). CONCLUSIONS: These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment. TRIAL REGISTRATION NUMBER: NCT02565992.
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Melanoma , Virus Oncolíticos , Humanos , Animales , Cabras , Anticuerpos Monoclonales Humanizados/efectos adversos , Melanoma/tratamiento farmacológico , Microambiente TumoralRESUMEN
OBJECTIVE: Patient microaggressions affect practitioners in all fields of healthcare and especially psychiatry. In multiple studies, healthcare professionals reported high rates of patient microaggressions and discrimination. To date, this is the first scoping review of recommendations and trainings on patient microaggressions. METHOD: A scoping review of articles indexed in PubMed, PsycINFO, Medline, ERIC, and MedEdPORTAL was conducted from July 2020 to August 2020 to identify recommendations and solutions for healthcare professionals on responding to patient microaggressions. RESULTS: The review identified 27 studies that provide recommendations and trainings for healthcare professionals to address patient microaggressions. Twenty studies outlined recommendations for healthcare professionals and systems on how to respond to patient offenses. These 20 studies were grouped into establishing a supportive culture, addressing the microaggression, supporting the targets of microaggressions, discriminatory requests, and institutional responses. Six articles described trainings that equip providers with tools to address patient microaggressions, including the ERASE framework ("Expect/Recognize/Address/Support/Establish, Encourage"); Stop, Talk, and Roll; interrupting microaggressions; XYZ ("I felt X when Y because Z"); the ACTION model ("Ask/Come/Tell/Impact/Own/Next"); and the OWTFD tool ("Observe/Why/Think/Feel/Desire"). CONCLUSION: Recommendations and trainings for the response to microaggressions are emerging, and results of trainings are encouraging. However, more work is needed to evaluate the effectiveness of these trainings in clinical settings and longitudinally.
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Personal de Salud , Microagresión , Atención a la Salud , Personal de Salud/educación , HumanosRESUMEN
Conifers depend on complex defense systems against herbivores. Stone cells (SC) and oleoresin are physical and chemical defenses of Sitka spruce that have been separately studied in previous work. Weevil oviposit at the tip of the previous year's apical shoot (PYAS). We investigated interactions between weevil larvae and trees in controlled oviposition experiments with resistant (R) and susceptible (S) Sitka spruce. R trees have an abundance of SC in the PYAS cortex. SC are mostly absent in S trees. R trees and S trees also differ in the composition of oleoresin terpenes. Transcriptomes of R and S trees revealed differences in long-term weevil-induced responses. Performance of larvae was significantly reduced on R trees compared with S trees under experimental conditions that mimicked natural oviposition behavior at apical shoot tips and may be attributed to the effects of SC. In oviposition experiments designed for larvae to feed below the area of highest SC abundance, larvae showed an unusual feeding behavior and oleoresin appeared to function as the major defense. The results support a role for both SC and oleoresin terpenes and possible synergies between these traits in the defense syndrome of weevil-resistant Sitka spruce.
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Extractos Vegetales/metabolismo , Terpenos/metabolismo , Tracheophyta/citología , Tracheophyta/metabolismo , Animales , Conducta Alimentaria , Tracto Gastrointestinal/fisiología , Regulación de la Expresión Génica de las Plantas , Larva/fisiología , Oviposición , Tracheophyta/genética , Transcriptoma/genética , Árboles/genética , Árboles/fisiología , Gorgojos/fisiologíaRESUMEN
Computers are now essential in all branches of science, but most researchers are never taught the equivalent of basic lab skills for research computing. As a result, data can get lost, analyses can take much longer than necessary, and researchers are limited in how effectively they can work with software and data. Computing workflows need to follow the same practices as lab projects and notebooks, with organized data, documented steps, and the project structured for reproducibility, but researchers new to computing often don't know where to start. This paper presents a set of good computing practices that every researcher can adopt, regardless of their current level of computational skill. These practices, which encompass data management, programming, collaborating with colleagues, organizing projects, tracking work, and writing manuscripts, are drawn from a wide variety of published sources from our daily lives and from our work with volunteer organizations that have delivered workshops to over 11,000 people since 2010.
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Seguridad Computacional/normas , Metodologías Computacionales , Exactitud de los Datos , Investigación/normas , Ciencia/normas , Programas Informáticos/normas , Documentación/normas , Guías como AsuntoRESUMEN
Synthetic lethality has been proposed as a way to leverage the genetic differences found in tumor cells to affect their selective killing. Cohesins, which tether sister chromatids together until anaphase onset, are mutated in a variety of tumor types. The elucidation of synthetic lethal interactions with cohesin mutants therefore identifies potential therapeutic targets. We used a cross-species approach to identify robust negative genetic interactions with cohesin mutants. Utilizing essential and non-essential mutant synthetic genetic arrays in Saccharomyces cerevisiae, we screened genome-wide for genetic interactions with hypomorphic mutations in cohesin genes. A somatic cell proliferation assay in Caenorhabditis elegans demonstrated that the majority of interactions were conserved. Analysis of the interactions found that cohesin mutants require the function of genes that mediate replication fork progression. Conservation of these interactions between replication fork mediators and cohesin in both yeast and C. elegans prompted us to test whether other replication fork mediators not found in the yeast were required for viability in cohesin mutants. PARP1 has roles in the DNA damage response but also in the restart of stalled replication forks. We found that a hypomorphic allele of the C. elegans SMC1 orthologue, him-1(e879), genetically interacted with mutations in the orthologues of PAR metabolism genes resulting in a reduced brood size and somatic cell defects. We then demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. This work demonstrates that large-scale genetic interaction screening in yeast can identify clinically relevant genetic interactions and suggests that PARP inhibitors, which are currently undergoing clinical trials as a treatment of homologous recombination-deficient cancers, may be effective in treating cancers that harbor cohesin mutations.
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Caenorhabditis elegans , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Replicación del ADN , Poli(ADP-Ribosa) Polimerasas , Saccharomyces cerevisiae , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Ciclo Celular/genética , Proliferación Celular , Cromátides/genética , Cromátides/metabolismo , Proteínas Cromosómicas no Histona/genética , Daño del ADN/genética , Epistasis Genética , Genes Letales , Células HCT116 , Recombinación Homóloga/genética , Humanos , Mutación , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Interferente Pequeño , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , CohesinasRESUMEN
This study evaluated pet affinity as a buffer between ambivalence over emotional expression (AEE) and social support. AEE occurs when one desires to express emotions but is reluctant to do so and is related to negative psychological outcomes. Individuals high in AEE may have difficulty receiving social support and thus may not gain accompanying benefits. Social support has been associated with positive health outcomes, and pet support is positively associated with human social support. The present study explores the potential protective effect of pet affinity. One hundred ninety-eight undergraduate dog owners completed measures assessing perceived social support, pet affinity, and AEE. AEE was expected to be negatively associated with social support, and pet affinity was expected to buffer the negative effects of AEE on social support. We found that AEE was negatively associated with perceived social support. An interaction between pet affinity and AEE emerged such that the negative association between AEE and social support was weaker among those higher in pet affinity. Thus, at high levels of AEE, those who felt a close connection with their pets reported more perceived social support than those less connected with their pets. Overall, these findings emphasize the potential benefits of pet affinity.
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Introduction At the start of the COVID-19 pandemic, many graduate medical education (GME) programs switched from in-person to virtual training to ensure a safe learning environment. However, the preferences of US residents in the wake of the COVID-19 pandemic are largely unknown. Objective The authors surveyed PGY-2 psychiatry residents about their perception of the pandemic's impact on their clinical skills, didactics experience, training preferences, and future career perceptions. Methods The cross-sectional study was conducted from October 31, 2021, to December 31, 2021. The authors emailed a survey to directors of US general psychiatry residency programs to disseminate to PGY-2 residents. The survey had Likert-scale and open-ended questions about the pandemic's perceived impact on PGY-1 training and future training preferences. The authors used descriptive statistics for Likert-scale questions and reflexive thematic analysis for open-ended questions. Results Out of an estimated 1800 residents, only 116 (6.4%) participated; post-pandemic preferences emerged. A strong preference was expressed for hybrid didactics, combining in-person and virtual learning. Virtual patient evaluations, especially in emergency and inpatient settings, were highly valued. Conversely, entirely virtual didactics and clinical rounds were deemed least preferred, emphasizing the importance of interactive, hands-on learning experiences. Conclusions Respondents emphasized the significance of incorporating hybrid models for both in-patient care and didactic sessions in GME. These preferences signify the need for adaptable and flexible approaches to education in psychiatry residency programs as we emerge from the pandemic.
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The Department of Veteran Affairs established Readjustment Counseling Service (RCS) to meet the mental health needs of active-duty service members, veterans, and their families. A diverse therapeutic skill set is needed to serve this complex population. To assess training needs, a national mixed-methods needs assessment consisting of a survey for RCS counselors and focus groups among counselors, RCS educational trainers, and national leadership was conducted. Survey results (n = 681) showed that RCS counselors were most interested in trainings on moral injury, acceptance and commitment therapy, and military sexual trauma (MST). Desired trainings aligned with populations served. Themes from focus groups revealed the need for foundational trainings so that all RCS counselors are adept in treating MST, moral injury, and posttraumatic disorder and proficient in caring for couples. Additionally, counselors desired advanced trainings tailored to individual counselors' needs. RCS counselors identified multiple trainings to help them treat those they serve.
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Terapia de Aceptación y Compromiso , Consejeros , Veteranos , Estados Unidos , Humanos , Veteranos/psicología , Consejeros/psicología , Evaluación de Necesidades , United States Department of Veterans Affairs , Consejo/métodosRESUMEN
Mental health clinicians frequently experience hate speech during patient care, resulting in an ethical dilemma. This study evaluated a 1-hour webinar discussing the ethics of working with Veterans who use hate speech, motivations and intentions of hate speech, and guidance on how to respond. The webinar was offered through the virtual Community-Based Outpatient Clinic Mental Health Grand Rounds session at the Veterans Health Administration (VHA). Rural mental health clinicians were the target audience; however, all VHA clinicians could attend. Participants were VHA clinicians who completed the evaluation for the training and received one continuing education unit for this training (n = 668). They were highly satisfied with the training and would recommend it to others. They also reported the intention to talk with coworkers and trainees about responding to hate speech and requested additional training. The recorded training can be viewed for free at https://www.mirecc.va.gov/visn16/working-with-patients-who-use-hate-speech.asp.
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A mental health treatment gap exists in which individuals who would benefit from evidence-based psychotherapies (EBPs) do not receive them. It is critical to take effective actions so that individuals with unmet mental health needs feel empowered to seek treatment. Direct-to-consumer (DTC) marketing meets this objective. DTC marketing is an effective, patient-centered approach that creates patient demand for a product or service by influencing patient behaviors, attitudes, and preferences. While primarily used in the United States and New Zealand to promote prescription drugs, uses and practices for DTC marketing with nonpharmaceutical EBPs are less established. This article highlights the value of leveraging this marketing approach to increase awareness and use of EBPs. Additionally, an illustrative example is presented that describes the use of social marketing and marketing mix principles to develop effective DTC marketing campaigns in psychotherapy practice.
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Video telehealth experienced rapid growth throughout the COVID-19 pandemic in many healthcare sectors, including mental health. The Veterans Health Administration's video telehealth platform, VA Video Connect, has been widely used to reach veterans who may have experienced difficulty accessing care, such as those living in rural areas or other barriers (e.g., transportation). Implementing VVC requires a multifaceted approach, including training providers on technical skills, increasing access to equipment for providers and veterans, and integrating VVC within the culture and processes of the clinic unit. Prior successful VVC implementation efforts in rural areas have focused on simultaneous one-on-one provider and leadership engagement using implementation facilitation (IF). However, given the rapid need for VVC expansion in light of limits and dangers associated with in-person care during the pandemic, our team developed group facilitation to increase the reach of VVC implementation through IF. Group facilitation combined training in technical and policy elements of VVC with IF with groups of providers from clinic units. This approach was designed to rapidly disseminate the necessary knowledge to conduct VVC combined with collaborative problem solving as a team to improve the ability of the clinical team to sustain VVC. Attendees were asked for feedback on the session through multiple choice and open-ended questions. Participants (N = 26) reported being highly satisfied with the training and reported a high degree of confidence in their ability to use VVC. Based on evaluation data and interview feedback, providers and clinic leaders were satisfied with group facilitation. Group facilitation may be a helpful tool in rapidly training clinical teams to implement and sustain video telemental health.
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PURPOSE: Sickle cell disease (SCD) is an inherited blood disorder with a natural course punctuated by acute complications including painful vaso-occlusive episodes. The objectives were: (1) to determine what proportion of patients with SCD receive opioids within 30 min of triage as recommended by the current clinical recommendations and quality standard; and (2) to identify facilitators to timely opioid administration for patients with SCD. METHODS: This was a retrospective observational study. The primary outcome was the proportion of visits in which patients received opioid analgesia within 30 min of triage. Secondary outcomes were time in minutes from triage to any analgesic administration and time from triage to first opioid administration. Patient demographics and ED encounter characteristics were included as potential associated variables. RESULTS: There were 236 patient visits (by 103 patients) that met inclusion criteria. Patients received opioid analgesia within 30 min of triage in only 5.2% of visits. The median time from triage to opioid analgesia was 80 (IQR = 49.0, 125.5) minutes. Using an order set and receiving opioid analgesia prior to physician assessment were both associated with shorter times to opioid analgesia. CONCLUSION: Existing recommendations are that opioid analgesia be provided within 30 min of triage for patients with SCD and VOEs. Our data show this target is rarely met, even in a department in which SCD VOEs are a common presenting concern. The association of earlier opioid analgesia with order set use and administration prior to physician assessment highlights potential avenues for improving time to analgesia.
RéSUMé: OBJECTIF: La drépanocytose (ou l'anémie falciforme) est une maladie héréditaire du sang dont l'évolution naturelle est ponctuée de complications aiguës, notamment des épisodes vaso-occlusifs douloureux. Les objectifs étaient : (1) de déterminer quelle proportion de patients atteints de drépanocytose reçoivent des opioïdes dans les 30 minutes suivant le triage, comme le recommandent les recommandations cliniques et la norme de qualité actuelles ; et (2) d'identifier les facteurs facilitant l'administration rapide d'opioïdes aux patients atteints de drépanocytose. MéTHODES: Il s'agissait d'une étude observationnelle rétrospective. Le critère de jugement principal était la proportion de visites au cours desquelles les patients ont reçu une analgésie opioïde dans les 30 minutes suivant le triage. Les critères de jugement secondaires étaient le temps en minutes écoulé entre le triage et l'administration de tout analgésique et le temps écoulé entre le triage et la première administration d'opioïdes. Les caractéristiques démographiques des patients et les caractéristiques des rencontres aux urgences ont été incluses comme variables potentiellement associées. RéSULTATS: Il y a eu 236 visites de patients (par 103 patients) qui répondaient aux critères d'inclusion. Les patients ont reçu une analgésie opioïde dans les 30 minutes suivant le triage dans seulement 5,2 % des visites. Le temps médian écoulé entre le triage et l'analgésie opioïde était de 80 (IQR = 49,0, 125,5) minutes. L'utilisation d'un ensemble de commandes et la réception d'une analgésie opioïde avant l'évaluation du médecin étaient toutes deux associées à des temps plus courts d'analgésie opioïde. CONCLUSIONS: Les recommandations existantes sont que l'analgésie opioïde soit fournie dans les 30 minutes suivant le triage pour les patients atteints de drépanocytose et d'EVO. Nos données montrent que cet objectif est rarement atteint, même dans un service où les EVO de la drépanocytose sont une préoccupation courante. L'association d'une analgésie opioïde plus précoce avec l'utilisation d'un ensemble de commandes et l'administration avant l'évaluation du médecin met en évidence des pistes potentielles pour améliorer le temps d'analgésie.
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Introduction: High-dose interleukin-2 (HD IL-2) and pembrolizumab are each approved as single agents by the U.S. F.D.A. for the treatment of metastatic melanoma. There is limited data using the agents concurrently. The objectives of this study were to characterize the safety profile of IL-2 in combination with pembrolizumab in patients with unresectable or metastatic melanoma. Methods: In this Phase Ib study, patients received pembrolizumab (200 mg IV every 3 weeks) and escalating doses of IL-2 (6,000 or 60,000 or 600,000 IU/kg IV bolus every 8 hours up to 14 doses per cycle) in cohorts of 3 patients. Prior treatment with a PD-1 blocking antibody was allowed. The primary endpoint was the maximum tolerated dose (MTD) of IL-2 when co-administered with pembrolizumab. Results: Ten participants were enrolled, and 9 participants were evaluable for safety and efficacy. The majority of the evaluable participants (8/9) had been treated with PD-1 blocking antibody prior to enrollment. Patients received a median of 42, 22, and 9 doses of IL-2 in the low, intermediate, and high dose cohorts, respectively. Adverse events were more frequent with increasing doses of IL-2. No dose limiting toxicities were observed. The MTD of IL-2 was not reached. One partial response occurred in 9 patients (11%). The responding patient, who had received treatment with an anti-PD-1 prior to study entry, was treated in the HD IL-2 cohort. Discussion: Although the sample size was small, HD IL-2 therapy in combination with pembrolizumab appears feasible and tolerable. Clinical trial registration: ClinicalTrials.gov, identifier NCT02748564.
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Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior.
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Providing telemental health services to older adults has become especially important during the COVID-19 pandemic. Video-to-home (VTH) treatment is an effective treatment modality; research shows that older adults are open to using VTH. However, there are unique barriers to using VTH with older adults. Barriers include access to technology, acceptance of technology, and physical and cognitive limitations. Additional concerns include establishing rapport with older patients and the policy and ethical concerns surrounding the use of VTH. Methods of addressing these barriers have been developed, and more research is needed to develop evidence-based VTH practice.
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PURPOSE: Racism and colonialism impact health, physician advancement, professional development and medical education in Canada. The Canadian Association of Emergency Physicians (CAEP) has committed to addressing inequities in health in their recent statement on racism. The objective of this project was to develop recommendations for addressing racism and colonialism in emergency medicine. METHODS: The authors, in collaboration with a 40 member working group, conducted a literature search, held a community consultation, solicited input from expert medical, academic and community advisors, conducted a national survey of emergency physicians, and presented draft recommendations at the 2021 CAEP Academic Symposium on Equity, Diversity and Inclusion for a live facilitated discussion with a post-session survey. RESULTS: Sixteen recommendations were generated in the areas of patient care, hospital and departmental commitment to Equity, Diversity, and Inclusion, physician advancement, and professional development and medical education. CONCLUSION: Emergency physicians are uniquely positioned to promote equity at each encounter with patients, peers and learners. The 16 recommendations presented here are practical steps to countering racism and colonialism everyday in emergency medicine.
RéSUMé: OBJECTIF: Le racisme et le colonialisme ont une incidence sur la santé, l'avancement des médecins, le développement professionnel et l'éducation médicale au Canada. L'Association canadienne des médecins d'urgence (ACMU) s'est engagée à lutter contre les inégalités en matière de santé dans sa récente déclaration sur le racisme. L'objectif de ce projet était d'élaborer des recommandations pour lutter contre le racisme et le colonialisme en médecine d'urgence. MéTHODES: Les auteurs, en collaboration avec un groupe de travail de 40 membres, ont effectué une recherche documentaire, tenu une consultation communautaire, sollicité les commentaires d'experts en médecine, en enseignement et en services communautaires, mené une enquête nationale auprès des médecins d'urgence et ont présenté des ébauches de recommandations lors du Symposium académique de l'ACMU 2021 sur l'Équité, la Diversité et l'inclusion pour une discussion animée en direct avec un sondage après la séance. RéSULTATS: Seize recommandations ont été formulées dans les domaines des soins aux patients, de l'engagement de l'hôpital et du service en matière d'Équité, de Diversité et d'Inclusion, de l'avancement des médecins, du développement professionnel et de l'éducation médicale. CONCLUSION: Les médecins urgentistes sont particulièrement bien placés pour promouvoir l'équité à chaque rencontre avec les patients, les pairs et les apprenants. Les 16 recommandations présentées ici sont des mesures pratiques pour contrer le racisme et le colonialisme au quotidien dans la médecine d'urgence.
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Medicina de Emergencia , Racismo , Canadá , Colonialismo , Medicina de Emergencia/educación , Humanos , Sociedades MédicasRESUMEN
Background: Point-of-care ultrasound (POCUS) training has become a standard component of Canadian emergency medicine (EM) residency programs. In resource-limited contexts, including Ethiopia, there is a critical shortage of local clinicians who can perform and teach POCUS. Our aim was to establish an introductory POCUS rotation within the EM residency program at Addis Ababa University (AAU) through The Toronto Addis Ababa Academic Collaboration in Emergency Medicine (TAAAC-EM). Methods: Through stakeholder engagement, the authors completed a quality improvement initiative and conducted a survey of AAU EM faculty and residents to understand which POCUS scans should be included in a core residency POCUS curriculum, "POCUS1". Results: 17 residents completed the POCUS1 program and 16 residents completed the written survey. Focused assessment with sonography for trauma, inferior vena cava, and lung (pneumothorax, pleural effusions, and interstitial syndrome) were identified as core introductory topics. Seventeen residents completed the initial POCUS1 program. Three program graduates were supported to become "POCUS1 Master Instructors" to continue the program during the SARS-CoV-2 global pandemic. Conclusion: The authors identified the highest yield POCUS scans through a written survey, successfully introduced a sustainable core POCUS curriculum at AAU for EM residents, and graduated three master instructors for curriculum continuation. We outline the structure and materials for implementation of POCUS programs for EM trainees and staff in similar low- and middle-income countries.