RESUMEN
We found that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with colony-forming unit-erythroid (CFU-E) activity (stress CFU-E [sCFU-E]) is expanded markedly to restore the erythron. sCFU-E cells are targets of erythropoietin (Epo), and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2- and STAT5-dependent expression of IRS2, thus engaging the progrowth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R and IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR-lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant JAK2(V617F) in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In samples from patients with myeloproliferative neoplasm, the number of sCFU-E-like cells increases, and inhibition of IGR1R and IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identified a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.
Asunto(s)
Eritropoyetina , Trastornos Mieloproliferativos , Neoplasias , Policitemia , Humanos , Eritropoyesis/fisiología , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Policitemia/metabolismo , Eritropoyetina/metabolismo , Trastornos Mieloproliferativos/metabolismo , Células Precursoras Eritroides/metabolismo , Neoplasias/metabolismo , Receptor IGF Tipo 1/metabolismoRESUMEN
Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Tromboembolia Venosa , Adulto , Humanos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/inducido químicamente , Estudios Retrospectivos , Receptores de Trasplantes , Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Administración Oral , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND: It has yet to be fully elucidated how differing populations of obstetric patients adapted to the disruptions in perinatal care and postpartum support from the COVID-19 pandemic. We surveyed an enriched sample of socioeconomically advantaged patients to understand the influence of COVID-19 on their perinatal care experience, well-being, and coping. METHODS: We surveyed pregnant and postpartum patients (n = 6140) at a large academic medical center in the Midwest of the United States using the Coronavirus and Perinatal Experiences instrument in Spring 2021. RESULTS: The survey was sent to 6141 pregnant and postpartum patients; 1180 (17.8%) respondents completed the survey, including 256 who were pregnant and 834 postpartum. Most pregnant patients experienced no changes in their prenatal care with 16.5% indicating somewhat worsened care. In the postpartum cohort, 37.5% stated their care had somewhat worsened. In describing influences on stress and mental health, 58.1% of postpartum respondents stated it was moderately, and 17.4% significantly, worse. The pandemic had a somewhat or moderately negative influence for 72.7% of respondents, with 11.0% stating these effects were extremely negative. Both cohorts characterized a range of coping strategies, most commonly, talking with friends and family (76.3%). CONCLUSION(S): Even among this sample of socioeconomically advantaged patients, respondents indicated that the pandemic disrupted many facets of their medical care and daily life, especially social activities and postpartum support. Our findings suggest that counseling on coping and adaptation strategies for stressors and increased health systems support be part of perinatal care during public health emergencies for all demographic groups.
Asunto(s)
COVID-19 , Embarazo , Femenino , Humanos , Estados Unidos/epidemiología , Pandemias , Periodo Posparto/psicología , Parto/psicología , Evaluación del Resultado de la Atención al PacienteRESUMEN
BACKGROUND: Telehealth has been increasingly adopted by health care systems since the start of the COVID-19 pandemic. Although telehealth may provide convenience for patients and clinicians, there are several barriers to accessing it and using it effectively to provide high-quality patient care. OBJECTIVE: This study was part of a larger multisite community-engaged study conducted to understand the impact of COVID-19 on diverse communities. The work described here explored the perceptions of and experience with telehealth use among diverse and underserved community members during COVID-19. METHODS: We used mixed methods across three regions in the United States (Midwest, Arizona, and Florida) from January to November 2021. We promoted our study through social media and community partnerships, disseminating flyers in English and Spanish. We developed a moderator guide and conducted focus groups in English and Spanish, mostly using a videoconferencing platform. Participants were placed in focus groups with others who shared similar demographic attributes and geographic location. Focus groups were audio-recorded and transcribed. We analyzed our qualitative data using the framework analytic approach. We developed our broader survey using validated scales and with input from community and scientific leaders, which was then distributed through social media in both English and Spanish. We included a previously published questionnaire that had been used to assess perceptions about telehealth among patients with HIV. We analyzed our quantitative data using SAS software and standard statistical approaches. We examined the effect of region, age, ethnicity/race, and education on the use and perceptions of telehealth. RESULTS: We included data from 47 focus groups. Owing to our mode of dissemination, we were not able to calculate a response rate for the survey. However, we received 3447 English-language and 146 Spanish-language responses. Over 90% of participants had internet access and 94% had used telehealth. Approximately half of all participants agreed or strongly agreed that telehealth would be beneficial in the future because it better fit their schedules and they would not need to travel. However, approximately half of the participants also agreed or strongly agreed they would not be able to express themselves well and could not be examined when using telehealth. Indigenous participants were especially concerned about these issues when compared to other racial groups. CONCLUSIONS: This work describes findings from a mixed methods community-engaged research study about telehealth, including perceived benefits and concerns. Although participants enjoyed the benefits of telehealth (eg, not having to travel and easier scheduling), they also had concerns (eg, not being able to express themselves well and not having a physical exam) about telehealth. These sentiments were especially notable among the Indigenous population. Our work highlights the importance of fully understanding the impact of these novel health delivery modalities on the patient experience and actual or perceived quality of care received.
Asunto(s)
COVID-19 , Telemedicina , Humanos , Estados Unidos , COVID-19/epidemiología , Pandemias , Atención a la Salud , EtnicidadRESUMEN
BACKGROUND: The COVID-19 pandemic has posed profound challenges for pregnant patients and their families. Studies conducted early in the pandemic found that pregnant individuals reported increased mental health concerns in response to pandemic-related stress. Many obstetric practices changed their healthcare delivery models, further impacting the experiences of pregnant patients. We conducted a survey study to explore the ways in which COVID-19 impacted the lives of pregnant and newly postpartum people. METHODS: A mixed-methods survey was distributed to all patients ≥18 years old who were pregnant between January 1st, 2020 - April 28, 2021 in a large Midwest health system. Open-ended survey responses were analyzed for common themes using standard qualitative methodology. RESULTS: Among the 1182 survey respondents, 647 women provided an open-ended response. Of these, 77% were in the postpartum period. The majority of respondents identified as white, were partnered or married, and owned their own home. Respondents reported feeling greater uncertainty, social isolation, as though they had limited social and practical support, and negative mental health effects as a result of the pandemic. Many cited sudden or arbitrary changes to their medical care as a contributing factor. Though in the minority, some respondents also reported benefits from the changes to daily life, including perceived improvements to medical care, better work-life balance, and opportunities for new perspectives. CONCLUSIONS: This large qualitative dataset provides insight into how healthcare policy and lifestyle changes impacted pregnant and postpartum people. Respondents expressed similar levels of uncertainty and mental health concerns compared to other cohorts but less overall positivity. Our findings suggest greater attention be given to the impact of pandemic-related stress on pregnant and postpartum women. As the pandemic continues, these data identify areas where investment in additional support may have the greatest impact.
Asunto(s)
COVID-19 , Adolescente , COVID-19/epidemiología , Femenino , Humanos , Menopausia , Salud Mental , Pandemias , Periodo Posparto/psicología , EmbarazoRESUMEN
Perinatal patients were faced with the decision to receive a COVID-19 vaccination in the absence of clinical trial data on COVID-19 vaccine safety and efficacy in pregnant and lactating patients. We used the Coronavirus Perinatal Experiences Impact Survey to explore the impact of the COVID-19 pandemic on the lives of perinatal patients. The mixed-method survey was distributed to all patients ≥ 18 years old who were pregnant between January 1st, 2020 - April 28, 2021 at a large academic health system in the upper Midwest. Open-ended responses were qualitatively analyzed. Of the 1182 respondents who completed the survey, 647 answered at least one open-ended question. Among these 647 participants, 85 discussed COVID-19 vaccination and were secondarily analyzed. The responses illustrated a wide range of perspectives regarding COVID-19 vaccination, with many citing concerns over the consequences of maternal vaccination on their child. Others highlighted the lack of information surrounding COVID-19 vaccination in perinatal women. Respondents also discussed challenges discussing their vaccination status with their healthcare provider and the impact of family member's vaccination decisions on postpartum support and childcare. The unprompted discussion of concerns about COVID-19 vaccination suggests this decision weighed on many participants, especially in the context of lack of information early in the pandemic. Our findings support the need for open discussion of perinatal patients with their providers on COVID-19 vaccination during the pregnancy and postpartum period.
Asunto(s)
COVID-19 , Pandemias , Adolescente , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Niño , Femenino , Humanos , Lactancia , Pandemias/prevención & control , Periodo Posparto , Embarazo , VacunaciónRESUMEN
The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.
Asunto(s)
Lesión Renal Aguda/metabolismo , Capilares/metabolismo , Eritropoyetina/metabolismo , Túbulos Renales Proximales/irrigación sanguínea , Túbulos Renales Proximales/metabolismo , Neovascularización Fisiológica , Receptores de Eritropoyetina/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Apoptosis , Autofagia , Capilares/patología , Capilares/fisiopatología , Hipoxia de la Célula , Células Cultivadas , Modelos Animales de Enfermedad , Fibrosis , Humanos , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/fisiopatología , Ratones de la Cepa 129 , Ratones Transgénicos , Receptores de Eritropoyetina/deficiencia , Receptores de Eritropoyetina/genética , Transducción de SeñalRESUMEN
Erythrocyte formation occurs throughout life in response to cytokine signaling. We show that microRNA-451 (miR-451) regulates erythropoiesis in vivo. Mice lacking miR-451 display a reduction in hematrocrit, an erythroid differentiation defect, and ineffective erythropoiesis in response to oxidative stress. 14-3-3zeta, an intracellular regulator of cytokine signaling that is repressed by miR-451, is up-regulated in miR-451(-/-) erythroblasts, and inhibition of 14-3-3zeta rescues their differentiation defect. These findings reveal an essential role of 14-3-3zeta as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors.
Asunto(s)
Proteínas 14-3-3/metabolismo , Diferenciación Celular , Células Eritroides/citología , Eritropoyesis/genética , MicroARNs/genética , MicroARNs/metabolismo , Animales , Células Eritroides/metabolismo , Células Eritroides/patología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hematócrito , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Oligonucleótidos/farmacología , Regulación hacia ArribaRESUMEN
The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild-type function.
Asunto(s)
Citocinas/farmacología , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Citometría de Flujo , Humanos , Janus Quinasa 2/genética , Mutación/genética , Fosforilación/efectos de los fármacos , Dominios Proteicos/genética , Dominios Proteicos/fisiologíaRESUMEN
Conditional mutagenesis is becoming a method of choice for studying gene function, but constructing conditional alleles is often laborious, limited by target gene structure, and at times, prone to incomplete conditional ablation. To address these issues, we developed a technology termed conditionals by inversion (COIN). Before activation, COINs contain an inverted module (COIN module) that lies inertly within the antisense strand of a resident gene. When inverted into the sense strand by a site-specific recombinase, the COIN module causes termination of the target gene's transcription and simultaneously provides a reporter for tracking this event. COIN modules can be inserted into natural introns (intronic COINs) or directly into coding exons as part of an artificial intron (exonic COINs), greatly simplifying allele design and increasing flexibility over previous conditional KO approaches. Detailed analysis of over 20 COIN alleles establishes the reliability of the method and its broad applicability to any gene, regardless of exon-intron structure. Our extensive testing provides rules that help ensure success of this approach and also explains why other currently available conditional approaches often fail to function optimally. Finally, the ability to split exons using the COIN's artificial intron opens up engineering modalities for the generation of multifunctional alleles.
Asunto(s)
Alelos , Silenciador del Gen , Ingeniería Genética/métodos , Mutagénesis Insercional/métodos , Inversión de Secuencia/genética , ADN Nucleotidiltransferasas/metabolismoRESUMEN
Erythropoietin (Epo) binding to the Epo receptor (EpoR) elicits downstream signaling that is essential for red blood cell production. One important negative regulatory mechanism to terminate Epo signaling is Epo-induced EpoR endocytosis and degradation. Defects in this mechanism play a key role in the overproduction of erythrocytes in primary familial and congenital polycythemia (PFCP). Here we have identified a novel mechanism mediating Epo-dependent EpoR internalization. Epo induces Cbl-dependent ubiquitination of the p85 regulatory subunit of PI3K, which binds to phosphotyrosines on EpoR. Ubiquitination allows p85 to interact with the endocytic protein epsin-1, thereby driving EpoR endocytosis. Knockdown of Cbl, expression of its dominant negative forms, or expression of an epsin-1 mutant devoid of ubiquitin-interacting motifs all compromise Epo-induced EpoR internalization. Mutated EpoRs mimicking those from PFCP patients cannot bind p85, co-localize with epsin-1, or internalize on Epo stimulation and exhibit Epo hypersensitivity. Similarly, knockdown of Cbl also causes Epo hypersensitivity in primary erythroid progenitors. Restoring p85 binding to PFCP receptors rescues Epo-induced epsin-1 co-localization and EpoR internalization and normalizes Epo hypersensitivity. Our results uncover a novel Cbl/p85/epsin-1 pathway in EpoR endocytosis and show that defects in this pathway contribute to excessive Epo signaling and erythroid hyperproliferation in PFCP.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Endocitosis/efectos de los fármacos , Eritropoyetina/farmacología , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Receptores de Eritropoyetina/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Línea Celular , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Células HEK293 , Humanos , Immunoblotting , Ratones , Ratones Noqueados , Mutación , Policitemia/congénito , Policitemia/genética , Policitemia/metabolismo , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-cbl/genética , Interferencia de ARN , Receptores de Eritropoyetina/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ubiquitinación/efectos de los fármacosAsunto(s)
MicroARNs/genética , Policitemia Vera , Policitemia , Animales , Apoptosis/genética , Eritroblastos/metabolismo , Eliminación de Gen , Hemólisis , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Ratones , Mutación , Estrés Oxidativo/genética , Policitemia/genética , Policitemia Vera/genéticaRESUMEN
The Janus Kinase 2 (JAK2) plays essential roles in transmitting signals from multiple cytokine receptors, and constitutive activation of JAK2 results in hematopoietic disorders and oncogenesis. JAK2 kinase activity is negatively regulated by its pseudokinase domain (JH2), where the gain-of-function mutation V617F that causes myeloproliferative neoplasms resides. In the absence of a crystal structure of full-length JAK2, how JH2 inhibits the kinase domain (JH1), and how V617F hyperactivates JAK2 remain elusive. We modeled the JAK2 JH1-JH2 complex structure using a novel informatics-guided protein-protein docking strategy. A detailed JAK2 JH2-mediated auto-inhibition mechanism is proposed, where JH2 traps the activation loop of JH1 in an inactive conformation and blocks the movement of kinase αC helix through critical hydrophobic contacts and extensive electrostatic interactions. These stabilizing interactions are less favorable in JAK2-V617F. Notably, several predicted binding interfacial residues in JH2 were confirmed to hyperactivate JAK2 kinase activity in site-directed mutagenesis and BaF3/EpoR cell transformation studies. Although there may exist other JH2-mediated mechanisms to control JH1, our JH1-JH2 structural model represents a verifiable working hypothesis for further experimental studies to elucidate the role of JH2 in regulating JAK2 in both normal and pathological settings.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Janus Quinasa 2/metabolismo , Sitio Alostérico , Sitios de Unión , Proliferación Celular , Análisis por Conglomerados , Biología Computacional , Cristalografía por Rayos X , Receptores ErbB/química , Humanos , Modelos Teóricos , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Programas Informáticos , Electricidad EstáticaRESUMEN
PURPOSE: To evaluate the safety of onabotulinum toxin A injected into the central upper eyelid and eyebrow regions. METHODS: The authors retrospectively reviewed the charts of all patients undergoing onabotulinum toxin A injection to the central upper eyelid and eyebrow between February, 2012, and November, 2012. Age, gender, indication, injection sites, number of central units, total number of units, and occurrence of adverse events were all recorded. RESULTS: A total of 300 procedures on 88 patients were performed, in whom the central upper eyelid and/or central eyebrow was injected with onabotulinum toxin A. There were 68 female and 20 male patients. Average age was 68.7±13.3 years (range, 42-92 years). Indications for central eyelid/eyebrow treatment included blepharospasm (34 patients, 176 procedures), hemifacial spasm (21 patients, 40 procedures), facial nerve disorders (2 patients, 9 procedures), and facial rhytides/eyebrow ptosis (31 patients, 75 procedures). The amount of neurotoxin injected into the central eyelid and eyebrow ranged from 2 to 12.5 units per encounter. Complications included diplopia (4% of total encounters), lagophthalmos (1% of total encounters), blepharoptosis (1% of total encounters), and blurry vision (1% of total encounters). Minor local effects, including bruising, bleeding, pain, and mild swelling, were recorded in 3.3% of total encounters. CONCLUSIONS: Placement of onabotulinum toxin A into the central upper eyelid and eyebrow is associated with a low rate of blepharoptosis. Central eyelid and eyebrow neurotoxin injection can be safely added to the regimen when treatment calls for chemodenervation of the central orbicularis oculi.
Asunto(s)
Inhibidores de la Liberación de Acetilcolina/administración & dosificación , Toxinas Botulínicas Tipo A/administración & dosificación , Cejas/efectos de los fármacos , Párpados/efectos de los fármacos , Inhibidores de la Liberación de Acetilcolina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Blefaroptosis/tratamiento farmacológico , Blefaroespasmo/tratamiento farmacológico , Toxinas Botulínicas Tipo A/efectos adversos , Enfermedades de los Párpados , Enfermedades del Nervio Facial/tratamiento farmacológico , Femenino , Espasmo Hemifacial/tratamiento farmacológico , Humanos , Inyecciones Intraoculares , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: To determine average dimensions of the orbicularis oculi muscle (OOM) from the orbital rim and to investigate polymorphic variations through anatomical dissection of nonpreserved, fresh-frozen human cadavers. METHODS: The OOM was exposed using sharp and blunt dissection until its distal borders were identified. A metric ruler was used to measure the superior (S line), inferior (I line), and lateral (L line) dimensions of the OOM from the orbital rim. Data collection included age, gender, and race. Data were analyzed using 2-sample t tests, paired t tests, and mixed effect models. A p-value of ≤0.05 was considered statistically significant. RESULTS: A total of 40 hemifaces of 20 cadavers were dissected. All specimens were Caucasian. Ten specimens were men. Average age was 73.9 years (56-92 years). The overall S line was 1.4 cm (95% confidence interval [CI], 1.23-1.57), the I line was 1.2 cm (95% CI, 1.00-1.36), and the L line was 2.5 cm (95% CI, 2.27-2.68). Men had significantly larger average T, L, and S line values than women (p = 0.003, 0.005, 0.008, respectively). I lines did not differ significantly between genders (p = 0.28). CONCLUSIONS: In senescent Caucasians, the OOM extends approximately 1.4 cm superior, 1.2 cm inferior, and 2.5 cm lateral to the orbital rim. The muscle extends significantly further superiorly and laterally in Caucasian men than in women. Knowledge of the extent of the OOM should improve the understanding and the treatment of conditions affecting this region.
Asunto(s)
Músculos Oculomotores/anatomía & histología , Órbita/anatomía & histología , Anciano , Anciano de 80 o más Años , Cadáver , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Población BlancaRESUMEN
Background: Assessing perceptions of the COVID-19 vaccines is essential for understanding vaccine hesitancy and for improving uptake during public health emergencies. In the complicated landscape of COVID-19 vaccine mandates and rampant misinformation, many individuals faced challenges during vaccination decision-making. The purpose of our mixed methods study is to elucidate factors affecting vaccine decision-making and to highlight the discourse surrounding the COVID-19 vaccines in diverse and underserved communities. Methods: This mixed methods study was conducted in Arizona, Florida, Minnesota, and Wisconsin between March and November 2021, combining a cross-sectional survey (n = 3593) and focus groups (n = 47). Results: The groups least likely to report receiving a vaccination were non-Hispanic Whites, Indigenous people, males, and those with moderate socioeconomic status (SES). Those indicating high and low SES reported similar vaccination uptake. Focus group data highlighted resistance to mandates, distrust, misinformation, and concerns about the rapid development surrounding the COVID-19 vaccines. Psychological reactance theory posits that strongly persuasive messaging and social pressure can be perceived as a threat to freedom, encouraging an individual to take action to restore that freedom. Conclusion: Our findings indicate that a subsection of participants felt pressured to get the vaccine, which led to weaker intentions to vaccinate. These results suggest that vaccine rollout strategies should be reevaluated to improve and facilitate informed decision-making.
RESUMEN
Objective: To investigate the experience of medical and graduate learners with second victim experience (SVE) after medical errors or adverse patient outcomes, including impact on training and identification of factors that shape their postevent recovery. Patients and Methods: The validated Second Victim Experience and Support Tool-Revised (SVEST-R), Physician Well-Being Index, and supplemental open-ended questions were administered to multidisciplinary health care learners between April 8, 2022, and May 30, 2022, across a large academic health institution. Open-ended responses were qualitatively analyzed for iterative themes related to impact of SVE on the training experience. Results: Of the 206 survey respondents, 144 answered at least 1 open-ended question, with 62.1% (n=91) reporting at least 1 SVE. Participants discussed a wide range of SVEs and indicated that their postevent response was influenced by their training environment. Lack of support from supervisors and staff exacerbated high stress situations. Some trainees felt blamed and unsupported after a traumatic experience. Others emphasized that positive training experiences and supportive supervisors helped them grow and regain confidence. Learners described postevent processing strategies helpful to their recovery. Some, however, felt disincentivized from seeking support. Conclusion: This multidisciplinary study of learners found that the training environment was influential in postevent recovery. Our findings support the need for the inclusion of education on SVEs and adaptive coping mechanisms as part of health care professional educational curriculums. Educators and health care staff may benefit from enhanced education on best practices to support trainees after stressful or traumatic patient events.
RESUMEN
OBJECTIVES: In 2018, the Healing Emotional Lives of Peers (HELP) Program was implemented at Mayo Clinic Rochester to guide healthcare professionals (HCPs) after a second victim experience, such as adverse patient events or medical errors. The HELP program was expanded to all HCPs in response to the anticipated stressors of the COVID-19 pandemic. This article aims to describe the rapid expansion of the peer support program and evaluate the effectiveness of peer support provided to affected colleagues (ACs). METHODS: Quantitative data collected from workshop evaluations, activations, and associated metrics ( TPS Self-Assessment , Encounter Form , and AC Self-Assessment ) were summarized through standard descriptive statistics using SAS version 9.4 software. Open-ended responses were qualitatively analyzed for iterative themes about the HELP program and associated workshops. RESULTS: Between April 2020 and December 2021, 22 virtual workshops to train peer supporters were conducted with 827 attendees. Of these, 464 employees completed the workshop evaluation. A total of 94.2% rated the workshop as excellent or very good. Participants perceived the workshop to be highly effective and felt more prepared to support ACs. Between May 2020 and December 2021, 247 activations were submitted through the HELP Program's intranet Web site and peer support was requested for 649 employees. Of the 268 TPS Self-Assessments , 226 (84.3%) felt that they provided helpful support to an AC. One hundred ACs evaluated support received, with 93% being "extremely" or "very satisfied." Affected colleagues appreciated having a TPS provide judgment-free support. CONCLUSIONS: The HELP Program promotes a culture of safety by helping HCPs process traumatic events. To effectively meet the needs of patients, healthcare organizations need to prioritize the well-being of their employees through interpersonal support.
Asunto(s)
COVID-19 , Pandemias , Humanos , Pandemias/prevención & control , COVID-19/epidemiología , COVID-19/prevención & control , Personal de Salud/psicología , Apoyo Social , Atención a la SaludRESUMEN
Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca2+ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 (SLC2A1) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.