RESUMO
Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV downregulates STAT1 mRNA and interferon signaling, and it upregulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response and provides a framework for characterizing host-virus interactions under maximum containment.
Assuntos
Ebolavirus/fisiologia , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/genética , Análise de Célula Única , Animais , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Efeito Espectador , Diferenciação Celular , Proliferação de Células , Citocinas/metabolismo , Ebolavirus/genética , Chaperona BiP do Retículo Endoplasmático , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Viral da Expressão Gênica , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferons/genética , Interferons/metabolismo , Macaca mulatta , Macrófagos/metabolismo , Monócitos/metabolismo , Mielopoese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Transcriptoma/genéticaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
Assuntos
COVID-19/metabolismo , Interações Hospedeiro-Patógeno , Biossíntese de Proteínas , Splicing de RNA , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismo , Células A549 , Animais , COVID-19/virologia , Chlorocebus aethiops , Células HEK293 , Humanos , Interferons/metabolismo , Transporte Proteico , RNA Mensageiro/metabolismo , RNA Ribossômico 18S/metabolismo , RNA Citoplasmático Pequeno/química , RNA Citoplasmático Pequeno/metabolismo , Partícula de Reconhecimento de Sinal/química , Partícula de Reconhecimento de Sinal/metabolismo , Células Vero , Proteínas não Estruturais Virais/químicaRESUMO
The magnitude of the 2013-2016 Ebola virus disease (EVD) epidemic enabled an unprecedented number of viral mutations to occur over successive human-to-human transmission events, increasing the probability that adaptation to the human host occurred during the outbreak. We investigated one nonsynonymous mutation, Ebola virus (EBOV) glycoprotein (GP) mutant A82V, for its effect on viral infectivity. This mutation, located at the NPC1-binding site on EBOV GP, occurred early in the 2013-2016 outbreak and rose to high frequency. We found that GP-A82V had heightened ability to infect primate cells, including human dendritic cells. The increased infectivity was restricted to cells that have primate-specific NPC1 sequences at the EBOV interface, suggesting that this mutation was indeed an adaptation to the human host. GP-A82V was associated with increased mortality, consistent with the hypothesis that the heightened intrinsic infectivity of GP-A82V contributed to disease severity during the EVD epidemic.
Assuntos
Ebolavirus/genética , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/virologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , África Ocidental/epidemiologia , Substituição de Aminoácidos , Animais , Callithrix , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Cheirogaleidae , Citoplasma/virologia , Ebolavirus/fisiologia , Doença pelo Vírus Ebola/epidemiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Proteína C1 de Niemann-Pick , Conformação Proteica em alfa-Hélice , Proteínas do Envelope Viral/metabolismo , Vírion/química , Vírion/patogenicidade , VirulênciaRESUMO
The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. VIDEO ABSTRACT.
Assuntos
Genoma Viral , Febre Lassa/virologia , Vírus Lassa/genética , RNA Viral/genética , África Ocidental/epidemiologia , Animais , Evolução Biológica , Reservatórios de Doenças , Ebolavirus/genética , Variação Genética , Glicoproteínas/genética , Doença pelo Vírus Ebola/virologia , Humanos , Febre Lassa/epidemiologia , Febre Lassa/transmissão , Vírus Lassa/classificação , Vírus Lassa/fisiologia , Murinae/genética , Mutação , Nigéria/epidemiologia , Proteínas Virais/genética , Zoonoses/epidemiologia , Zoonoses/virologiaRESUMO
The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission.
Assuntos
Ebolavirus/genética , Ebolavirus/isolamento & purificação , Genoma Viral , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/virologia , Mutação , Evolução Biológica , Surtos de Doenças , Ebolavirus/classificação , Doença pelo Vírus Ebola/transmissão , Humanos , Serra Leoa/epidemiologia , Manejo de EspécimesRESUMO
The CRISPR effector Cas13 could be an effective antiviral for single-stranded RNA (ssRNA) viruses because it programmably cleaves RNAs complementary to its CRISPR RNA (crRNA). Here, we computationally identify thousands of potential Cas13 crRNA target sites in hundreds of ssRNA viral species that can potentially infect humans. We experimentally demonstrate Cas13's potent activity against three distinct ssRNA viruses: lymphocytic choriomeningitis virus (LCMV); influenza A virus (IAV); and vesicular stomatitis virus (VSV). Combining this antiviral activity with Cas13-based diagnostics, we develop Cas13-assisted restriction of viral expression and readout (CARVER), an end-to-end platform that uses Cas13 to detect and destroy viral RNA. We further screen hundreds of crRNAs along the LCMV genome to evaluate how conservation and target RNA nucleotide content influence Cas13's antiviral activity. Our results demonstrate that Cas13 can be harnessed to target a wide range of ssRNA viruses and CARVER's potential broad utility for rapid diagnostic and antiviral drug development.
Assuntos
Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Marcação de Genes/métodos , Estabilidade de RNA , Vírus de RNA/enzimologia , RNA Viral/metabolismo , Células A549 , Animais , Proteínas Associadas a CRISPR/genética , Chlorocebus aethiops , Cães , Escherichia coli/enzimologia , Escherichia coli/genética , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Vírus de RNA/genética , RNA Viral/genética , Células VeroRESUMO
During wound healing and surgical implantation, the body establishes a delicate balance between immune activation to fight off infection and clear debris and immune tolerance to control reactivity against self-tissue. Nonetheless, how such a balance is achieved is not well understood. Here we describe that pro-regenerative biomaterials for muscle injury treatment promote the proliferation of a BATF3-dependent CD103+XCR1+CD206+CD301b+ dendritic cell population associated with cross-presentation and self-tolerance. Upregulation of E-cadherin, the ligand for CD103, and XCL-1 in injured tissue suggests a mechanism for cell recruitment to trauma. Muscle injury recruited natural killer cells that produced Xcl1 when stimulated with fragmented extracellular matrix. Without cross-presenting cells, T-cell activation increases, pro-regenerative macrophage polarization decreases and there are alterations in myogenesis, adipogenesis, fibrosis and increased muscle calcification. These results, previously observed in cancer progression, suggest a fundamental mechanism of immune regulation in trauma and material implantation with implications for both short- and long-term injury recovery.
Assuntos
Materiais Biocompatíveis , Células Dendríticas , Materiais Biocompatíveis/farmacologiaRESUMO
DNA polymerases catalyze DNA synthesis with high efficiency, which is essential for all life. Extensive kinetic and structural efforts have been executed in exploring mechanisms of DNA polymerases, surrounding their kinetic pathway, catalytic mechanisms, and factors that dictate polymerase fidelity. Recent time-resolved crystallography studies on DNA polymerase η (Pol η) and ß have revealed essential transient events during the DNA synthesis reaction, such as mechanisms of primer deprotonation, separated roles of the three metal ions, and conformational changes that disfavor incorporation of the incorrect substrate. DNA-embedded ribonucleotides (rNs) are the most common lesion on DNA and a major threat to genome integrity. While kinetics of rN incorporation has been explored and structural studies have revealed that DNA polymerases have a steric gate that destabilizes ribonucleotide triphosphate binding, the mechanism of extension upon rN addition remains poorly characterized. Using steady-state kinetics, static and time-resolved X-ray crystallography with Pol η as a model system, we showed that the extra hydroxyl group on the primer terminus does alter the dynamics of the polymerase active site as well as the catalysis and fidelity of DNA synthesis. During rN extension, Pol η error incorporation efficiency increases significantly across different sequence contexts. Finally, our systematic structural studies suggest that the rN at the primer end improves primer alignment and reduces barriers in C2'-endo to C3'-endo sugar conformational change. Overall, our work provides further mechanistic insights into the effects of rN incorporation on DNA synthesis.
Assuntos
Replicação do DNA , DNA Polimerase Dirigida por DNA , Ribonucleotídeos , Domínio Catalítico , DNA/biossíntese , DNA/metabolismo , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Cinética , Ribonucleotídeos/metabolismo , Conformação Proteica , Humanos , DNA Polimerase tetaRESUMO
BACKGROUND: Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes. METHODS: This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts. RESULTS: Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways. CONCLUSIONS: This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05297825.
Assuntos
Envelhecimento , Metilação de DNA , Dieta Vegana , Epigênese Genética , Humanos , Feminino , Masculino , Envelhecimento/genética , Pessoa de Meia-Idade , Idoso , Dieta , Gêmeos/genética , Dieta VegetarianaRESUMO
In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.
Assuntos
Adaptação Fisiológica/genética , Lisina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Nutrientes/farmacologia , Saccharomyces cerevisiae/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Evolução Biológica , Glucose/metabolismo , Glucose/farmacologia , Lisina/deficiência , Redes e Vias Metabólicas/genética , Nitrogênio/metabolismo , Nitrogênio/farmacologia , Nutrientes/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Sirolimo/farmacologia , Estresse FisiológicoRESUMO
Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests.
Assuntos
Filogenia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia , Zika virus/genética , Zika virus/isolamento & purificação , Animais , Brasil/epidemiologia , Colômbia/epidemiologia , Culicidae/virologia , Surtos de Doenças/estatística & dados numéricos , Genoma Viral/genética , Mapeamento Geográfico , Honduras/epidemiologia , Humanos , Metagenoma/genética , Epidemiologia Molecular , Mosquitos Vetores/virologia , Mutação , Vigilância em Saúde Pública , Porto Rico/epidemiologia , Estados Unidos/epidemiologia , Zika virus/classificação , Zika virus/patogenicidade , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologiaRESUMO
BACKGROUND: Following a concussion, approximately 15% of individuals experience persistent symptoms that can lead to functional deficits. However, underlying symptom-clusters that persist beyond 12 months have not been adequately characterized, and their relevance to functional deficits are unclear. The aim of this study was to characterize the underlying clusters of prolonged post-concussive symptoms lasting more than 12 months, and to investigate their association with functional impairments. METHODS: Although hierarchical clustering is ideally suited in evaluating subjective symptom severities, it has not been applied to the Rivermead Post-Concussion Questionnaire (RPQ). The RPQ and functional impairments questions were administered via a smartphone application to 445 individuals who self-reported prolonged post-concussive symptoms. Symptom-clusters were obtained using agglomerative hierarchical clustering, and their association with functional deficits were investigated with sensitivity analyses, and corrected for multiple comparisons. RESULTS: Five symptom-clusters were identified: headache-related, sensitivity to light and sound, cognitive, mood-related, and sleep-fatigue. Individuals with more severe RPQ symptoms were more likely to report functional deficits (p < 0.0001). Whereas the headache and sensitivity clusters were associated with at most one impairment, at-least-mild sleeping difficulties and fatigue were associated with four, and moderate-to-severe cognitive difficulties with five (all p < 0.01). CONCLUSIONS: Symptom-clusters may be clinically useful for functional outcome stratification for targeted rehabilitation therapies. Further studies are required to replicate these findings in other cohorts and questionnaires, and to ascertain the effects of symptomatic intervention on functional outcomes.
Assuntos
Concussão Encefálica , Síndrome Pós-Concussão , Humanos , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/etiologia , Síndrome Pós-Concussão/psicologia , Concussão Encefálica/diagnóstico , Cefaleia , Inquéritos e Questionários , AutorrelatoRESUMO
BACKGROUND: Laparoscopic cholecystectomy is increasingly performed in an ever ageing population; however, the risks are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of cholecystectomy in the elderly population compared to younger patients. METHOD: A systematic literature search of PubMed, EMBASE and the Cochrane Library databases were conducted including studies reporting laparoscopic cholecystectomy in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were conversion to open surgery, bile leaks, postoperative mortality and length of stay. RESULTS: This review identified 99 studies incorporating 326,517 patients. Increasing age was significantly associated with increased rates of overall complications (OR 2.37, CI95% 2.00-2.78), major complication (OR 1.79, CI95% 1.45-2.20), risk of conversion to open cholecystectomy (OR 2.17, CI95% 1.84-2.55), risk of bile leaks (OR 1.50, CI95% 1.07-2.10), risk of postoperative mortality (OR 7.20, CI95% 4.41-11.73) and was significantly associated with increased length of stay (MD 2.21 days, CI95% 1.24-3.18). CONCLUSION: Postoperative outcomes such as overall and major complications appear to be significantly higher in all age cut-offs in this meta-analysis. This study demonstrated there is a sevenfold increase in perioperative mortality which increases by tenfold in patients > 80 years old. This study appears to confirm preconceived suspicions of higher risks in elderly patients undergoing cholecystectomy and may aid treatment planning and informed consent.
Assuntos
Colecistectomia Laparoscópica/métodos , Conversão para Cirurgia Aberta/métodos , Doenças da Vesícula Biliar/cirurgia , Complicações Pós-Operatórias/epidemiologia , Fatores Etários , Idoso , Saúde Global , Humanos , Incidência , Fatores de RiscoRESUMO
INTRODUCTION: Currently, the American Joint Commission on Cancer (AJCC) staging system is used for prognostication for oesophageal cancer. However, several prognostically important factors have been reported but not incorporated. This meta-analysis aimed to characterize the impact of preoperative, operative, and oncological factors on the prognosis of patients undergoing curative resection for oesophageal cancer. METHODS: This systematic review was performed according to PRISMA guidelines and eligible studies were identified through a search of PubMed, Scopus, and Cochrane CENTRAL databases up to 31 December 2018. A meta-analysis was conducted with the use of random-effects modeling to determine pooled univariable hazard ratios (HRs). The study was prospectively registered with the PROSPERO database (Registration: CRD42018157966). RESULTS: One-hundred and seventy-one articles including 73,629 patients were assessed quantitatively. Of the 122 factors associated with survival, 39 were significant on pooled analysis. Of these. the strongly associated prognostic factors were 'pathological' T stage (HR: 2.07, CI95%: 1.77-2.43, P < 0.001), 'pathological' N stage (HR: 2.24, CI95%: 1.95-2.59, P < 0.001), perineural invasion (HR: 1.54, CI95%: 1.36-1.74, P < 0.001), circumferential resection margin (HR: 2.17, CI95%: 1.82-2.59, P < 0.001), poor tumor grade (HR: 1.53, CI95%: 1.34-1.74, P < 0.001), and high neutrophil:lymphocyte ratio (HR: 1.47, CI95%: 1.30-1.66, P < 0.001). CONCLUSION: Several tumor biological variables not included in the AJCC 8th edition classification can impact on overall survival. Incorporation and validation of these factors into prognostic models and next edition of the AJCC system will enable personalized approach to prognostication and treatment.
Assuntos
Neoplasias Esofágicas , Esofagectomia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Humanos , Margens de Excisão , Estadiamento de Neoplasias , PrognósticoRESUMO
Anastomotic leaks (AL) are a major complication after esophagectomy. This meta-analysis aimed to determine identify risks factors for AL (preoperative, intra-operative, and post-operative factors) and assess the consequences to outcome on patients who developed an AL. This systematic review was performed according to PRISMA guidelines, and eligible studies were identified through a search of PubMed, Scopus, and Cochrane CENTRAL databases up to 31 December 2018. A meta-analysis was conducted with the use of random-effects modeling and prospectively registered with the PROSPERO database (Registration CRD42018130732). This review identified 174 studies reporting outcomes of 74,226 patients undergoing esophagectomy. The overall pooled AL rates were 11%, ranging from 0 to 49% in individual studies. Majority of studies were from Asia (n = 79). In pooled analyses, 23 factors were associated with AL (17 preoperative and six intraoperative). AL were associated with adverse outcomes including pulmonary (OR: 4.54, CI95%: 2.99-6.89, P < 0.001) and cardiac complications (OR: 2.44, CI95%: 1.77-3.37, P < 0.001), prolonged hospital stay (mean difference: 15 days, CI95%: 10-21 days, P < 0.001), and in-hospital mortality (OR: 5.91, CI95%: 1.41-24.79, P = 0.015). AL are a major complication following esophagectomy accounting for major morbidity and mortality. This meta-analysis identified modifiable risk factors for AL, which can be a target for interventions to reduce AL rates. Furthermore, identification of both modifiable and non-modifiable risk factors will facilitate risk stratification and prediction of AL enabling better perioperative planning, patient counseling, and informed consent.
Assuntos
Fístula Anastomótica , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Risco Ajustado/métodos , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Esofagectomia/métodos , HumanosRESUMO
BACKGROUND: Major liver resection can lead to significant morbidity and mortality. Blood loss is one of the most important factors predicting a good outcome. Although various transection methods have been reported, there is no consensus on the best technique. This systematic review and network meta-analysis aims to characterise and identify the best reported technique for elective parenchymal liver transection based on published randomised controlled trials (RCT's). METHODS: A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Central to identify RCT's up to 5th June 2019 that examined parenchymal transection for liver resection. Data including study characteristics and outcomes including intraoperative (blood loss, operating time) and postoperative measures (overall and major complications, bile leaks) were extracted. Indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analyses (NMA) which maintains randomisation within trials. RESULTS: This study identified 22 RCT's involving 2360 patients reporting ten parenchymal transection techniques. Bipolar cautery has lower blood loss and shorter operating time than stapler (mean difference: 85 mL; 22min) and Tissue Link (mean difference: 66 mL; 29min). Bipolar cautery was ranked first for blood loss and operating time followed by stapler and TissueLink. Harmonic scalpel is associated with lower overall complications than Hydrojet (Odds ratio (OR): 0.48), BiClamp forceps (OR: 0.46) and clamp crushing (OR: 0.41). CONCLUSION: Bipolar cautery techniques appear to best at reducing blood loss and associated with shortest operating time. In contrast, Harmonic scalpel appears best for overall and major complications. Given the paucity of data and selective outcome reporting, it is still hard to identify what is the best technique for liver resection. Therefore, further high-quality large-scale RCT's are still needed.
Assuntos
Hepatectomia/métodos , Perda Sanguínea Cirúrgica/prevenção & controle , Cauterização , Hepatectomia/efeitos adversos , Humanos , Duração da Cirurgia , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Right ventricular (RV) failure is the main cause of mortality in pulmonary arterial hypertension (PAH). Exercise testing helps identify early RV maladaptation and systolic dysfunction and facilitates therapy. Myocardial strain has been shown to be more sensitive than ejection fraction (EF) in detecting subclinical ventricular contractile dysfunction. Chronic pressure overload in PAH had been associated with changes in left ventricular (LV) filling. PURPOSE: To compare biventricular strains and ventriculo-ventricular interaction in PAH and controls using cardiac magnetic resonance feature tracking (cMRI-FT) and to determine the reproducibility of strain analysis. STUDY TYPE: Prospective. POPULATION: Nine PAH and nine control subjects. FIELD STRENGTH/SEQUENCE: 1.5T MRI balanced steady state free precession. ASSESSMENT: RV and LV longitudinal strain (EllRV and EllLV ) were derived using the mid-axial images. Radial (ErrLV ) and circumferential strain (EccLV ) were derived using the mid-ventricular short-axis images. Relationships between strain and volumetric parameters were assessed at rest and during submaximal in-magnet exercise. STATISTICAL TESTS: Comparison of rest-to-exercise data between PAH and controls was analyzed using two-way repeated measures analysis of variance. The relationship between volumetric parameters and cMRI-FT were assessed using Pearson's correlation. Reproducibility was assessed by using Bland-Altman plots. RESULTS: PAH had significantly lower EllRV at rest (-16.6 ± 2.7 vs. -20.1 ± 3.6, P = 0.03) despite normal RVEF. During exercise, RV systolic contractile reserve measured by EllRV was significantly reduced in PAH (PInteraction = 0.02). In PAH, indexed RV end-systolic volume (ESVi) significantly correlated with EccLV and ErrLV at rest (r = -0.65 and r = -0.70, P < 0.05) and with ErrLV during exercise (r = -0.43, P < 0.05). High observer agreement was demonstrated. DATA CONCLUSION: Despite normal resting RVEF, RV systolic function and contractile reserve as measured by EllRV was significantly reduced in PAH. The close relation between RVESVi with EccLV and ErrLV provides evidence of systolic ventriculo-ventricular interaction in PAH. Exercise cMRI-FT may provide a quantitative metric for detection of subclinical RV dysfunction in PAH. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1427-1436.
Assuntos
Teste de Esforço , Imageamento por Ressonância Magnética/métodos , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/fisiopatologia , Disfunção Ventricular Direita/complicações , Disfunção Ventricular Direita/fisiopatologia , Adulto , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
PURPOSE: To investigate the tunnel enlargement rate and clinical function by comparing double-bundle anterior cruciate ligament reconstruction (ACLR) using different fixation devices. METHODS: Patients receiving primary arthroscopic double-bundle ACLR were screened and divided into 2 groups on the basis of the method of graft fixation: bioabsorbable interference screw (BS) group and cortical button (CB) group. Bone tunnel size was assessed digitally using magnetic resonance imaging, which was performed a minimum of 2 years postoperatively. Clinical evaluations were performed using the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee score, and KT-1000 arthrometer 2 years postoperatively. RESULTS: Sixty patients receiving primary arthroscopic double-bundle ACLR were included. Overall, the BS group showed greater tunnel enlargement than the CB group, as well as a significantly increased rate of tunnel communication (P = .029). The average anteromedial tunnel enlargement rates for the BS and CB groups were 50% and 28%, respectively. The enlargement rate of the posterolateral (PL) femoral tunnel was similar in both groups. In the PL tibial tunnel, the CB group showed a significant increase in enlargement compared with the BS group (64% vs 45%, P = .0001). Both groups showed functional improvement in the Knee Injury and Osteoarthritis Outcome Score and International Knee Documentation Committee score. No significant difference in postoperative functional outcomes was found between the 2 groups. CONCLUSIONS: The BS group showed significantly greater tunnel enlargement in anteromedial tunnels and an increased tunnel communication rate compared with the CB group. On the other hand, the CB group showed greater tunnel enlargement in tibial PL tunnels. Tunnel communication was observed mostly on the tibial side in the BS patients. Equivalent clinical function outcomes were noted at 2 years after surgery in both groups of patients. LEVEL OF EVIDENCE: Level II, randomized controlled clinical trial.
Assuntos
Reconstrução do Ligamento Cruzado Anterior/instrumentação , Parafusos Ósseos , Implantes Absorvíveis , Adulto , Ligamento Cruzado Anterior/diagnóstico por imagem , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Artroscopia/métodos , Feminino , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Seguimentos , Tendões dos Músculos Isquiotibiais/transplante , Humanos , Traumatismos do Joelho/cirurgia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Adulto JovemRESUMO
BACKGROUND: Exercise training is an integral component of evidence-based management programs for many chronic cardiac and respiratory conditions. Despite this, there are limited high-quality studies available on the significance of exercise training in pulmonary hypertension (PH). The aim of this study is to evaluate the short and long-term effectiveness of exercise training in PH patients in terms of exercise capacity, quality of life, cardiac function and disease progression. METHODS: This randomized control trial will aim to recruit 50 medically stable PH patients categorised as New York Heart Association functional classification II-III. Participants will be randomly allocated to either the supervised exercise training group or usual care group for the 8-week study period. Exercise training will be conducted in an outpatient setting. Measurements at baseline and following the 8-week study period include exercise capacity (6 min walk distance and cardiopulmonary exercise test), cardiac function (exercise cardiac magnetic resonance imaging [CMRI] and echocardiography), health-related quality of life (Cambridge Pulmonary Hypertension Outcome Review), adverse responses to exercise training and time to clinical worsening. In addition, participants will be followed up for a minimum of 2 year period from commencement of the study so as to monitor long-term clinical outcomes i.e. time to clinical worsening. DISCUSSION: This study will determine whether an 8-week outpatient based supervised exercise training program is safe and beneficial for medically stable PH patients in the short and long term. This will be the first study to examine the impact of exercise training on right heart function using exercise CMRI. Results from the study will contribute new knowledge in relation to the impact of exercise training on cardiac function, long-term prognosis and inform clinical practice guidelines for this patient population. Moreover, the study will add to our understanding regarding the efficacy of exercise training in individuals with PH in an outpatient setting. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12616001467426 . Registered 21st October, 2016.
Assuntos
Terapia por Exercício , Tolerância ao Exercício , Hipertensão Pulmonar/reabilitação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Teste de Caminhada , Adulto JovemRESUMO
In one patient over time, we found that concentration of Ebola virus RNA in semen during recovery is remarkably higher than blood at peak illness. Virus in semen is replication-competent with no change in viral genome over time. Presence of sense RNA suggests replication in cells present in semen.