RESUMO
While medical and health science librarians' median salaries have increased over the last forty years; however, inflation-adjusted salaries are lower than in 2008. Utilizing data from the Medical Library Association's salary surveys from 1983 to 2023, this column explores median salary changes over time by discussing the median salary's performance against inflation and how the 2008 recession and the 2020 COVID-19 pandemic impacted salaries. From 2017 to 2023, the median salary increased by 18%, but after adjusting for inflation, the median salary decreased by almost 6%. The findings have serious implications for recruitment and retention in medical and health sciences librarianship.
Assuntos
COVID-19 , Bibliotecários , SARS-CoV-2 , Salários e Benefícios , Humanos , COVID-19/epidemiologia , Salários e Benefícios/estatística & dados numéricos , Estados Unidos , Feminino , Bibliotecas Médicas/economia , Bibliotecas Médicas/organização & administração , Masculino , Adulto , Pandemias , Pessoa de Meia-IdadeRESUMO
Background: Librarians at Preston Medical Library sought to understand whether marketing research techniques could be adapted to libraries to better understand what patrons value. Specifically, this study sought to learn why patrons continue using a consumer health information service, develop insights to improve the service, and a methodology to use with other patron groups. Case Presentation: Librarian researchers conducted customer value research using laddering interviews, an interview technique utilized in marketing research to learn users' goals in using a product or service. The PML research team interviewed six frequent users of a medical library's consumer health information service. Researchers conducted laddering interviews, covering patron views of basic attributes of the service, leading on to consequences of their interaction with it, and finally discussing what they hoped to achieve in using the service. The results were visualized in customer value hierarchy diagrams, graphically showing relationships between valued attributes of a product or service, how the patron used it, and how that helped patrons achieve goals. This allowed the research team to identify which features of service contribute the most to patron satisfaction. Conclusion: Customer value learning utilizing laddering interviews enables librarians to see their service through the patrons' eyes, focusing on those aspects of the service that they view as most important. This study allowed librarians to learn that users desired to feel more in control of their health and gain peace of mind by obtaining trusted information. The library's work in providing information leads to self-empowerment for these patrons.
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Informação de Saúde ao Consumidor , Bibliotecários , Bibliotecas Médicas , Serviços de Biblioteca , Humanos , AprendizagemRESUMO
Induction of general anaesthesia is often accompanied by hypotension. Standard haemodynamic monitoring during anaesthesia relies on intermittent blood pressure and heart rate. Continuous monitoring systemic blood pressure requires invasive or advanced modalities creating a barrier for obtaining important information of the circulation. The Peripheral Perfusion Index (PPI) is obtained non-invasively and continuously by standard photoplethysmography. We hypothesized that different patterns of changes in systemic haemodynamics during induction of general anaesthesia would be reflected in the PPI. Continuous values of PPI, stroke volume (SV), cardiac output (CO), and mean arterial pressure (MAP) were evaluated in 107 patients by either minimally invasive or non-invasive means in a mixed population of surgical patients. 2 min after induction of general anaesthesia relative changes of SV, CO, and MAP was compared to the relative changes of PPI. After induction total cohort mean(± st.dev.) MAP, SV, and CO decreased to 65(± 16)%, 74(± 18)%, and 63(± 16)% of baseline values. In the 38 patients where PPI decreased MAP was 57(± 14)%, SV was 63(± 18)%, and CO was 55(± 18)% of baseline values 2 min after induction. In the 69 patients where PPI increased the corresponding values were MAP 70(± 15)%, SV 80(± 16)%, and CO 68(± 17)% (all differences: p < 0,001). During induction of general anaesthesia changes in PPI discriminated between the degrees of reduction in blood pressure and algorithm derived cardiac stroke volume and -output. As such, the PPI has potential to be a simple and non-invasive indicator of the degree of post-induction haemodynamic changes.
Assuntos
Hemodinâmica , Índice de Perfusão , Humanos , Débito Cardíaco , Anestesia Geral , Pressão SanguíneaRESUMO
This study compares health science librarian job postings in the MEDLIB-L listserv from 2018-2019 and 2021-2022 to assess whether there was an increase in remote or hybrid schedule arrangements listed in job advertisements after the pandemic's onset. Results indicated a notable increase in advertising remote/hybrid work arrangements rising from 1.2% of listings in 2018-2019 to 16% of listings in 2021-2022. Data from a 2022 survey of library directors, however, indicated that approximately 70% of respondents expressed confidence in the continuance of remote/hybrid work. Additionally, from a very limited sample size, salaries for remote/hybrid positions did not appear to be less than in-person postings. While current employees at many institutions may benefit from flexible scheduling, this study examines whether job postings, which are often the primary information available to applicants, included information about remote and hybrid work options.
Assuntos
COVID-19 , Bibliotecários , Humanos , Pandemias , Recursos Humanos , Inquéritos e QuestionáriosRESUMO
Objective: At many institutions, literature search services are an important aspect of health science librarianship. This exploratory study analyzes how the COVID-19 pandemic impacted the use of an academic hospital medical library's literature search service. Methods: To evaluate the pandemic's impact on literature searching at The University of Tennessee Medical Center's Preston Medical Library, data were analyzed for changes from the year before the pandemic (March 1, 2019 to February 29, 2020) to the first year during the pandemic (March 1st, 2020 to February 28, 2021). This was accomplished using LibWizard, a library feedback and assessment application, to review literature search data during the two periods. Variables of interest included total searches, purpose of searches, affiliation of the searcher, and searches with a pandemic-related research question. Results: A 36.6% drop in literature search service usage was reported from the pre-pandemic year to the during-pandemic year. There was a 55.3% decrease in searches intended for research, as well as significant decreases in the number of searches requested by all patron affiliations. After March 2020, 10% of all searches concerned a COVID-related topic. Conclusion: The overall decrease in literature search requests, decrease in research searches, decrease in searches among all patron affiliations, and increase in searches on a COVID-related topic suggest that healthcare worker and institutional priorities changed during the pandemic. The results revealed research interests during the first year of the pandemic, as well as an overall change in library service functionality.
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COVID-19 , Bibliotecas Médicas , Biblioteconomia , Serviços de Biblioteca , Humanos , PandemiasRESUMO
Since 2006, the University of Tennessee's Preston Medical Library has collected survey feedback from exiting residents through targeted emails or at the required exit process in the library. Questions ask residents which types of articles or sources they use to find information and address the resident's use of the library's physical space. Survey results from 2006 to 2021 were examined for trends and changes in resident utilization of resources to better inform future library decisions on instruction and marketing. Resident resource usage varied over time and demonstrated an encouraging increase in attention to evidence-based tools. UpToDate's consistent popularity shows the durability of the product. A reported increase in use of reviews, randomized controlled trials, case reports, and practice guidelines reflects greater employment of more in-depth resources than merely expert opinion. At the same time, residents clearly valued the library's physical space. Survey results will inform future outreach focus.
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Internato e Residência , Bibliotecas Médicas , Inquéritos e QuestionáriosRESUMO
The ability to be flexible and adapt quickly to changing circumstances is a crucial skill for librarians to develop in a world increasingly characterized by rapid change. It can take a crisis to learn how effective librarians have become in developing the needed adaptive behaviors, including a willingness to change workstyles, experiment with new technologies and readily move on from failed experiments. In this paper, librarians from the Preston Medical Library at the University of Tennessee Graduate School of Medicine, prompted by the crisis of COVID-19, present their response. Beginning with a description of how services were provided prior to the pandemic, librarians detail their response in several key areas and show how they implemented new approaches to teaching, collaboration, and mutual support, working together to handle patron issues and pursue scholarly activities.
Assuntos
Adaptação Psicológica , COVID-19 , Disseminação de Informação/métodos , Bibliotecários/psicologia , Bibliotecas Digitais/organização & administração , Bibliotecas Médicas/organização & administração , Teletrabalho/estatística & dados numéricos , Adulto , Feminino , Humanos , Bibliotecas Digitais/estatística & dados numéricos , Bibliotecas Médicas/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , TennesseeRESUMO
BACKGROUND: In 2014, the Preston Medical Library underwent a radical change, moving from an academic office building to the main floor of a regional medical center. While the library had previously served the public, health information requests have substantially increased in volume due to the new location. Researchers analyzed request data to see if the service's reach has expanded to counties that previously had not used the service, to see which counties have requested the most health information, and to ascertain whether more requests are from counties with higher poverty rates. CASE PRESENTATION: Each health information request is logged with the subject nature and patron contact information. Consumer health request data were downloaded from the library database. Names and other identifying data were removed. Request forms were sorted and reviewed by zip code and county, comparing number of requests as well as poverty levels. Tableau was utilized to create maps, visually showing patron concentrations and poverty levels. CONCLUSIONS: There were 3,141 health information requests from September 21, 2014, to May 31, 2019. The majority of requests were from local counties. Requests were also received from counties that had not been previously reached and counties with elevated poverty levels. Collecting data on patron interactions is not only critical for institutional reporting, but also for community outreach. Understanding that data require taking additional steps to filter the information, assess local demographics, and customize library services. Researchers anticipate being able to better tailor services to the community based on the results.
Assuntos
Informação de Saúde ao Consumidor/estatística & dados numéricos , Hospitais , Bibliotecas Médicas/estatística & dados numéricos , Marketing , Humanos , Comportamento de Busca de Informação , TennesseeRESUMO
As the main input structure of the basal ganglia (BG), the striatum collects and integrates information from several brain areas and funnels them forward to other BG nuclei. The striatal projection neurons are medium-sized spiny neurons classified in two main subpopulations, based on their neurochemical characterization and projection targets. These subpopulations are segregated into two distinct circuits, the direct and the indirect pathway, which originate in the striatum and interconnect the BG, ultimately reaching their output nuclei. In this review, we discuss current opinions on the striatal circuit and present different strategies to decipher this circuit complexity by utilizing cell ablation, opto- and chemogenetics, tetanus toxin-induced neuronal silencing, and calcium imaging techniques. We also describe genetically encoded biosensors to monitor signaling dynamics in the striatal circuit with high spatial and temporal resolution by targeting both glutamate and dopamine transmission together with downstream signaling effectors. Recent findings revealing transcriptional, functional diversity, and regionally distinct signaling properties of spiny projection neurons argue that refined interrogation will be pertinent for a deeper understanding of this circuit. Moreover, future mapping the G-protein-coupled receptor repertoire in SPNs will potentially enable pathway-specific modulation of SPN activity and provide a novel framework for targeting BG diseases. Overall, these tools will be critical for designing next-generation treatments for BG diseases.
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Corpo Estriado/fisiologia , Técnicas Genéticas , Vias Neurais/fisiologia , Animais , HumanosRESUMO
PURPOSE: To compare long-term outcomes after bilateral lateral rectus recession (BLRc) or unilateral lateral rectus recession combined with medial rectus resection in the same eye (R&R) for primary treatment of childhood intermittent exotropia (IXT). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: One hundred ninety-seven children 3 to younger than 11 years of age with basic-type IXT, a largest deviation by prism and alternate cover test at any distance of 15 to 40 prism diopters (PD), and near stereoacuity of at least 400 seconds of arc. METHODS: Random assignment to BLRc or R&R and masked examinations conducted every 6 months after surgery for 3 years. MAIN OUTCOME MEASURES: Proportion of participants meeting suboptimal surgical outcome by 3 years, defined as: (1) exotropia of 10 PD or more at distance or near using simultaneous prism and cover test (SPCT); or (2) constant esotropia of 6 PD or more at distance or near using SPCT; (3) loss of 2 octaves or more of stereoacuity from baseline, at any masked examination; or (4) reoperation without meeting any of these criteria. RESULTS: Cumulative probability of suboptimal surgical outcome by 3 years was 46% (43/101) in the BLRc group versus 37% (33/96) in the R&R group (treatment group difference of BLRc minus R&R, 9%; 95% confidence interval [CI], -6% to 23%). Reoperation by 3 years occurred in 9 participants (10%) in the BLRc group (8 of 9 met suboptimal surgical outcome criteria) and in 4 participants (5%) in the R&R group (3 of 4 met suboptimal surgical outcome criteria; treatment group difference of BLRc minus R&R, 5%; 95% CI, -2% to 13%). Among participants completing the 3-year visit, 29% (25 of 86) in the BLRc group and 17% (13 of 77) in the R&R group underwent reoperation or met suboptimal surgical outcome criteria at 3 years (treatment group difference of BLRc minus R&R, 12%; 95% CI, -1% to 25%). CONCLUSIONS: We did not find a statistically significant difference in suboptimal surgical outcome by 3 years between children with IXT treated with BLRc compared with those treated with R&R. Based on these findings, we are unable to recommend one surgical approach over the other for childhood IXT.
Assuntos
Exotropia/cirurgia , Movimentos Oculares/fisiologia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Visão Binocular , Acuidade Visual , Criança , Pré-Escolar , Exotropia/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Músculos Oculomotores/fisiopatologia , Resultado do TratamentoRESUMO
PURPOSE: To describe the course of intermittent exotropia (IXT) in children followed up without treatment for 3 years. DESIGN: Observation arm from randomized trial of short-term occlusion versus observation. PARTICIPANTS: One hundred eighty-three children 3 to 10 years of age with previously untreated IXT and 400 seconds of arc (arcsec) or better near stereoacuity. METHODS: Participants were to receive no treatment unless deterioration criteria were met at a follow-up visit occurring at 3 months, 6 months, or 6-month intervals thereafter for 3 years. MAIN OUTCOME MEASURES: The primary outcome was deterioration by 3 years, defined as meeting motor criterion (constant exotropia ≥10 prism diopters [Δ] at distance and near) or near stereoacuity criterion (≥2-octave decrease from best previous measure). For the primary analysis, participants also were considered to have deteriorated if treatment was prescribed without meeting either deterioration criterion. RESULTS: The cumulative probability of protocol-specified deterioration by 3 years was 15% (95% confidence interval, 10%-22%), but that was likely an overestimate, partly because of misclassification. Among 25 deteriorations, 2 met motor deterioration, 11 met stereoacuity deterioration, and 12 started treatment without meeting either criteria (7 for social concern, 1 for diplopia, 4 for other reasons). Among the 132 participants who completed the 3-year visit and had not been treated during the study, only 1 (<1%) met motor or stereoacuity deterioration criteria at 3 years. Of the 4 participants completing the 3-year visit who met deterioration criteria previously and had not started treatment, none still met deterioration criteria. Between the baseline and 3-year examination for these 132 patients, improvement occurred in distance and near stereoacuity (mean improvement, 0.14 and 0.14 logarithm of arcsec; P ≤ 0.001 and P ≤ 0.001, respectively), distance exotropia control (mean improvement, 0.6 points; P ≤ 0.001), and distance exodeviation magnitude (mean improvement, 2.2 Δ; P = 0.002). CONCLUSIONS: Among children 3 to 10 years of age with IXT for whom surgery was not considered to be the immediately necessary treatment, stereoacuity deterioration or progression to constant exotropia over 3 years was uncommon, and exotropia control, stereoacuity, and magnitude of deviation remained stable or improved slightly.
Assuntos
Percepção de Profundidade/fisiologia , Exotropia/fisiopatologia , Acuidade Visual/fisiologia , Bandagens , Criança , Pré-Escolar , Exotropia/terapia , Feminino , Seguimentos , Humanos , Masculino , Privação Sensorial , Fatores de Tempo , Testes VisuaisRESUMO
PURPOSE: Two strategies were compared for managing moderate hyperopia without manifest strabismus among 1- and 2-year-old children: (1) immediate prescription of glasses versus (2) observation without glasses unless reduced distance visual acuity (VA), reduced stereoacuity, or manifest strabismus. DESIGN: Prospective randomized clinical trial. PARTICIPANTS: A total of 130 children aged 1 to 2 years with hyperopia between +3.00 diopters (D) and +6.00 D spherical equivalent (SE) in at least 1 eye, anisometropia ≤1.50 D SE, and astigmatism ≤1.50 D based on cycloplegic refraction and no manifest strabismus. METHODS: Participants were randomly assigned to glasses (1.00 D less than full cycloplegic hyperopia) versus observation and followed every 6 months for 3 years. Glasses were prescribed to those assigned to observation if they met prespecified deterioration criteria of distance VA or near stereoacuity below age norms, or development of manifest strabismus. MAIN OUTCOME MEASURES: At the 3-year primary outcome examination, participants were classified as failing the randomized management regimen if distance VA or stereoacuity was below age norms or manifest strabismus was observed (each with and without correction in trial frames, confirmed by masked retest, irrespective of whether deterioration had occurred previously), or if strabismus surgery had been performed. RESULTS: Of the 106 participants (82%) completing the 3-year primary outcome examination, failure occurred in 11 (21%) of 53 in the glasses group and 18 (34%) of 53 in the observation group (difference = -13%; 95% confidence interval [CI], -31 to 4; P = 0.14). Sixty-two percent (95% CI, 49-74) in the observation group and 34% (95% CI, 23-48) in the glasses group met deterioration criteria (requiring glasses if not wearing). CONCLUSIONS: For 1- and 2-year-olds with uncorrected moderate hyperopia (+3.00 D to +6.00 D SE), our estimates of failure, after 3 years of 6-month follow-ups, are inconclusive and consistent with a small to moderate benefit or no benefit of immediate prescription of glasses compared with careful observation (with glasses only if deteriorated).
Assuntos
Percepção de Profundidade/fisiologia , Óculos , Hiperopia/terapia , Acuidade Visual/fisiologia , Anisometropia/fisiopatologia , Astigmatismo/fisiopatologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Hiperopia/fisiopatologia , Lactente , Masculino , Cooperação do Paciente , Prescrições , Estudos Prospectivos , Tempo para o Tratamento , Testes VisuaisRESUMO
Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.
Assuntos
Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , HumanosRESUMO
The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy, determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective. We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients.
Assuntos
Aneuploidia , Neoplasias da Mama/genética , Mutação , Proteínas Proto-Oncogênicas c-myc/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , DNA de Neoplasias/genética , Feminino , Citometria de Fluxo , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region ß chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.
Assuntos
Enterotoxinas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-17/biossíntese , Proteínas de Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Síndrome de Sézary/metabolismo , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Síndrome de Sézary/patologia , Linfócitos T/patologiaRESUMO
B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK-induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo.
Assuntos
Carcinogênese/genética , Ativação Linfocitária/genética , Linfoma Cutâneo de Células T/genética , Quinases da Família src/genética , Animais , Linfócitos B/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Cutâneo de Células T/patologia , Camundongos , Proto-Oncogene Mas , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/biossínteseRESUMO
Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24â h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition.
Assuntos
Inibição Neural , Vias Neurais , Córtex Pré-Frontal , Tálamo , Animais , Córtex Pré-Frontal/fisiologia , Vias Neurais/fisiologia , Masculino , Feminino , Camundongos , Inibição Neural/fisiologia , Tálamo/fisiologia , Camundongos Endogâmicos C57BL , Núcleo Accumbens/fisiologia , Células Piramidais/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologiaRESUMO
Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuit connectivity during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in the mouse from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target twenty-four hours later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III nucleus accumbens (NAc) and layer V/VI medio-dorsal thalamus projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosally-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).
RESUMO
OBJECTIVE: After treatment with refractive correction and patching, some patients have residual amblyopia resulting from strabismus or anisometropia. We conducted a clinical trial to evaluate the effectiveness of increasing prescribed daily patching from 2 to 6 hours in children with stable residual amblyopia. DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: A total of 169 children aged 3 to <8 years (mean, 5.9 years) with stable residual amblyopia (20/32-20/160) after 2 hours of daily patching for at least 12 weeks. INTERVENTION: Random assignment to continue 2 hours of daily patching or increase patching time to an average of 6 hours/day. MAIN OUTCOME MEASURES: Best-corrected visual acuity (VA) in the amblyopic eye after 10 weeks. RESULTS: Baseline VA was 0.44 logarithm of the minimum angle of resolution (logMAR) (20/50(-2)). Ten weeks after randomization, amblyopic eye VA had improved an average of 1.2 lines in the 6-hour group and 0.5 line in the 2-hour group (difference in mean VA adjusted for acuity at randomization = 0.6 line; 95% confidence interval, 0.3-1.0; P = 0.002). Improvement of 2 or more lines occurred in 40% of participants patched for 6 hours versus 18% of those who continued to patch for 2 hours (P = 0.003). CONCLUSIONS: When amblyopic eye VA stops improving with 2 hours of daily patching, increasing the daily patching dosage to 6 hours results in more improvement in VA after 10 weeks compared with continuing 2 hours daily.
Assuntos
Ambliopia/terapia , Privação Sensorial , Ambliopia/etiologia , Ambliopia/fisiopatologia , Anisometropia/complicações , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Cooperação do Paciente , Estudos Prospectivos , Estrabismo/complicações , Fatores de Tempo , Resultado do Tratamento , Testes Visuais , Acuidade Visual/fisiologiaRESUMO
Importance: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia. Objective: To compare atropine, 0.01%, eye drops with placebo for slowing myopia progression in US children. Design, Setting, and Participants: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (-1.00 diopters [D] to -6.00 D spherical equivalent refractive error [SER]). Intervention: Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation. Main Outcome and Measures: Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo. Results: A total of 187 children (mean [SD] age, 10.1 [1.8] years; age range, 5.1-12.9 years; 101 female [54%]; 34 Black [18%], 20 East Asian [11%], 30 Hispanic or Latino [16%], 11 multiracial [6%], 6 West/South Asian [3%], 86 White [46%]) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95% CI) change in SER from baseline was -0.82 (-0.96 to -0.68) D and -0.80 (-0.98 to -0.62) D in the atropine and placebo groups, respectively (adjusted difference = -0.02 D; 95% CI, -0.19 to +0.15 D; P = .83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was -0.04 D (95% CI, -0.25 to +0.17 D). Adjusted mean (95% CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = -0.002 mm; 95% CI, -0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009 mm (95% CI, -0.115 to 0.134 mm). Conclusions and Relevance: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children. Trial Registration: ClinicalTrials.gov Identifier: NCT03334253.