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1.
PLoS Genet ; 17(10): e1009813, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34665823

RESUMO

Translation of messenger RNAs (mRNAs) with premature termination codons produces truncated proteins with potentially deleterious effects. This is prevented by nonsense-mediated mRNA decay (NMD) of these mRNAs. NMD is triggered by ribosomes terminating upstream of a splice site marked by an exon-junction complex (EJC), but also acts on many mRNAs lacking a splice junction after their termination codon. We developed a genome-wide CRISPR flow cytometry screen to identify regulators of mRNAs with premature termination codons in K562 cells. This screen recovered essentially all core NMD factors and suggested a role for EJC factors in degradation of PTCs without downstream splicing. Among the strongest hits were the translational repressors GIGYF2 and EIF4E2. GIGYF2 and EIF4E2 mediate translational repression but not mRNA decay of a subset of NMD targets and interact with NMD factors genetically and physically. Our results suggest a model wherein recognition of a stop codon as premature can lead to its translational repression through GIGYF2 and EIF4E2.


Assuntos
Proteínas de Transporte/genética , Fator de Iniciação 4E em Eucariotos/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Regiões 3' não Traduzidas/genética , Linhagem Celular , Linhagem Celular Tumoral , Códon sem Sentido/genética , Códon de Terminação/genética , Éxons/genética , Células HEK293 , Humanos , Células K562 , Splicing de RNA/genética
2.
Appl Environ Microbiol ; 89(1): e0167022, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36519847

RESUMO

Metagenomic sequencing is a swift and powerful tool to ascertain the presence of an organism of interest in a sample. However, sequencing coverage of the organism of interest can be insufficient due to an inundation of reads from irrelevant organisms in the sample. Here, we report a nuclease-based approach to rapidly enrich for DNA from certain organisms, including enterobacteria, based on their differential endogenous modification patterns. We exploit the ability of taxon-specific methylated motifs to resist the action of cognate methylation-sensitive restriction endonucleases that thereby digest unwanted, unmethylated DNA. Subsequently, we use a distributive exonuclease or electrophoretic separation to deplete or exclude the digested fragments, thus enriching for undigested DNA from the organism of interest. As a proof of concept, we apply this method to enrich for the enterobacteria Escherichia coli and Salmonella enterica by 11- to 142-fold from mock metagenomic samples and validate this approach as a versatile means to enrich for genomes of interest in metagenomic samples. IMPORTANCE Pathogens that contaminate the food supply or spread through other means can cause outbreaks that bring devastating repercussions to the health of a populace. Investigations to trace the source of these outbreaks are initiated rapidly but can be drawn out due to the labored methods of pathogen isolation. Metagenomic sequencing can alleviate this hurdle but is often insufficiently sensitive. The approach and implementations detailed here provide a rapid means to enrich for many pathogens involved in foodborne outbreaks, thereby improving the utility of metagenomic sequencing as a tool in outbreak investigations. Additionally, this approach provides a means to broadly enrich for otherwise minute levels of modified DNA, which may escape unnoticed in metagenomic samples.


Assuntos
Enzimas de Restrição do DNA , DNA Bacteriano , Escherichia coli , Metagenômica , Salmonella enterica , DNA , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Metagenoma , Metagenômica/métodos , Salmonella enterica/genética , Salmonella enterica/isolamento & purificação , DNA Bacteriano/genética
3.
Depress Anxiety ; 39(1): 71-82, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34752690

RESUMO

BACKGROUND: To address shortages of mental health specialists in low- and middle-income countries, task-shifting approaches have been employed to train nonspecialists to deliver evidence-based scalable psychosocial interventions. Problem Management Plus (PM+) is a brief transdiagnostic nontrauma focused intervention for people affected by adversity. This study reports on the capacity of PM+ to address specific symptoms of posttraumatic stress disorder (PTSD). METHODS: Individual patient data from three randomised controlled trials were combined and analysed to observe the impacts of PM+ (n = 738) or enhanced treatment as usual (ETAU) (n = 742) interventions on specific PTSD symptoms at posttreatment and 3-month follow-up. The PTSD-Checklist for DSM-5 (PCL-5) was used to index PTSD symptoms, and presence of each symptom was defined as moderate severity (score ≥ 2 on individual items). RESULTS: The average PCL-5 score at baseline was 26.1 (SD: 16.8) with 463 (31.3%) scoring above 33, indicative of a diagnosis of PTSD. Following intervention, 12.5% and 5.8% of participants retained a score greater than 33 at postassessment and follow-up, respectively. There was greater symptom reduction for PM+ than for ETAU for most symptoms. Hyperarousal symptoms were the most common residual symptoms after PM+, with more than 30% of participants reporting persistent sleep disturbance, concentration difficulties, and anger. CONCLUSION: PM+ led to greater reduction in symptoms relating to re-experiencing and avoidance. The evidence indicates that strategies focusing on hyperarousal symptoms including sleep, concentration, and anger difficulties, could be strengthened in this brief intervention.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Terapia Comportamental , Intervenção em Crise , Países em Desenvolvimento , Humanos , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/psicologia
4.
J Card Surg ; 37(12): 4295-4300, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36131523

RESUMO

INTRODUCTION: Inflation of transcatheter aortic valve replacement (TAVR) procedures compared to surgical aortic valve replacement (SAVR) has increased the number of patients requiring a postprocedure permanent pacemaker (PPM). We investigate the impact of PPM on mid-term mortality comparing SAVR versus TAVR procedures and risk factors for early and late (>14 days) need of PPM. METHODS: We conducted a retrospective, single-center evaluation of 903 patients that underwent either SAVR or TAVR procedures at the Yale New Haven Hospital from 2012 to 2017. Patients were stratified into PPM and non-PPM groups. We performed Kaplan-Meier and Cox proportional hazard analysis to characterize mid-term mortality. Further subgroup analysis was performed to identify risk factors for early and late PPM implantation in the TAVR cohort. RESULTS: There was no correlation between PPM implantation and mid-term mortality in both SAVR (hazard ratio [HR] = 0.69; confidence interval [CI] = 0.21-2.30; p = .56) and TAVR (HR = 0.70; CI = 0.42-1.17; p = .18) patients. The presence of the right bundle branch block (Odds ratio = 24.07; 95% CI = 2.34-247.64, p = .007) was associated with higher odds of early PPM requirement after TAVR procedures. CONCLUSION: PPM placement after SAVR or TAVR procedures is not associated with increased mid-term mortality. In-depth characterization of risk factors for early and late PPM implantation will require further analysis in the growing TAVR patient population.


Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Marca-Passo Artificial , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Estudos Retrospectivos , Estenose da Valva Aórtica/cirurgia , Resultado do Tratamento , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Fatores de Risco
5.
Subst Abus ; 43(1): 206-211, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34038333

RESUMO

INTRODUCTION: Rates of injection-drug use associated infective endocarditis (IDU-IE) are rising, and most patients with IDU-IE do not receive addiction care during hospitalization. We sought to characterize cardiac surgeons' practices and attitudes toward patients with IDU-IE due to their integral role treating them. METHODS: This is a survey of 201 cardiac surgeons in the U.S who were asked about the addiction care they engage for patients with IDU-IE along with questions pertaining to stigma against people who use drugs (PWUD). Descriptive statistics and multivariable logistic regression were used to identify patterns in surgeons' practices and determine associations between attitudes toward substance use disorder (SUD) and beliefs about medications for opioid use disorder (MOUD). RESULTS: A minority of surgeons have access to specialty addiction services (35%) in their hospital, but when available 93% consult them for patients with IDU-IE. A quarter of surgeons reported thinking that SUD is a choice and do not believe MOUD have a role in reducing IDU-IE recurrence. Conversely, 69% of surgeons agreed with the disease model of addiction and were four times more likely to believe that MOUD has a role in reducing IDU-IE recurrence (aOR 4.09, 95% CI 1.8-9.27, p = 0.001). CONCLUSION: Access to addiction specialists is limited in most hospital settings, but when available, most surgeons report consulting them and supporting MOUD. However, a significant proportion of surgeons hold non-evidence-based attitudes toward SUD and PWUD. This suggests that lack of education and stigma may affect the care of patients with IDU-IE, highlighting the need for education about, and destigmatization of addiction within health systems.


Assuntos
Atitude do Pessoal de Saúde , Cardiologia , Transtornos Relacionados ao Uso de Opioides , Abuso de Substâncias por Via Intravenosa , Cirurgiões , Humanos , Transtornos Relacionados ao Uso de Opioides/psicologia , Transtornos Relacionados ao Uso de Opioides/terapia , Estudos Retrospectivos , Abuso de Substâncias por Via Intravenosa/psicologia , Abuso de Substâncias por Via Intravenosa/terapia , Cirurgiões/psicologia
6.
J Child Psychol Psychiatry ; 62(5): 514-535, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33905120

RESUMO

BACKGROUND: Autism presents with similar prevalence and core impairments in diverse populations. We conducted a scoping review of reviews to determine key barriers and innovative strategies which can contribute to attaining universal health coverage (UHC), from early detection to effective interventions for autism in low- and middle-income countries (LAMIC). METHODS: A systematic literature search of review articles was conducted. Reviews relevant to the study research question were included if they incorporated papers from LAMIC and focused on children (

Assuntos
Transtorno do Espectro Autista , Cobertura Universal do Seguro de Saúde , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/terapia , Criança , Desenvolvimento Infantil , Pré-Escolar , Países em Desenvolvimento , Humanos , Pobreza , Literatura de Revisão como Assunto
7.
J Card Surg ; 36(8): 2621-2627, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33896034

RESUMO

OBJECTIVE: To assess the impact of surgeon experience on the outcomes of degenerative mitral valve disease. METHODS: We reviewed all patients who had surgery for degenerative mitral valve disease between 2011 and 2016. Experienced surgeon was defined as performing ≥ 25 mitral valve operations/year. Patient characteristics and outcomes were compared. Competing risk analysis was performed to identify factors associated with mitral regurgitation (MR) recurrence. Survival analysis for mortality was done using Kaplan Meier curve and Cox proportional hazard method. RESULTS: There were 575 patients treated by 9 surgeons for severe MR caused by degenerative mitral valve disease between 2011 and 2016. Three experienced surgeons performed 77.2% of the operations. Patients treated by less experienced surgeons had worse comorbidity profile and were more likely to have an urgent or emergent operation (p = .001). Experienced surgeons were more likely to attempt repair (p = .024), to succeed in repair (94.7% vs. 87%; p = .001), had shorter cross-clamp times (p = .001), and achieved higher repair rate (81.3% vs. 69.7%; p = .005). Experienced surgeons were more likely to use neochordae (p = .001) and less likely to use chordae transfer (p = .001). Surgeon experience was not associated with recurrence of moderate or higher degree of MR after repair but was an independent risk factor for mortality (HR = 2.64; p = .002). CONCLUSIONS: Techniques of degenerative mitral valve surgery differ with surgeon experience, with higher rates of repair and better outcomes associated with more experienced surgeons.


Assuntos
Implante de Prótese de Valva Cardíaca , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral , Prolapso da Valva Mitral , Cirurgiões , Humanos , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/cirurgia , Prolapso da Valva Mitral/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
8.
J Card Surg ; 36(7): 2442-2451, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33896038

RESUMO

BACKGROUND: The opioid epidemic has seen a drastic increase in the incidence of drug-associated infective endocarditis (IE). No clinical tool exists to predict operative morbidity and mortality in patients undergoing surgery. METHODS: A multi-institutional database was reviewed between 2011 and 2018. Multivariate logistic regression was fitted in an automated stepwise fashion. The STratification risk analysis in OPerative management of drug-associated IE (STOP) score was constructed. Morbidity was defined as reintubation, prolonged ventilation, pneumonia, renal failure, dialysis, stroke, reoperation for bleeding, and a permanent pacemaker. Cross-validation provided an unbiased estimate of out-of-sample performance. RESULTS: A total of 1181 patients underwent surgery for drug-associated IE (median age, 39; interquartile range [IQR], 30-54, 386 women [32.7%], 341 reoperations for prosthetic valve endocarditis [28.9%], 316 patients with multivalve disease [26.8%]). Operative morbidity and mortality were 41.1% and 5.9%, respectively. Predictors of morbidity were dialysis (95% confidence interval [CI], 1.16-2.82), emergent intervention (1.83-4.73), multivalve procedure (1.01-1.98), causative organisms other than Streptococcus (1.09-2.02), and type of valve procedure performed [aortic valve procedure (1.07-2.15), mitral valve replacement (1.03-2.05), tricuspid valve replacement (1.21-2.60)]. Predictors of mortality were dialysis (1.29-5.74), active endocarditis (1.32-83), lung disease (1.25-5.43), emergent intervention (1.69-6.60), prosthetic valve endocarditis (1.24-3.69), aortic valve procedure (1.49-5.92) and multivalve disease (1.00-2.95). Variables maximizing explanatory power were translated into a scoring system. Each point increased odds of morbidity and mortality by 22.0% and 22.4% with an accuracy of 94.0% and 94.1%, respectively. CONCLUSION: Drug-related IE is associated with significant morbidity and mortality. An easily-applied risk stratification score may aid in clinical decision-making.


Assuntos
Endocardite Bacteriana , Endocardite , Próteses Valvulares Cardíacas , Preparações Farmacêuticas , Adulto , Endocardite/cirurgia , Endocardite Bacteriana/cirurgia , Feminino , Humanos , Diálise Renal , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
9.
Child Adolesc Ment Health ; 26(1): 80-82, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33372717

RESUMO

The burden from mental disorder in the Eastern Mediterranean Region (EMR) has risen steadily over the last three decades. The unmet need for interventions puts pressure on policymakers for urgent action, often leading to the introduction of programmes developed in high-income countries, with very little attention to how well these meet local needs. Till well-designed local research including randomised controlled trials become common practice in low- and middle-income countries, implementation science could provide relatively cheaper and quicker ways of ensuring that these interventions do indeed lead to patient benefit. We present a case study of a teacher-delivered school mental health intervention developed by international experts, and implemented in the EMR under the auspices of the World Health Organization. We used an implementation research framework to adapt the programme to local needs, obtain stakeholder buy-in, and design an online-training programme for rapid dissemination in local schools in Egypt, Iran, Jordan and Pakistan. Within the official roll-out of the programme in one EMR country (Pakistan), we embedded a hybrid effectiveness-implementation cluster randomised control trial to evaluate both clinical and implementation outcomes of the adapted intervention. The approach allows for rapid adaptation and evidence building within real-world implementation settings. Capacity in low- and middle-income countries for such research needs to be developed.


Assuntos
Ciência da Implementação , Transtornos Mentais , Humanos , Saúde Mental , Políticas , Instituições Acadêmicas
10.
Child Adolesc Ment Health ; 26(2): 182-183, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33754481

RESUMO

Depression and anxiety are leading causes of morbidity in children and adolescents worldwide. In Pakistan, young people are exposed to many chronic adversities including violence, social and economic inequalities, and are at greater risk of developing mental health problems. Yet there is a lack of trained human resources, in-patient child and adolescent mental healthcare facilities, and training opportunities in child and adolescent psychiatry and mental health in Pakistan. Given the poor economic condition of the country, which has been made even worse by the COVID-19 pandemic, it is very unlikely that dedicated resources will be made available in near future to develop specialist child and adolescent mental health services in Pakistan. To bridge this treatment gap, we propose a multitiered, transdiagnostic, task-shifting strategy-based model for child and adolescent mental health services in Pakistan.


Assuntos
Psiquiatria do Adolescente , Psiquiatria Infantil , Hospitais Psiquiátricos , Serviços de Saúde Mental , Adolescente , Criança , Humanos , Transtornos Mentais/terapia , Serviços de Saúde Mental/economia , Serviços de Saúde Mental/organização & administração , Paquistão
11.
Lancet ; 393(10182): 1733-1744, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-30948286

RESUMO

BACKGROUND: Many women are affected by anxiety and depression after armed conflict in low-income and middle-income countries, yet few scalable options for their mental health care exist. We aimed to establish the effectiveness of a brief group psychological intervention for women in a conflict-affected setting in rural Swat, Pakistan. METHODS: In a single-blind, cluster, randomised, controlled trial, 34 community clusters in two union councils of rural Swat, Pakistan, were randomised using block permutation at a 1:1 ratio to intervention (group intervention with five sessions incorporating behavioural strategies facilitated by non-specialists) or control (enhanced usual care) groups. Researchers responsible for identifying participants, obtaining consent, enrolment, and outcome assessments were masked to allocation. A community cluster was defined as neighbourhood of about 150 households covered by a lady health worker. Women aged 18-60 years who provided written informed consent, resided in the participating cluster catchment areas, scored at least 3 on the General Health Questionnaire-12, and at least 17 on the WHO Disability Assessment Schedule were recruited. The primary outcome, combined anxiety and depression symptoms, was measured 3 months after the intervention with the Hospital Anxiety and Depression Scale (HADS). Modified intention-to-treat analyses were done using mixed models adjusted for covariates and clusters defined a priori. The trial is registered with the Australian New Zealand Clinical Trials Registry, number 12616000037404, and is now closed to new participants. FINDINGS: From 34 eligible community clusters, 306 women in the intervention group and 306 women in the enhanced usual care (EUC) group were enrolled between Jan 11, 2016, and Aug 21, 2016, and the results of 288 (94%) of 306 women in the intervention group and 290 (95%) of 306 women in the EUC group were included in the primary endpoint analysis. At 3 months, women in the intervention group had significantly lower mean total scores on the HADS than women in the control group (10·01 [SD 7·54] vs 14·75 [8·11]; adjusted mean difference [AMD] -4·53, 95% CI -7·13 to -1·92; p=0·0007). Individual HADS anxiety scores were also significantly lower in the intervention group than in the control group (5·43 [SD 4·18] vs 8·02 [4·69]; AMD -2·52, 95% CI -4·04 to -1·01), as were depression scores (4·59 [3·87] vs 6·73 [3·91]; AMD -2·04, -3·19 to -0·88). No adverse events were reported in either group. INTERPRETATION: Our group psychological intervention resulted in clinically significant reductions in anxiety and depressive symptoms at 3 months, and might be a feasible and effective option for women with psychological distress in rural post-conflict settings. FUNDING: WHO through a grant from the Office for Foreign Disaster Assistance.


Assuntos
Transtornos de Ansiedade/terapia , Conflitos Armados/psicologia , Transtorno Depressivo/terapia , Psicoterapia Breve/métodos , Adolescente , Adulto , Transtornos de Ansiedade/etiologia , Análise por Conglomerados , Transtorno Depressivo/etiologia , Exposição à Violência/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Paquistão , Saúde da População Rural , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
12.
Br J Psychiatry ; 217(5): 623-629, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32720628

RESUMO

BACKGROUND: With the development of evidence-based interventions for treatment of priority mental health conditions in humanitarian settings, it is important to establish the cost-effectiveness of such interventions to enable their scale-up. AIMS: To evaluate the cost-effectiveness of the Problem Management Plus (PM+) intervention compared with enhanced usual care (EUC) for common mental disorders in primary healthcare in Peshawar, Pakistan. Trial registration ACTRN12614001235695 (anzctr.org.au). METHOD: We randomly allocated 346 participants to either PM+ (n = 172) or EUC (n = 174). Effectiveness was measured using the Hospital Anxiety and Depression Scale (HADS) at 3 months post-intervention. Cost-effectiveness analysis was performed as incremental costs (measured in Pakistani rupees, PKR) per unit change in anxiety, depression and functioning scores. RESULTS: The total cost of delivering PM+ per participant was estimated at PKR 16 967 (US$163.14) using an international trainer and supervisor, and PKR 3645 (US$35.04) employing a local trainer. The mean cost per unit score improvement in anxiety and depression symptoms on the HADS was PKR 2957 (95% CI 2262-4029) (US$28) with an international trainer/supervisor and PKR 588 (95% CI 434-820) (US$6) with a local trainer/supervisor. The mean incremental cost-effectiveness ratio (ICER) to successfully treat a case of depression (PHQ-9 ≥ 10) using an international supervisor was PKR 53 770 (95% CI 39 394-77 399) (US$517), compared with PKR 10 705 (95% CI 7731-15 627) (US$102.93) using a local supervisor. CONCLUSIONS: The PM+ intervention was more effective but also more costly than EUC in reducing symptoms of anxiety, depression and improving functioning in adults impaired by psychological distress in a post-conflict setting of Pakistan.


Assuntos
Transtornos de Ansiedade/economia , Transtornos de Ansiedade/terapia , Análise Custo-Benefício , Depressão/economia , Depressão/terapia , Organização Mundial da Saúde/economia , Organização Mundial da Saúde/organização & administração , Adulto , Ansiedade/economia , Ansiedade/terapia , Humanos , Paquistão , Resultado do Tratamento
13.
Int J Geriatr Psychiatry ; 35(2): 163-173, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31657091

RESUMO

OBJECTIVE: The aim of the present study was to characterize the clinical pathways that people with dementia (PwD) in different countries follow to reach specialized dementia care. METHODS: We recruited 548 consecutive clinical attendees with a standardized diagnosis of dementia, in 19 specialized public centres for dementia care in 15 countries. The WHO "encounter form," a standardized schedule that enables data concerning basic socio-demographic, clinical, and pathways data to be gathered, was completed for each participant. RESULTS: The median time from the appearance of the first symptoms to the first contact with specialist dementia care was 56 weeks. The primary point of access to care was the general practitioners (55.8%). Psychiatrists, geriatricians, and neurologists represented the most important second point of access. In about a third of cases, PwD were prescribed psychotropic drugs (mostly antidepressants and tranquillizers). Psychosocial interventions (such as psychological counselling, psychotherapy, and practical advice) were delivered in less than 3% of situations. The analyses of the "pathways diagram" revealed that the path of PwD to receiving care is complex and diverse across countries and that there are important barriers to clinical care. CONCLUSIONS: The study of pathways followed by PwD to reach specialized care has implications for the subsequent course and the outcome of dementia. Insights into local differences in the clinical presentations and the implementation of currently available dementia care are essential to develop more tailored strategies for these patients, locally, nationally, and internationally.


Assuntos
Procedimentos Clínicos/organização & administração , Demência/terapia , Acessibilidade aos Serviços de Saúde , Internacionalidade , Especialização , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/uso terapêutico , Feminino , Humanos , Masculino , Psicotrópicos/uso terapêutico , Encaminhamento e Consulta
14.
Nucleic Acids Res ; 46(4): 2060-2073, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29253221

RESUMO

Upf1 is an SF1-family RNA helicase that is essential for the nonsense-mediated decay (NMD) process in eukaryotes. While Upf1 has been shown to interact with 80S ribosomes, the molecular details of this interaction were unknown. Using purified recombinant proteins and high-throughput sequencing combined with Fe-BABE directed hydroxyl radical probing (HTS-BABE) we have characterized the interaction between Upf1 and the yeast 80S ribosome. We identify the 1C domain of Upf1, an alpha-helical insertion in the RecA helicase core, to be essential for ribosome binding, and determine that the L1 stalk of 25S rRNA is the binding site for Upf1 on the ribosome. Using the cleavage sites identified by hydroxyl radical probing and high-resolution structures of both yeast Upf1 and the human 80S ribosome, we provide a model of a Upf1:80S structure. Our model requires that the L1 stalk adopt an open configuration as adopted by an un-rotated, or classical-state, ribosome. Our results shed light on the interaction between Upf1 and the ribosome, and suggest that Upf1 may specifically engage a classical-state ribosome during translation.


Assuntos
RNA Helicases/química , RNA Helicases/metabolismo , RNA Ribossômico/química , RNA Ribossômico/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Sítios de Ligação , Sequenciamento de Nucleotídeos em Larga Escala , Radical Hidroxila , Modelos Moleculares , Fatores de Iniciação de Peptídeos/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Domínios Proteicos , Proteínas de Ligação a RNA/metabolismo , Ribossomos/química , Ribossomos/metabolismo , Análise de Sequência de RNA , Fator de Iniciação de Tradução Eucariótico 5A
15.
Catheter Cardiovasc Interv ; 93(6): E337-E342, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30269424

RESUMO

BACKGROUND: Recent reports describe increases in the case volume of surgical aortic valve replacement (SAVR) after centers establish a transcatheter aortic valve replacement (TAVR) program. We investigate contemporary temporal trends in SAVR and TAVR case volumes and risk profiles at a high volume academic medical center. METHODS: We conducted a retrospective, descriptive evaluation of consecutive patients who underwent TAVR (n = 538) or SAVR (n = 657) in 2011-2016. The STS predicted risk of mortality (PROM) for isolated SAVR was used to calculate PROM for both SAVR and TAVR patients. Patients were stratified based on STS PROM as follows: low risk (<4%), intermediate risk (4-8%), and high risk (≥8%). Temporal changes in patient risk-profile were characterized descriptively. RESULTS: Median STS PROM for the study period was 6.3% and 2.0% for TAVR and SAVR cohorts, respectively (P < 0.001). Since 2011, TAVR volume consistently increased, while SAVR volume increased initially, peaking in 2013 and steadily declined. The STS PROM for SAVR remained stable during the entire study period, while that for TAVR showed a steady decline. The proportions of intermediate and low STS PROM patients undergoing TAVR increased. Proportions of each risk category in SAVR cohort remained stable over time. CONCLUSIONS: SAVR volume increased initially but declined eventually following the implementation of TAVR program. The distribution of the STS PROM in TAVR cohort changed dramatically with increasing proportion of patients in lower risk categories. These findings suggest the converging patient populations in TAVR and SAVR, which may be associated with the decline in the overall SAVR volume.


Assuntos
Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/tendências , Padrões de Prática Médica/tendências , Substituição da Valva Aórtica Transcateter/tendências , Centros Médicos Acadêmicos/tendências , Idoso , Idoso de 80 Anos ou mais , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/mortalidade , Hospitais com Alto Volume de Atendimentos/tendências , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do Tratamento
16.
Thorac Cardiovasc Surg ; 67(8): 631-636, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30296813

RESUMO

INTRODUCTION: Surgical management for tricuspid valve (TV) endocarditis is usually TV repair or replacement. When repair is not feasible, and concerns for patient recidivism preclude TV replacement, tricuspid valvectomy without replacement is an option to alleviate symptoms and allow time for addiction management. METHODS: We reviewed our institution's experience with isolated tricuspid valvectomy for cases of intravenous drug use (IVDU)-associated endocarditis (n = 7) from 2009 to 2017. RESULTS: The decision for tricuspid valvectomy was based on each patient's comorbid condition and realization of active IVDU. This intervention resulted in 100% perioperative and mid-term survival with a mean follow-up of 25.4 months. One patient required a valve replacement in the long term only after appropriate substance abuse management was completed. CONCLUSION: Cardiac surgeons increasingly encounter patients with active endocarditis who suffer from IVDU addiction. Drug addiction increases the risk for recurrent endocarditis and requires an effective management plan. Multidisciplinary endocarditis care teams may play a pivotal role in improving outcomes by better addressing addiction treatment.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Endocardite Bacteriana/cirurgia , Abuso de Substâncias por Via Intravenosa/reabilitação , Valva Tricúspide/cirurgia , Adulto , Antibacterianos/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/microbiologia , Endocardite Bacteriana/fisiopatologia , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Recuperação de Função Fisiológica , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Valva Tricúspide/microbiologia , Valva Tricúspide/fisiopatologia , Adulto Jovem
18.
Arthroscopy ; 34(3): 903-913, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29146162

RESUMO

PURPOSE: To identify and describe in the existing literature any criteria used for return to play following surgical stabilization for traumatic, anterior shoulder instability. METHODS: We performed a systematic review evaluating surgical stabilization for primary traumatic anterior shoulder instability in skeletally mature patients with a minimum of 1-year follow-up using Level I to IV studies in PubMed and EMBASE from January 1994 to January 2017. RESULTS: Fifty-eight studies with at least 1 explicitly stated criterion for return to play were identified from a review of more than 5,100 published articles. Seven different categories of return to play criteria were identified, the most common of which were time from surgery (89.6%), strength (18.9%), and range of motion (13.8%). Pain, stability, proprioception, and postoperative radiographic evaluation were also used. As hypothesized, in 75.8% of the included studies (44/58), time was the only criterion explicitly used. The most commonly used time for return to play was 6 months. CONCLUSIONS: This systematic review identifies 7 criteria that have been used in the available literature to determine when patients are ready to return to play; however, consistent with our hypothesis, 75% of studies used time from surgery as the sole listed criterion, with the most commonly used time point of 6 months postoperative. All of these criteria can be used in future research to develop a comprehensive checklist of functional criteria in hopes of reducing recurrent injury. LEVEL OF EVIDENCE: Level IV, systematic review.


Assuntos
Traumatismos em Atletas/cirurgia , Instabilidade Articular/cirurgia , Volta ao Esporte , Lesões do Ombro , Articulação do Ombro/cirurgia , Artralgia/fisiopatologia , Traumatismos em Atletas/diagnóstico por imagem , Traumatismos em Atletas/fisiopatologia , Humanos , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/fisiopatologia , Força Muscular/fisiologia , Propriocepção/fisiologia , Radiografia , Amplitude de Movimento Articular , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/fisiopatologia , Fatores de Tempo
19.
J Card Surg ; 33(2): 107-114, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29405382

RESUMO

BACKGROUND: Nontraumatic, spontaneous rupture of the ascending aorta is rare and the etiology is largely unknown. METHODS: We reviewed seven patients from our institution, with no known aortic disease or hereditary connective tissue disorder that presented with spontaneous ascending aortic rupture from 2012 to 2017. RESULTS: Most patients presented with non-radiating chest pain along with hypertension (71.4%). The mean ascending aortic diameter at rupture was 4.60 ± 0.62 cm. The median door-to-operating room time was 2.58 h, resulting from effective implementation of an aortic emergency protocol. There were no operative mortalities. CONCLUSIONS: In patients with ascending aortic rupture, aortic diameter may not always correlate with the risk of rupture. Rapid diagnosis combined with a multidisciplinary approach is vital for the successful management of these high-risk patients.


Assuntos
Aorta/diagnóstico por imagem , Aorta/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/cirurgia , Adolescente , Adulto , Idoso , Aorta/patologia , Doenças da Aorta/complicações , Dor no Peito/etiologia , Emergências , Feminino , Humanos , Hipertensão/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Risco , Ruptura Espontânea , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
20.
J Shoulder Elbow Surg ; 27(6): 962-967, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29599038

RESUMO

BACKGROUND: Opioids are commonly administered for the treatment of acute and chronic pain symptoms. The current health care system is struggling to deal with increasing medication abuse and rising mortality rates from overdose. Preoperative patient-targeted education on opioid use is an avenue yet to be explored. The purpose of the study was to determine whether preoperative narcotics education reduces consumption after arthroscopic rotator cuff repair (ARCR). METHODS: Patients undergoing primary ARCR at our institution were randomized to receiving opioid-related preoperative education or not. Patients filled out preoperative questionnaires detailing complete medical history and visual analog scale (VAS) for pain. Patients completed questionnaires regarding their opioid consumption and pain at their 2-week, 6-week, and 3-month follow-up. RESULTS: The study enrolled 140 patients. Patients in the study group consumed significantly less narcotics than the control group at the 3-month follow-up. Patients in the education group were 2.2 times more likely to discontinue narcotic use by the end of follow-up (odds ratio, 2.19; P = .03). In addition, patients with a history of preoperative narcotic use that were in the education group were 6.8 times more likely to discontinue narcotics by the end of follow-up (odds ratio, 6.8; P = .008). DISCUSSION/CONCLUSIONS: The findings of this study determined that preoperative education intervention significantly decreased the number of narcotic pills consumed at 3 months after ARCR. In addition, education resulted in earlier cessation of opioids; therefore, directed patient education can help alleviate the current opioid epidemic.


Assuntos
Analgésicos Opioides/uso terapêutico , Artroscopia/efeitos adversos , Distinções e Prêmios , Dor Pós-Operatória/prevenção & controle , Educação de Pacientes como Assunto , Lesões do Manguito Rotador/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Medição da Dor , Dor Pós-Operatória/etiologia , Período Pré-Operatório , Estudos Prospectivos , Inquéritos e Questionários , Escala Visual Analógica
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