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INTRODUCTION: Paediatric cardiologists and nurse practitioners lack structured education tools focused on basic cardiac surgery principles. However, non-surgical specialties caring for surgical patients require this knowledge for comprehensive clinical care. We created a cardiac surgical educational curriculum focused on improving knowledge and attitudes towards communication for non-surgical trainees and advanced practice providers. METHODS: Over one academic year, six paediatric cardiology fellows and seven paediatric cardiac surgery nurse practitioners at Seattle Children's Hospital participated in this study. With surgical supervision, six lectures were prepared by each fellow and delivered monthly. Sessions were hybrid and recorded for later viewing. Pre- and post-intervention survey of attitudes regarding surgical topics and pre- and post- test-based knowledge assessments were administered. RESULTS: Participants positively rated the usefulness of the lecture series (4.2/5) and would recommend it to a colleague (4.5/5). Self-reported confidence discussing surgical concepts with patients increased from 2.3 to 3.4 among paediatric cardiology fellows (p < 0.001) and from 2.8 to 3.9 among nurse practitioners (p < 0.001), out of 5. In both groups, knowledge assessment scores improved from 54 to 79% post-intervention (p < 0.001). CONCLUSIONS: After a six-part educational series taught by paediatric cardiology fellows, both paediatric cardiology fellows and paediatric cardiac surgery nurse practitioners demonstrated improved knowledge and reported increased comfort counselling families on basic cardiac surgery topics. Structured, active-learning lessons taught by fellows for non-surgical audiences can improve attitudes and build clinically relevant knowledge. Creating an effective level-appropriate multidisciplinary curriculum accessible to various types of medical providers could enhance comprehensive care of complex congenital cardiac surgery patients.
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Procedimentos Cirúrgicos Cardíacos , Cardiologia , Profissionais de Enfermagem , Humanos , Criança , Escolaridade , CurrículoRESUMO
Many transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with coactivators to activate transcription. Historically, DNA-binding domains and TADs have been considered as modular units, but recent studies have shown that TADs can influence DNA binding. Whether these results can be generalized to more TADs is not clear. Here, we biophysically characterized the NFκB p50/RelA heterodimer including the RelA TAD and investigated the TAD's influence on NFκB-DNA interactions. In solution, we show the RelA TAD is disordered but compact, with helical tendency in two regions that interact with coactivators. We determined that the presence of the TAD increased the stoichiometry of NFκB-DNA complexes containing promoter DNA sequences with tandem κB recognition motifs by promoting the binding of NFκB dimers in excess of the number of κB sites. In addition, we measured the binding affinity of p50/RelA for DNA containing tandem κB sites and single κB sites. While the presence of the TAD enhanced the binding affinity of p50/RelA for all κB sequences tested, it also increased the affinity for nonspecific DNA sequences by over 10-fold, leading to an overall decrease in specificity for κB DNA sequences. In contrast, previous studies have generally reported that TADs decrease DNA-binding affinity and increase sequence specificity. Our results reveal a novel function of the RelA TAD in promoting binding to nonconsensus DNA, which sheds light on previous observations of extensive nonconsensus DNA binding by NFκB in vivo in response to strong inflammatory signals.
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Subunidade p50 de NF-kappa B , Fator de Transcrição RelA , Ativação Transcricional , Sequência de Bases , DNA/química , Subunidade p50 de NF-kappa B/química , Subunidade p50 de NF-kappa B/genética , Ligação Proteica , Domínios Proteicos , Multimerização Proteica , Fator de Transcrição RelA/química , Fator de Transcrição RelA/genéticaRESUMO
From 6 Jan 22 to 17 Feb 22, a total of 729,367 close contacts classified into four distinct groups (i.e., household, social, school and nursing/ welfare home contacts) were managed by the Health Risk Warning system. High COVID-19-positive rates were demonstrated amongst household contacts, i.e., 10.9% (37,220/342,302) were detected via antigen rapid test kits and 56.5% (4,952/8,767) were detected via polymerase chain reaction testing. Household contacts represent the highest risk of being infected by virtue of the sustained close-proximity interactions in the household setting. Social, school and nursing/ welfare home contacts continue to remain at-risk groups for close monitoring. At a population level, household and symptomatic close contacts should be the groups of focus in the early phases of the pandemic, including future potential waves involving COVID-19 variants of concern.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Busca de Comunicante , PandemiasRESUMO
INTRODUCTION: Cranial vault surgery in children with ventricular shunts is more complex due to the possible interference of shunt location with surgical planning and increased risk of shunt related complications. The study evaluated the management of ventricular shunts during cranial vault remodeling (CVR) and subsequent outcomes and complications following CVR. METHODS: An IRB-approved retrospective chart review was performed including patients who underwent CVR in presence of a ventricular shunt. Measured outcomes were number of shunt revisions following CVR, 30-day complication rate, 3-month complication rate, and post-CVR Whitaker classification. Finally, a review of the literature was performed, and our results were compared to previous reports. RESULTS: Eleven patients met the inclusion criteria. Ventricular shunt was not exposed in 18%; exposed and not revised in 54%; exposed and left on a bone peninsula in 18% and simultaneously exposed and revised in 18%. Two patients experienced complications within 30-days. Three additional patients experienced complications within 3-months. An average of 2.2 shunt revisions per patient were performed following CVR. Whitaker classification was I in 7 patients, II in 1 patient and III in 2 patients. Shunt revision rate for patients undergoing CVR for hydrocephalic macrocephaly was on average of 1.2 and 1.9 for shunt-induced craniosynostosis in literature. CONCLUSIONS: Cranial vault abnormalities in the presence of a ventricular shunt can be effectively treated with CVR. The presence of a shunt does not seem to interfere with final head shape. While leaving the shunt unexposed may appear less morbid, shunt related complications can still occur with this approach.
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Crânio/cirurgia , Derivações do Líquido Cefalorraquidiano , Craniossinostoses/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Megalencefalia/cirurgia , Estudos RetrospectivosRESUMO
The graduate course in research ethics in the Graduate School for Integrative Sciences and Engineering at the National University of Singapore consists of a semester long mandatory course titled: "Research Ethics and Scientific Integrity." The course provides students with guiding principles for appropriate conduct in the professional and social settings of scientific research and in making morally weighted and ethically sound decisions when confronted with moral dilemmas. It seeks to enhance understanding and appreciation of the moral reasoning underpinning various rules and legislative constraints associated with research subjects and procedures. Further, students are trained to critically analyse cases and issues associated with scientific misconduct preparing them to act in a responsible and effective manner should they encounter such cases. The diverse background and training of the cohort also provide a unique setting and opportunity for student-initiated collaborative interdisciplinary learning. This article offers a reflective account of the course and some preliminary insights into learning outcomes.
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Ética em Pesquisa , Má Conduta Científica , Engenharia , Humanos , Estudos Interdisciplinares , EstudantesRESUMO
PURPOSE: To identify prognostic factors for poor visual outcome in patients with birdshot retinochoroidopathy. METHODS: A case-control study of 98 patients with birdshot retinochoroidopathy (196 eyes) was evaluated with a follow-up period of at least 12 months. After exclusion of glaucoma, optic atrophy, and macular scar, the remaining eligible patients were categorized into two groups: poor visual outcomes and good visual outcomes. Poor visual outcome was defined as less than -6 mean deviation score on Swedish interactive threshold algorithm (SITA) short-wavelength automated perimetry (SWAP) test and abnormality (amplitude or implicit time) of 30 Hz flicker electroretinogram at 4-year follow-up and at the most recent visit for separate analysis. Potential factors between both groups were statistically analyzed by Chi-square test and logistic regression model. RESULTS: After the aforementioned exclusion, the remaining 77 patients with an average follow-up period of 52 ± 29 months (335 person-years, 36% with follow-up of more than 5 years) were divided into two groups. Sixteen patients were categorized as having poor visual outcome. Univariate analysis identified significant association of abnormal 30 Hz flicker electroretinogram amplitude (P = 0.004), implicit time (P = 0.002), and SITA SWAP mean deviation at the initial visit (P < 0.001) in the poor visual outcome group. Multivariate logistic regression analysis identified only SITA SWAP mean deviation to be associated with poor visual outcome (adjusted odds ratio, 32.50; 95% confidence interval [3.84-275.32]; P = 0.001) at the initial visit. To verify the model validity, an analysis of 42 patients at 4-year follow-up was performed and the outcome was confirmed (adjusted odds ratio, 8.80; 95% confidence interval [1.58-49.16]; P = 0.013). CONCLUSION: Worse SITA SWAP mean deviation at the initial visit is a predictor of poor visual outcome in patients with birdshot retinochoroidopathy, and may serve as a proxy marker for delayed effective steroid sparing therapy in patients with birdshot retinochoroidopathy.
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Coriorretinite/diagnóstico , Transtornos da Visão/diagnóstico , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto , Idoso , Coriorretinopatia de Birdshot , Estudos de Casos e Controles , Coriorretinite/fisiopatologia , Eletrorretinografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Testes de Campo Visual/métodos , Adulto JovemRESUMO
The quantity and quality of collagen fibrils in the extracellular matrix (ECM) have a pivotal role in dictating biological processes. Several collagen-binding proteins (CBPs) are known to modulate collagen deposition and fibril diameter. However, limited studies exist on alterations in the fibril ultrastructure by CBPs. In this study, we elucidate how the collagen receptor, discoidin domain receptor 1 (DDR1) regulates the collagen content and ultrastructure in the adventitia of DDR1 knock-out (KO) mice. DDR1 KO mice exhibit increased collagen deposition as observed using Masson's trichrome. Collagen ultrastructure was evaluated in situ using transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Although the mean fibril diameter was not significantly different, DDR1 KO mice had a higher percentage of fibrils with larger diameter compared with their wild-type littermates. No significant differences were observed in the length of D-periods. In addition, collagen fibrils from DDR1 KO mice exhibited a small, but statistically significant, increase in the depth of the fibril D-periods. Consistent with these observations, a reduction in the depth of D-periods was observed in collagen fibrils reconstituted with recombinant DDR1-Fc. Our results elucidate how DDR1 modulates collagen fibril ultrastructure in vivo, which may have important consequences in the functional role(s) of the underlying ECM.
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Colágeno/ultraestrutura , Receptor com Domínio Discoidina 1/genética , Matriz Extracelular/genética , Animais , Receptor com Domínio Discoidina 1/metabolismo , Camundongos , Camundongos Knockout , Ligação ProteicaRESUMO
Peripheral arterial disease is a common manifestation of systemic atherosclerosis, which results in more serious consequences of ischemic events in peripheral tissues such as the lower extremities. Cell therapy has been tested as a treatment for peripheral ischemia that functions by inducing angiogenesis in the ischemic region. However, the poor survival and engraftment of transplanted cells limit the efficacy of cell therapy. In order to overcome such challenges, we applied genetically engineered cell sheets using a cell-interactive and thermosensitive hydrogel and nonviral polymer nanoparticles. C2C12 myoblast sheets were formed on Tetronic-tyramine (Tet-TA)-RGD hydrogel prepared through a highly efficient and noncytotoxic enzymatic reaction. The myoblast sheets were then transfected with vascular endothelial growth factor (VEGF) plasmids using poly(ß-amino ester) nanoparticles to increase the angiogenic potential of the sheets. The transfection increased the VEGF expression and secretion from the C2C12 sheets. The enhanced angiogenic effect of the VEGF-transfected C2C12 sheets was confirmed using an in vitro capillary formation assay. More importantly, the transplantation of the VEGF-transfected C2C12 sheets promoted the formation of capillaries and arterioles in ischemic muscles, attenuated the muscle necrosis and fibrosis progressed by ischemia, and eventually prevented ischemic limb loss. In conclusion, the combination of cell sheet engineering and genetic modification can provide more effective treatment for therapeutic angiogenesis.
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Engenharia Genética/métodos , Mioblastos/fisiologia , Mioblastos/transplante , Neovascularização Patológica/genética , Neovascularização Patológica/cirurgia , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/fisiologia , Células Endoteliais da Veia Umbilical Humana/transplante , Humanos , Isquemia/genética , Isquemia/cirurgia , CamundongosRESUMO
Investigating the intricate and rapid folding kinetics of large RNA-protein complexes (RNPs), like the bacterial ribosome, remains a formidable challenge in structural biology. Previous genetic approaches to probe assembly have focused on modulating the expression of either r-proteins or assembly factors. Here, anti-sense oligonucleotides (ASOs) were used to disrupt native RNA/RNA and RNA/protein interactions, in order to generate novel folding intermediates. In an in vitro co-transcriptional assembly assay, 8 assembly inhibitor ASOs were identified. Using cryo-electron microscopy, 38 new intermediate structures were determined resulting from the specific inhibitions. In particular a novel intermediate class provided compelling evidence of independent rRNA domain folding before proper interdomain docking. Three PNAs targeting domain-I of 23S-rRNA further subdivided the previously identified assembly core into smaller blocks representing the earliest steps in assembly. The resulting assembly graph reveals template-directed RNA foldon docking and domain consolidation, which provides a hierarchical view of the RNP assembly process.
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Cortical myosin contraction and cell adhesion work together to promote tissue shape changes, but how they are modulated to achieve diverse morphogenetic outcomes remains unclear. Epithelial folding occurs via apical constriction, mediated by apical accumulation of contractile myosin engaged with adherens junctions, as in Drosophila ventral furrow formation. While levels of contractile myosin correlate with apical constriction, whether levels of adherens junctions modulate apical constriction is unknown. We identified a novel Drosophila gene moat that maintains low levels of Bazooka/Par3-dependent adherens junctions and thereby restricts apical constriction to ventral furrow cells with high-level contractile myosin. In moat mutants, abnormally high levels of Bazooka/Par3-dependent adherens junctions promote ectopic apical constriction in cells with low-level contractile myosin, insufficient for apical constriction in wild type. Such ectopic apical constriction expands infolding behavior from ventral furrow to ectodermal anterior midgut, which normally forms a later circular invagination. In moat mutant ventral furrow, a perturbed apical constriction gradient delays infolding. Our results indicate that levels of adherens junctions can modulate the outcome of apical constriction, providing an additional mechanism to define morphogenetic boundaries.
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Contractile myosin and cell adhesion work together to induce tissue shape changes, but how they are patterned to achieve diverse morphogenetic outcomes remains unclear. Epithelial folding occurs via apical constriction, mediated by apical contractile myosin engaged with adherens junctions, as in Drosophila ventral furrow formation. While it has been shown that a multicellular gradient of myosin contractility determines folding shape, the impact of multicellular patterning of adherens junction levels on tissue folding is unknown. We identified a novel Drosophila gene moat essential for differential apical constriction and folding behaviors across the ventral epithelium which contains both folding ventral furrow and nonfolding ectodermal anterior midgut (ectoAMG). We show that Moat functions to downregulate polarity-dependent adherens junctions through inhibiting cortical clustering of Bazooka/Par3 proteins. Such downregulation of polarity-dependent junctions is critical for establishing a myosin-dependent pattern of adherens junctions, which in turn mediates differential apical constriction in the ventral epithelium. In moat mutants, abnormally high levels of polarity-dependent junctions promote ectopic apical constriction in cells with low-level contractile myosin, resulting in expansion of infolding from ventral furrow to ectoAMG, and flattening of ventral furrow constriction gradient. Our results demonstrate that tissue-scale distribution of adhesion levels patterns apical constriction and establishes morphogenetic boundaries.
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Junções Aderentes , Polaridade Celular , Proteínas de Drosophila , Drosophila melanogaster , Animais , Junções Aderentes/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Polaridade Celular/fisiologia , Epitélio/metabolismo , Miosinas/metabolismo , Células Epiteliais/metabolismo , Adesão Celular/fisiologia , Morfogênese , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Numerous human pathologies result from unrepaired oxidative DNA damage. Base excision repair (BER) is responsible for the repair of oxidative DNA damage that occurs in both nuclei and mitochondria. Despite the importance of BER in maintaining genomic stability, knowledge concerning the regulation of this evolutionarily conserved repair pathway is almost nonexistent. The Saccharomyces cerevisiae BER protein, Ntg1, relocalizes to organelles containing elevated oxidative DNA damage, indicating a novel mechanism of regulation for BER. We propose that dynamic localization of BER proteins is modulated by constituents of stress response pathways. In an effort to mechanistically define these regulatory components, the elements necessary for nuclear and mitochondrial localization of Ntg1 were identified, including a bipartite classical nuclear localization signal, a mitochondrial matrix targeting sequence and the classical nuclear protein import machinery. Our results define a major regulatory system for BER which when compromised, confers a mutator phenotype and sensitizes cells to the cytotoxic effects of DNA damage.
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Núcleo Celular/enzimologia , Dano ao DNA , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , Mitocôndrias/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Transporte Ativo do Núcleo Celular , Substituição de Aminoácidos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/análise , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Sinais de Localização Nuclear , Estresse Oxidativo , Sinais Direcionadores de Proteínas , Proteínas de Saccharomyces cerevisiae/análise , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: In repaired tetralogy of Fallot (rTOF), right ventricular (RV) enlargement leads to poor outcomes. However, evaluating the RV has limitations; cardiac magnetic resonance (CMR) and 3D echocardiography have barriers including cost and accessibility. Traditional echocardiography is limited given the complex geometry and anterior location of the RV. We propose a novel echocardiographic evaluation of RV volume using 2 separate views. METHODS: This is a retrospective study of rTOF patients with echocardiogram, CMR, and exercise tests. By echocardiogram, we collected RV length in parasternal long axis (PLAX), area in 4-chamber (4C) view, and measurements per standard guidelines. RV end-diastolic and end-systolic volume (RVEDV and RVESV) were calculated as 5/9 (4C area * PLAX length). RESULTS: Forty-five patients with 66 sets of CMR, echocardiogram, and exercise tests were included (mean age 13.3 ± 3.2 years). The echocardiographic RVEDV and RVESV showed strong correlation with CMR parameters (r = 0.81 and 0.72; p≤ 0.0001), and moderate correlation with peak oxygen pulse (0.63 and 0.49; p≤0.0001). Guideline measurements had no significant correlation. Echocardiographic RVEDV and RVESV were higher in those requiring subsequent pulmonary valve replacement. Indexed echocardiographic RVEDV of 93 ml/m2 had 92% sensitivity and 50% specificity (area under curve 0.75 (p = 0.001)) in predicting CMR RV/LV EDV ratio > 2, which is an early indicator for pulmonary valve replacement. CONCLUSIONS: This novel technique correlates strongly with CMR, better than traditional parameters. While echocardiogram will not replace CMR, this method would be useful in predicting the RV volume, progression of dilation, and timing of CMR.
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Procedimentos Cirúrgicos Cardíacos , Tetralogia de Fallot , Disfunção Ventricular Direita , Adolescente , Procedimentos Cirúrgicos Cardíacos/métodos , Criança , Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Estudos Retrospectivos , Volume Sistólico , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Função Ventricular DireitaRESUMO
BACKGROUND AND OBJECTIVE: Brainstem metastases comprise fewer than 7% of all brain metastases. Nonetheless, they present clinicians with unique clinical challenges in symptom management and treatment. No comprehensive review summarizing the management of brainstem metastases exists. This review aims to summarize epidemiology, anatomy, clinical correlation, prognosis, options for management of symptoms, treatment, treatment toxicity, and dose and fractionation for brainstem stereotactic radiosurgery (SRS) as reported in the literature. METHODS: In July 2021, we searched PubMed and Embase for retrospective studies of brainstem metastasis treatment, as well as case series and case reports describing diagnosis and clinical management of brainstem metastasis. Keywords and MeSH terms searched included "brainstem metastasis", "symptomatic brainstem metastasis", "brain metastasis", "stereotactic radiosurgery brainstem", "whole brain radiation brainstem", "brainstem metastasis resection", "brainstem radiation toxicity", "brainstem radiosurgery toxicity", "brainstem radiosurgery dose", and "radiosurgery dose tolerance". Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. KEY CONTENT AND FINDINGS: Single-institution studies and multicenter retrospective analyses from 1993 to 2021 reflect a shift from reliance on whole-brain radiation therapy (WBRT) to SRS for primary treatment of brainstem metastases. Recent multicenter retrospective analyses and single-institution case series support the safety and efficacy of SRS of brainstem metastases in symptom management and preservation of quality of life. Incidence of radiation-induced toxicity following SRS of brainstem metastases is comparable to that of SRS for other brain metastases. Complications following brainstem SRS are most strongly associated with prior WBRT. CONCLUSIONS: Radiation oncologists play a central role in the treatment of brainstem metastases due to reliance on SRS. Dose and fractionation of brainstem SRS remain largely institution-dependent. The field would benefit from inclusion of brainstem metastases in prospective trials of SRS and studies of adverse effects of salvage WBRT after prior SRS of brainstem metastases.
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Neoplasias Encefálicas , Lesões por Radiação , Radiocirurgia , Neoplasias Encefálicas/secundário , Tronco Encefálico , Irradiação Craniana , Humanos , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Qualidade de Vida , Lesões por Radiação/etiologia , Lesões por Radiação/cirurgia , Radiocirurgia/efeitos adversos , Estudos RetrospectivosRESUMO
AIMS: Atrial fibrillation (AF) is a common comorbid condition in heart failure with preserved ejection fraction (HFpEF). The effect of AF on heart failure (HF) exacerbation in HFpEF has not been well described. This study investigated how AF modifies the clinical trajectory of HFpEF patients after hospitalization for decompensated HF. METHODS AND RESULTS: We stratified HFpEF subjects by AF diagnosis and performed longitudinal analysis to compare risk for HF hospitalization after index hospitalization for decompensated HF. All-cause mortality, 30 day all-cause readmissions, and response to inpatient diuresis were also evaluated. Of 90 subjects enrolled, 35.6% (n = 32) had AF. Subjects with AF were older (72.5 vs. 60.5 years; P < 0.01), more often male (46.9% vs. 24.1%; P = 0.03), and had greater left atrial diameter (4.9 vs. 3.8 cm; P < 0.01) compared with those without AF. Subjects with AF had a higher risk for HF hospitalization than their counterparts without AF (P = 0.02); this relationship remained significant following multivariable competing risk regression with propensity score weighting (hazard ratio 2.53, P = 0.04 and hazard ratio 2.91, P = 0.04, with overlap and inverse probability weighting, respectively). Although having AF appeared to increase the risk of all-cause hospital readmission within 30 days of discharge (37.5% vs. 17.5%; P = 0.036), this relationship failed to remain significant following propensity score adjustment for clinical covariates. CONCLUSIONS: Atrial fibrillation is an independent risk factor for HF rehospitalization in HFpEF. Further understanding of the interplay between AF and HFpEF will be critical to guide the selection of appropriate rhythm management strategies in this population.
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Fibrilação Atrial , Insuficiência Cardíaca , Humanos , Masculino , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/diagnóstico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/diagnóstico , Volume Sistólico/fisiologia , Prognóstico , Fatores de Risco , HospitalizaçãoRESUMO
Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with nonsyndromic and syndromic retinitis pigmentosa. Here, we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicate that ADIPOR1 encoded the most abundantly expressed ceramidase in mice and one of the 2 most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1-/- retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine/L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1-/- mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters. These results highlight the importance of ADIPOR1 ceramidase in the retina and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.
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Ceramidases/antagonistas & inibidores , DNA/genética , Mutação , Receptores de Adiponectina/genética , Células Fotorreceptoras Retinianas Cones/metabolismo , Doenças Retinianas/genética , Animais , Análise Mutacional de DNA , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Adiponectina/metabolismo , Células Fotorreceptoras Retinianas Cones/patologia , Doenças Retinianas/metabolismo , Doenças Retinianas/patologiaRESUMO
Epiglottitis is a potentially life-threatening condition that requires quick and accurate diagnoses. The gold standard for diagnosis is for laryngoscopic visualisation of the epiglottis. However, this may not be well-tolerated in a patient with impending airway collapse, and lateral neck radiographs may support the diagnosis. The thumb sign is a recognized radiological feature of epiglottitis. We present a case of a 57-year-old gentleman with epiglottitis, whose lateral neck radiograph had the interesting feature of a double thumb sign. In spite of the significant airway oedema, he was conservatively managed with subsequent full recovery. The objective of this case report is to highlight the severity of airway narrowing with this radiological finding of double thumb sign, to alert the clinician to have closer monitoring or to consider artificial airway support.
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BACKGROUND: Clinician burnout is a work-related syndrome characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. It is associated with reduced quality of care, as well as the occurrence of medical errors and mental illness. Although burnout has been extensively studied in populations of physicians and nurses, there is limited research assessing burnout in pharmacists and their exposure to burnout-related education. OBJECTIVES: To determine the prevalence of burnout and its associated risk factors among hospital pharmacists and to explore the status of preventive programs in pharmacy school curricula. METHODS: A cross-sectional online survey was conducted with hospital pharmacists working in the province of Ontario, Canada. Respondents completed the Maslach Burnout Inventory (MBI) and responded to questions about career characteristics and professional satisfaction. A multivariable regression analysis was used to determine factors independently associated with burnout. In addition, all pharmacy schools in Canada were surveyed electronically about their burnout-prevention curricula. RESULTS: Of 2465 hospital pharmacists in Ontario, 270 responded (11% response rate). Most respondents were women (77% [195/252]) and were working full-time (90% [227/252]), with a substantial proportion working in the acute care setting (39% [96/246]). The burnout rate was 61.1% (165/270; 95% confidence interval 55.5%-66.8%). Factors independently associated with burnout were dissatisfaction with work-life balance (odds ratio [OR] 2.62, p = 0.005) and feeling that contributions were unappreciated (OR 2.60, p = 0.019). Of those whose MBI score indicated burnout, 23% (36/158) were not aware of experiencing burnout. All 10 Canadian pharmacy schools responded to the survey, with 9 (90%) reporting that they did not have burnout-prevention curricula; however, 8 (80%) reported interest in incorporating such material. CONCLUSIONS: The rate of burnout among hospital pharmacists in Ontario was high, and preventive action is needed. Opportunities exist to both improve pharmacists' resilience at the undergraduate level and reduce institutional stressors in the workplace.
CONTEXTE: L'épuisement professionnel du clinicien est un syndrome lié au travail qui se caractérise par une fatigue émotionnelle, une dépersonnalisation et l'amoindrissement des réalisations personnelles. Il est associé à la réduction de la qualité des soins, à la survenance d'erreurs médicales et à la maladie mentale. Bien que ce sujet ait fait l'objet d'études approfondies dans les populations de médecins et d'infirmiers, les recherches qui se penchent sur l'épuisement des pharmaciens et la possibilité qui leur est offerte de bénéficier de formations relatives à l'épuisement sont limitées. OBJECTIFS: Déterminer la prévalence du surmenage professionnel et des facteurs de risque qui lui sont associés parmi les pharmaciens d'hôpitaux et examiner les programmes de prévention dans les formations en école de pharmacie. MÉTHODE: Une enquête transversale en ligne a été menée auprès des pharmaciens hospitaliers travaillant en Ontario, au Canada. Les répondants ont rempli le Maslach Burnout Inventory (MBI) [Evaluation du syndrome de l'épuisement professionnel de Maslach] et répondu à des questions portant sur les caractéristiques d'emploi et la satisfaction professionnelle. Une analyse de régression multivariable a permis de déterminer les facteurs indépendamment associés à l'épuisement. De plus, une enquête électronique portant sur le programme de prévention de l'épuisement a été menée dans toutes les écoles de pharmacie au Canada. RÉSULTATS: Sur les 2465 pharmaciens d'hôpitaux en Ontario, 270 ont répondu (taux de réponse de 11 %). La plupart des répondants étaient des femmes (77 % [195/252]) travaillant à temps plein (90 % [227/252]); une part importante travaillait dans un environnement de soins aigus (39 % [96/246]). Le taux d'épuisement était de 61,1 % (165/270, intervalle de confiance 95 % 55,5 %66,8 %). Les facteurs indépendamment associés à l'épuisement étaient l'insatisfaction liée à l'équilibre entre sa vie professionnelle et sa vie personnelle (rapport de cotes [RC] 2,62, p = 0,005) et l'impression d'un manque d'appréciation de sa contribution (RC 2,60, p = 0,019). Parmi les personnes dont le score MBI indiquait un épuisement professionnel, 23 % (36/158) ne savaient pas qu'elles en étaient victimes. Les dix écoles de pharmacie canadiennes ont répondu à l'enquête et neuf (90 %) ont rapporté ne pas avoir de programme axé sur la prévention de l'épuisement professionnel, cependant, huit (80 %) ont montré leur intérêt pour un tel programme. CONCLUSIONS: Le taux d'épuisement professionnel parmi les pharmaciens d'hôpitaux en Ontario était élevé et des actions préventives sont nécessaires. Les possibilités existent pour améliorer la résilience des pharmaciens au niveau du premier cycle universitaire et réduire les facteurs de stress institutionnels sur le lieu de travail.
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Background: Gastrostomy tube (g-tube) complications are typically minor and site related with major complications related to dislodgment before tract establishment. With the recent adoption of 12F g-tubes; size of tube has not been evaluated. There is limited research on the efficacy and dislodgment rates of 12 and 14F g-tubes within the early dislodgment window (<42 days postsurgery). Materials and Methods: A retrospective study from June 1, 2013 to May 25, 2020 was performed. A total of 888 patient encounters were identified, with a final data set of 835 being used for analysis. A subset of 21 patients was evaluated based on early dislodgment status. Fisher's exact test and Welch's two-sample test analyses were used to test for significance between groups (P < .05). Results: The early dislodgment rate is low at 2.5% (21/835). There was a significant impact of g-tube size on dislodgment rates. When evaluated by g-tube size, 12F g-tubes are nearly four times more likely to dislodge before 6 weeks than 14F g-tubes. In addition, the average age of 12F patients who dislodged early was significantly lower than that of the population for 14F patients. Conclusions: There is a significant difference in early dislodgment rate and age between the 12F g-tube compared with a 14F. These data suggest a trade-off of the smaller balloon in 12F g-tubes and potential for more limited use in our smallest children.