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Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.
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Colesterol/metabolismo , Imunidade Inata , Interferon gama/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Humanos , Interferon beta-1b , Proteínas de Membrana/metabolismo , Ácido Mevalônico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
To plan for an expansion of healthcare services in newly developed neighbourhoods, a planning initiative was conducted to better understand the needs of the population. Ensuring equity of care was identified as a priority for this initiative. To evaluate how closely the planning adhered to the principles of health equity, we applied Ontario Health's Equity, Inclusion, Diversity, and Anti-Racism Framework to determine which areas of action were successfully addressed, and which areas of action require further focus. The framework contains 11 components, each delineating a key area of action. Using this framework helped identify areas where the principles of equity were well addressed, as well as pointing to additional areas where further efforts are required. Healthcare organizations must take a leadership role in advancing health equity by planning, delivering, improving, and advocating for the services and systematic changes that will allow its local community members to realize their highest attainable standard of health. Using such a framework can help develop strategic approaches to advancing equity.
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Equidade em Saúde , Racismo , Humanos , Liderança , OntárioRESUMO
Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.
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Hepacivirus/patogenicidade , Hepatite C/imunologia , Interações Hospedeiro-Patógeno/imunologia , Evasão da Resposta Imune , Interferons/imunologia , Proteínas Mitocondriais/imunologia , Proteínas Virais/imunologia , Sistemas CRISPR-Cas , Linhagem Celular , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Biblioteca Gênica , Genoma Viral , Hepacivirus/genética , Hepatite C/virologia , Humanos , Imunidade Inata , Interferons/genética , Interferons/metabolismo , Fígado/imunologia , Fígado/metabolismo , Potencial da Membrana Mitocondrial/imunologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutagênese Insercional , Transdução de Sinais , Proteínas Virais/genética , Replicação ViralRESUMO
Purpose: Risk factors for the development of chronic postsurgical pain (CPSP) have been reported in primary studies and an increasing number of reviews. The objective of this umbrella review was to compile and understand the published presurgical risk factors associated with the development of CPSP for various surgery types. Methods: Six databases were searched from January 2000 to June 2023 to identify meta-analyses, scoping studies, and systematic reviews investigating presurgical CPSP predictors in adult patients. Articles were screened by title/abstract and subsequently by full text by two independent reviewers. The selected papers were appraised for their scientific quality and validity. Data were extracted and descriptively analyzed. Results: Of the 2344 retrieved articles, 36 reviews were selected for in-depth scrutiny. The number of primary studies in these reviews ranged from 4 to 317. The surgery types assessed were arthroplasty (n = 13), spine surgery (n = 8), breast surgery (n = 4), shoulder surgery (n = 2), thoracic surgery (n = 2), and carpal tunnel syndrome (n = 1). One review included a range of orthopedic surgeries; six reviews included a variety of surgeries. A total of 39 presurgical risk factors were identified, some of which shared the same defining tool. Risk factors were themed into six broad categories: psychological, pain-related, health-related, social/lifestyle-related, demographic, and genetic. The strength of evidence for risk factors was inconsistent across different reviews and, in some cases, conflicting. A consistently high level of evidence was found for preoperative pain, depression, anxiety, and pain catastrophizing. Conclusion: This umbrella review identified a large number of presurgical risk factors which have been suggested to be associated with the development of CPSP after various surgeries. The identification of presurgical risk factors is crucial for the development of screening tools to predict CPSP. Our findings will aid in designing screening tools to better identify patients at risk of developing CPSP and inform strategies for prevention and treatment.
Chronic postsurgical pain (CPSP) is pain experienced predominantly at the surgical site for longer than 3 months after a surgical procedure. Depending on surgery type, it can affect between 10 and 80% of people undergoing major surgeries, which may have negative effects such as a lower quality of life, disability, and persistent opioid use. Targeted identification and management of at risk patients in the presurgical phase may decrease the risk of CPSP. This umbrella review generated a list of potential risk factors for CPSP from evidence-based reviews of the current literature. Thirty-nine presurgical risk factors were identified in this review. Risk factors are divided into six broad categories: psychological, pain-related, health-related, demographic, genetic, and social/lifestyle-related. Although the strength of evidence for individual risk factors varied across reviews, risk factors in the psychological category consistently showed a strong impact on the development of CPSP. It is vital to understand which individuals are vulnerable and at risk for CPSP. The findings of this umbrella review will aid in designing screening tools to identify surgical candidates at risk. Some risk factors, such as genetics, cannot be altered. However, many identified risk factors are modifiable and may inform strategies for the prevention and treatment of CPSP using screening tools. Our findings may guide future research to consider an in-depth analysis of risk factor characterization to group modifiable presurgical risk factors. At risk patients will be offered psychological, physical, and pharmacological treatments accordingly to mitigate their risk of developing CPSP and ultimately improve patient outcomes in surgery.
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With the entire world in the midst of COVID-19 pandemic, several health care facilities have stopped or delayed performing elective surgeries in order to cater to ever increasing number of COVID-19 patients. Moreover, there were initial reports of poor surgical outcomes in patients who underwent surgery and were found to be positive for COVID-19 infection in post-operative period. In this study, we have evaluated the short-term outcomes of head and neck oncology patients operated in our institute following a strict screening protocol and conducting COVID-19 testing by Reverse transcriptase polymerase chain reaction once the test was available. 68 patients operated between 1st April and 30th September, 2020 (COVID-19 era, study group) were compared with 59 patients operated during 1st October, 2019 to 31st March 2020 (Non COVID-19 era, control group). The comparison between the groups was done by measuring 30 days complication rate as defined by Dindo-Clavien classification. 10.3% of patients developed complications in study group as compared to 8.5% of patients in control group which was statistically non-significant (p = 0.7). Importantly, none of the patients developed any sign or symptom suggestive of COVID-19 infection in post-operative period in study group. Head and neck oncology related cancer procedures including complex reconstruction can safely be performed during COVID-19 era by proper screening and pre-operative testing for COVID-19. We also suggest use of N95 masks and face shields as bare minimum in order to ensure the safety of health care workers even after a negative COVID-19 report.
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Human metapneumovirus (hMPV) is a major cause of acute respiratory infections in infants and older adults, for which no vaccines or therapeutics are available. The viral fusion (F) glycoprotein is required for entry and is the primary target of neutralizing antibodies; however, little is known about the humoral immune response generated from natural infection. Here, using prefusion-stabilized F proteins to interrogate memory B cells from two older adults, we obtain over 700 paired non-IgM antibody sequences representing 563 clonotypes, indicative of a highly polyclonal response. Characterization of 136 monoclonal antibodies reveals broad recognition of the protein surface, with potently neutralizing antibodies targeting each antigenic site. Cryo-EM studies further reveal two non-canonical sites and the molecular basis for recognition of the apex of hMPV F by two prefusion-specific neutralizing antibodies. Collectively, these results provide insight into the humoral response to hMPV infection in older adults and will help guide vaccine development.
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Metapneumovirus , Idoso , Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , Metapneumovirus/fisiologia , Proteínas Virais de FusãoRESUMO
The redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is an exotic wood-boring insect that vectors the mycopathogen responsible for laurel wilt, a lethal vascular disease of trees in the Lauraceae. High mortality has occurred in native Persea species in the southeastern U.S., and the vector-pathogen complex poses an imminent threat to the production of commercial avocado, P. americana, in south Florida. There is a critical need for effective attractants to detect, monitor, and control this invasive pest. This study combined field tests and laboratory bioassays to evaluate the response of female X. glabratus to host-based volatiles from wood of avocado (cultivars of West Indian, Guatemalan, and Mexican races); from wood of lychee (Litchi chinensis, a presumed non-host that is high in the sesquiterpene α-copaene, a putative attractant); and to commercial lures containing manuka and phoebe oils, two reported attractive baits. Volatile collections and GC-MS analyses were performed to quantify the sesquiterpene content of test substrates. In the field, traps baited with lychee wood captured more beetles than those with wood from avocado cultivars; traps baited with phoebe oil lures captured more beetles than those with manuka oil lures (the current monitoring tool). In field and laboratory tests, X. glabratus did not show a preference among avocado races in either attraction or host acceptance (initiation of boring). In choice tests, lychee was more attractive than avocado initially, but a higher percentage of beetles bored into avocado, suggesting that lychee emits more powerful olfactory/visual cues, but that avocado contains more of the secondary cues necessary for host recognition. Emissions of α-copaene, ß-caryophyllene, and α-humulene were correlated with field captures, and lychee wood may be a source of additional semiochemicals for X. glabratus.
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Besouros/fisiologia , Controle de Insetos/métodos , Litchi/parasitologia , Persea/parasitologia , Animais , Feminino , Óleos Voláteis/metabolismo , Olfato , Madeira/parasitologiaRESUMO
OBJECTIVE: The purpose of this study is to analyze predisposing factors for a higher risk of recurrence in esophageal cancer patient who underwent surgery for curative intent and to do survival analysis of prognostic factors. MATERIALS AND METHODS: Between February 2018 and March 2020, we retrospectively identified 28 cases staged T1b to T4a managed electively at our institute as per multidisciplinary management plan. Demographic, clinical, radiological, operative, histopathological parameters, upfront surgery done or not, type of preoperative, and adjuvant treatment used and whether neoadjuvant or adjuvant therapy was planned along with waiting time for surgery, were assessed as potential risk factors. End point of study was to find potential risk factors for recurrence and to do their subgroup survival analysis. RESULTS: The recurrence rate in our study was 25% with a mean follow-up of 24 months. The median time of recurrence was 8.5 months, all recurrence occurred within 1 year. Overall DFS at 2 years was 72%. On univariate analysis, following prognostic factors were associated with high risk of recurrence, male sex X2 (1) =4.42, p = 0.035; histology subtype of adenocarcinoma X2 (1) = 7.07, p = 0.008; margin positive X2 (1) =3.76, p = 0.05; presence of lymph vascular invasion (LVI) X2 (1) =7.88, p = 0.005; presence of perineural invasion (PNI) X2 (1) =5.97, p = 0.015; postoperative T size >4 cm X2 (1) =3.86, p = 0.049; and nodal positivity X2 (3) =13.47, p = 0.004. CONCLUSIONS: Male sex, adenocarcinoma histological subtype, positive resected margin, presence of LVI and PNI, postoperative T size >4 cm, and high postoperative nodal positivity and whether neoadjuvant versus adjuvant therapy given (on K. M analysis) were the identified predictors of recurrence which compromised DFS.
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Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante/mortalidade , Neoplasias Esofágicas/terapia , Esofagectomia/mortalidade , Recidiva Local de Neoplasia/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Terapia Combinada , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human γ-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a framework for effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.
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In conventional attenuated viral vaccines, immunogenicity is often suboptimal. Here we present a systematic approach for vaccine development that eliminates interferon (IFN)-modulating functions genome-wide while maintaining virus replication fitness. We applied a quantitative high-throughput genomics system to influenza A virus that simultaneously measured the replication fitness and IFN sensitivity of mutations across the entire genome. By incorporating eight IFN-sensitive mutations, we generated a hyper-interferon-sensitive (HIS) virus as a vaccine candidate. HIS virus is highly attenuated in IFN-competent hosts but able to induce transient IFN responses, elicits robust humoral and cellular immune responses, and provides protection against homologous and heterologous viral challenges. Our approach, which attenuates the virus and promotes immune responses concurrently, is broadly applicable for vaccine development against other pathogens.
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Imunogenicidade da Vacina/genética , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Interferons/imunologia , Animais , Furões , Aptidão Genética , Genoma Viral , Estudo de Associação Genômica Ampla , Humanos , Imunidade Celular , Vírus da Influenza A/efeitos dos fármacos , Interferons/farmacologia , Camundongos , Mutação , Infecções por Orthomyxoviridae/prevenção & controle , Replicação Viral/genéticaRESUMO
BACKGROUND: The Asian citrus citrus psyllid, Diaphorina citri Kuwayama, transmits a bacterium that causes huanglongbing in citrus. Frequent and repeated use of neurotoxic insecticides against D. citri has resulted in the development of insecticide resistance. We evaluated the effects of the juvenile hormone analog methoprene on egg hatch, nymphal development, adult emergence, reproduction and behavior of D. citri. RESULTS: Methoprene significantly reduced the viability of eggs that were between 0 and 4 days old. Egg hatch of 0-48-h-old and 49-96-h-old eggs was 8 and 9%, respectively, when treated with 320 µg mL(-1) of methoprene. Methoprene caused significant mortality of first-, third- and fifth-instar D. citri nymphs and reduced adult emergence as compared with controls. Methoprene caused less than 5% adult emergence when first- and third-instar stages were treated, respectively, and less than 40% adult emergence when fifth instars were treated. Reduced fertility of females was observed when they emerged from methoprene-treated fifth instars. CONCLUSION: Methoprene was effective in reducing egg hatch, suppressing nymphal development and decreasing adult emergence of D. citri under laboratory conditions. Treatment of fifth instars reduced the fertility of females. Methoprene might be a possible tool for integrated management of D. citri.