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Transmission spectroscopy has been a workhorse technique used over the past two decades to constrain the physical and chemical properties of exoplanet atmospheres1-5. One of its classical key assumptions is that the portion of the atmosphere it probes-the terminator region-is homogeneous. Several works from the past decade, however, have put this into question for highly irradiated, hot (Teq â³ 1,000 K) gas giant exoplanets, both empirically6-10 and through three-dimensional modelling11-17. While models have predicted clear differences between the evening (day-to-night) and morning (night-to-day) terminators, direct morning and evening transmission spectra in a wide wavelength range have not been reported for an exoplanet so far. Under the assumption of precise and accurate orbital parameters for the exoplanet WASP-39 b, here we report the detection of inhomogeneous terminators on WASP-39 b, which has allowed us to retrieve its morning and evening transmission spectra in the near-infrared (2-5 µm) using the James Webb Space Telescope. We have observed larger transit depths in the evening, which are, on average, 405 ± 88 ppm larger than the morning ones, and also have qualitatively larger features than the morning spectrum. The spectra are best explained by models in which the evening terminator is hotter than the morning terminator by 17 7 - 57 + 65 K, with both terminators having C/O ratios consistent with solar. General circulation models predict temperature differences broadly consistent with the above value and point towards a cloudy morning terminator and a clearer evening terminator.
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The recent inference of sulfur dioxide (SO2) in the atmosphere of the hot (approximately 1,100 K), Saturn-mass exoplanet WASP-39b from near-infrared JWST observations1-3 suggests that photochemistry is a key process in high-temperature exoplanet atmospheres4. This is because of the low (<1 ppb) abundance of SO2 under thermochemical equilibrium compared with that produced from the photochemistry of H2O and H2S (1-10 ppm)4-9. However, the SO2 inference was made from a single, small molecular feature in the transmission spectrum of WASP-39b at 4.05 µm and, therefore, the detection of other SO2 absorption bands at different wavelengths is needed to better constrain the SO2 abundance. Here we report the detection of SO2 spectral features at 7.7 and 8.5 µm in the 5-12-µm transmission spectrum of WASP-39b measured by the JWST Mid-Infrared Instrument (MIRI) Low Resolution Spectrometer (LRS)10. Our observations suggest an abundance of SO2 of 0.5-25 ppm (1σ range), consistent with previous findings4. As well as SO2, we find broad water-vapour absorption features, as well as an unexplained decrease in the transit depth at wavelengths longer than 10 µm. Fitting the spectrum with a grid of atmospheric forward models, we derive an atmospheric heavy-element content (metallicity) for WASP-39b of approximately 7.1-8.0 times solar and demonstrate that photochemistry shapes the spectra of WASP-39b across a broad wavelength range.
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Photochemistry is a fundamental process of planetary atmospheres that regulates the atmospheric composition and stability1. However, no unambiguous photochemical products have been detected in exoplanet atmospheres so far. Recent observations from the JWST Transiting Exoplanet Community Early Release Science Program2,3 found a spectral absorption feature at 4.05 µm arising from sulfur dioxide (SO2) in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass (0.28 MJ) gas giant exoplanet orbiting a Sun-like star with an equilibrium temperature of around 1,100 K (ref. 4). The most plausible way of generating SO2 in such an atmosphere is through photochemical processes5,6. Here we show that the SO2 distribution computed by a suite of photochemical models robustly explains the 4.05-µm spectral feature identified by JWST transmission observations7 with NIRSpec PRISM (2.7σ)8 and G395H (4.5σ)9. SO2 is produced by successive oxidation of sulfur radicals freed when hydrogen sulfide (H2S) is destroyed. The sensitivity of the SO2 feature to the enrichment of the atmosphere by heavy elements (metallicity) suggests that it can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an inferred metallicity of about 10× solar. We further point out that SO2 also shows observable features at ultraviolet and thermal infrared wavelengths not available from the existing observations.
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BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Chromosome instability (CIN, an increased rate of chromosome gains and losses) is believed to play a fundamental role in the development and evolution of HGSOC. Importantly, overexpression of Cyclin E1 protein induces CIN, and genomic amplification of CCNE1 contributes to HGSOC pathogenesis in ~20% of patients. Cyclin E1 levels are normally regulated in a cell cycle-dependent manner by the SCF (SKP1-CUL1-FBOX) complex, an E3 ubiquitin ligase that includes the proteins SKP1 and CUL1. Conceptually, diminished SKP1 or CUL1 expression is predicted to underlie increases in Cyclin E1 levels and induce CIN. METHODS: This study employs fallopian tube secretory epithelial cell models to evaluate the impact diminished SKP1 or CUL1 expression has on Cyclin E1 and CIN in both short-term (siRNA) and long-term (CRISPR/Cas9) studies. RESULTS: Single-cell quantitative imaging microscopy approaches revealed changes in CIN-associated phenotypes and chromosome numbers and increased Cyclin E1 in response to diminished SKP1 or CUL1 expression. CONCLUSIONS: These data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.
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Instabilidade Cromossômica/genética , Cistadenocarcinoma Seroso , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Proteínas Culina/genética , Proteínas Culina/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Gradação de Tumores , Células-Tronco Neoplásicas/patologia , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Células Tumorais CultivadasRESUMO
RATIONALE: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. OBJECTIVES: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. METHODS: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. MEASUREMENTS AND MAIN RESULTS: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. CONCLUSIONS: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).
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Cuidados Críticos/métodos , Unidades de Terapia Intensiva , Sepse/diagnóstico , Teste Bactericida do Soro/métodos , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Adulto , Idoso , Estudos de Coortes , Estado Terminal , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Sepse/sangue , Síndrome de Resposta Inflamatória Sistêmica/sangue , Estados UnidosRESUMO
BACKGROUND: Systemic inflammation is a whole body reaction having an infection-positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs could be discovered that would (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility. The goal of this study was to identify and validate such a molecular classifier. METHODS AND FINDINGS: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91-1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2-5; 249 patients after excluding 37 patients with an infection likelihood of "possible") gave an AUC of 0.89 (95% CI 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein. CONCLUSIONS: SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use.
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Estado Terminal , Técnicas e Procedimentos Diagnósticos/instrumentação , Inflamação/diagnóstico , Sepse/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Estudos de Casos e Controles , Estudos de Coortes , Técnicas e Procedimentos Diagnósticos/normas , Feminino , Humanos , Inflamação/etiologia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Países Baixos , Queensland , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/etiologia , Adulto JovemRESUMO
The avian Gammacoronavirus infectious bronchitis virus (IBV) causes major economic losses in the poultry industry as the aetiological agent of infectious bronchitis, a highly contagious respiratory disease in chickens. IBV causes major economic losses to poultry industries across the globe and is a concern for global food security. IBV vaccines are currently produced by serial passage, typically 80 to 100 times in chicken embryonated eggs (CEE) to achieve attenuation by unknown molecular mechanisms. Vaccines produced in this manner present a risk of reversion as often few consensus level changes are acquired. The process of serial passage is cumbersome, time consuming, solely dependent on the supply of CEE and does not allow for rapid vaccine development in response to newly emerging IBV strains. Both alternative rational attenuation and cell culture-based propagation methods would therefore be highly beneficial. The majority of IBV strains are however unable to be propagated in cell culture proving a significant barrier to the development of cell-based vaccines. In this study we demonstrate the incorporation of a heterologous Spike (S) gene derived from the apathogenic Beaudette strain of IBV into a pathogenic M41 genomic backbone generated a recombinant IBV denoted M41K-Beau(S) that exhibits Beaudette's unique ability to replicate in Vero cells, a cell line licenced for vaccine production. The rIBV M41K-Beau(S) additionally exhibited an attenuated in vivo phenotype which was not the consequence of the presence of a large heterologous gene demonstrating that the Beaudette S not only offers a method for virus propagation in cell culture but also a mechanism for rational attenuation. Although historical research suggested that Beaudette, and by extension the Beaudette S protein was poorly immunogenic, vaccination of chickens with M41K-Beau(S) induced a complete cross protective immune response in terms of clinical disease and tracheal ciliary activity against challenge with a virulent IBV, M41-CK, belonging to the same serogroup as Beaudette. This implies that the amino acid sequence differences between the Beaudette and M41 S proteins have not distorted important protective epitopes. The Beaudette S protein therefore offers a significant avenue for vaccine development, with the advantage of a propagation platform less reliant on CEE.
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Gammacoronavirus , Vírus da Bronquite Infecciosa , Vacinas , Animais , Chlorocebus aethiops , Glicoproteína da Espícula de Coronavírus/genética , Células Vero , Galinhas , Vírus da Bronquite Infecciosa/genéticaRESUMO
Avian infectious bronchitis is an acute respiratory disease of poultry of particular concern for global food security. Investigation of infectious bronchitis virus (IBV), the causative agent of avian infectious bronchitis, via reverse genetics enables deeper understanding of virus biology and a rapid response to emerging variants. Classic methods of reverse genetics for IBV can be time consuming, rely on recombination for the introduction of mutations, and, depending on the system, can be subject to genome instability and unreliable success rates. In this study, we have applied data-optimized Golden Gate Assembly design to create a rapidly executable, flexible, and faithful reverse genetics system for IBV. The IBV genome was divided into 12 fragments at high-fidelity fusion site breakpoints. All fragments were synthetically produced and propagated in E. coli plasmids, amenable to standard molecular biology techniques for DNA manipulation. The assembly can be carried out in a single reaction, with the products used directly in subsequent viral rescue steps. We demonstrate the use of this system for generation of point mutants and gene replacements. This Golden Gate Assembly-based reverse genetics system will enable rapid response to emerging variants of IBV, particularly important to vaccine development for controlling spread within poultry populations.
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Vírus da Bronquite Infecciosa , Genética Reversa , Vírus da Bronquite Infecciosa/genética , Genética Reversa/métodos , Animais , Genoma Viral , Infecções por Coronavirus/virologia , Infecções por Coronavirus/veterinária , Plasmídeos/genética , Doenças das Aves Domésticas/virologia , Escherichia coli/genéticaRESUMO
(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.
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Silicon photonic biosensors are highly attractive for multiplexed Lab-on-Chip systems. Here, we characterize the sensing performance of 3 µm TE-mode and 10 µm dual TE/TM-mode silicon photonic micro-disk resonators and demonstrate their ability to detect the specific capture of biomolecules. Our experimental results show sensitivities of 26 nm/RIU and 142 nm/RIU, and quality factors of 3.3x10(4) and 1.6x10(4) for the TE and TM modes, respectively. Additionally, we show that the large disks contain both TE and TM modes with differing sensing characteristics. Finally, by serializing multiple disks on a single waveguide bus in a CMOS compatible process, we demonstrate a biosensor capable of multiplexed interrogation of biological samples.
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Biopolímeros/análise , Técnicas Biossensoriais/instrumentação , Refratometria/instrumentação , Silício/química , Ressonância de Plasmônio de Superfície/instrumentação , Desenho de Equipamento , Análise de Falha de Equipamento , Miniaturização , Coloração e RotulagemRESUMO
Bone graft substitutes have become an essential component in a number of orthopedic applications. Autologous bone has long been the gold standard for bone void fillers. However, the limited supply and morbidity associated with using autologous graft material has led to the development of many different bone graft substitutes. Allogeneic demineralized bone matrix (DBM) has been used extensively to supplement autograft bone because of its inherent osteoconductive and osteoinductive properties. Synthetic and natural bone graft substitutes that do not contain growth factors are considered to be osteoconductive only. Bioactive glass has been shown to facilitate graft containment at the operative site as well as activate cellular osteogenesis. In the present study, we present the results of a comprehensive in vitro and in vivo characterization of a combination of allogeneic human bone and bioactive glass bone void filler, NanoFUSE(®) DBM. NanoFUSE(®) DBM is shown to be biocompatible in a number of different assays and has been cleared by the FDA for use in bone filling indications. Data are presented showing the ability of the material to support cell attachment and proliferation on the material thereby demonstrating the osteoconductive nature of the material. NanoFUSE(®) DBM was also shown to be osteoinductive in the mouse thigh muscle model. These data demonstrate that the DBM and bioactive glass combination, NanoFUSE(®) DBM, could be an effective bone graft substitute.
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Materiais Biocompatíveis/farmacologia , Matriz Óssea/química , Substitutos Ósseos/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Osseointegração/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Matriz Óssea/ultraestrutura , Adesão Celular/efeitos dos fármacos , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Gelatina/farmacologia , Cobaias , Humanos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Osteogênese/efeitos dos fármacos , CoelhosRESUMO
SeptiCyte® RAPID is a gene expression assay measuring the relative expression levels of host response genes PLA2G7 and PLAC8, indicative of a dysregulated immune response during sepsis. As severe forms of COVID-19 may be considered viral sepsis, we evaluated SeptiCyte RAPID in a series of 94 patients admitted to Foch Hospital (Suresnes, France) with proven SARS-CoV-2 infection. EDTA blood was collected in the emergency department (ED) in 67 cases, in the intensive care unit (ICU) in 23 cases and in conventional units in 4 cases. SeptiScore (0-15 scale) increased with COVID-19 severity. Patients in ICU had the highest SeptiScores, producing values comparable to 8 patients with culture-confirmed bacterial sepsis. Receiver operating characteristic (ROC) curve analysis had an area under the curve (AUC) of 0.81 for discriminating patients requiring ICU admission from patients who were immediately discharged or from patients requiring hospitalization in conventional units. SeptiScores increased with the extent of the lung injury. For 68 patients, a chest computed tomography (CT) scan was performed within 24 h of COVID-19 diagnosis. SeptiScore >7 suggested lung injury ≥50% (AUC = 0.86). SeptiCyte RAPID was compared to other biomarkers for discriminating Critical + Severe COVID-19 in ICU, versus Moderate + Mild COVID-19 not in ICU. The mean AUC for SeptiCyte RAPID was superior to that of any individual biomarker or combination thereof. In contrast to C-reactive protein (CRP), correlation of SeptiScore with lung injury was not impacted by treatment with anti-inflammatory agents. SeptiCyte RAPID can be a useful tool to identify patients with severe forms of COVID-19 in ED, as well as during follow-up.
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COVID-19 , Lesão Pulmonar , Sepse , Humanos , Teste para COVID-19 , COVID-19/diagnóstico , SARS-CoV-2/genética , Sepse/diagnóstico , Área Sob a Curva , ProteínasRESUMO
Tools for the evaluation of COVID-19 severity would help clinicians with triage decisions, especially the decision whether to admit to ICU. The aim of this study was to evaluate SeptiCyte RAPID, a host immune response assay (Immunexpress, Seattle USA) as a triaging tool for COVID-19 patients requiring hospitalization and potentially ICU care. SeptiCyte RAPID employs a host gene expression signature consisting of the ratio of expression levels of two immune related mRNAs, PLA2G7 and PLAC8, measured from whole blood samples. Blood samples from 146 adult SARS-CoV-2 (+) patients were collected within 48 h of hospital admission in PAXgene blood RNA tubes at Hospital del Mar, Barcelona, Spain, between July 28th and December 1st, 2020. Data on demographics, vital signs, clinical chemistry parameters, radiology, interventions, and SeptiCyte RAPID were collected and analyzed with bioinformatics methods. The performance of SeptiCyte RAPID for COVID-19 severity assessment and ICU admission was evaluated, relative to the comparator of retrospective clinical assessment by the Hospital del Mar clinical care team. In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity: critical vs. mild (AUC = 0.93, p < 0.0001), critical vs. moderate (AUC = 0.77, p = 0.002), severe vs. mild (AUC = 0.85, p = 0.0003), severe vs. moderate (AUC = 0.63, p = 0.05). This discrimination was significantly better (by AUC or p-value) than could be achieved by CRP, lactate, creatine, IL-6, or D-dimer. Some of the critical or severe cases had "early" blood draws (before ICU admission; n = 33). For these cases, when compared to moderate and mild cases not in ICU (n = 37), SeptiCyte RAPID had AUC = 0.78 (p = 0.00012). In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity as defined by the WHO COVID-19 Clinical Management Living Guidance of January 25th, 2021. Measurements taken early (before a patient is considered for ICU admission) suggest that high SeptiScores could aid in predicting the need for later ICU admission.
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COVID-19 , Adulto , Humanos , COVID-19/diagnóstico , SARS-CoV-2/genética , Estudos Retrospectivos , Triagem , Espanha , Unidades de Terapia Intensiva , ProteínasRESUMO
Objectives: Intraluminal prosthetic graft thrombus (IPT) following Endovascular Aneurysm Repair (EVAR) can have serious consequences. The aim of this study was to assess the prevalence of IPT and to identify the risk factors for its formation and progression. Methods: This was a retrospective study of 258 patients who had EVAR between 2015 and 2018. Demographic data, comorbidities, operative data, antithrombotic therapy, CT anatomical data, IPT characteristics (site, regression, and progression), and re-interventions were collected. Univariable analysis followed by multivariable logistic regression and Cox regression were used for data analysis. Results: The mean age of patients was 76 years (range 55-95) and 27 (10.5 %) were females. IPT was present in 26 patients (10.1%) with a median time to occurrence of six (range 1- - 24) months. Of the group that developed IPT, six (23.1 %) developed symptoms and two (7.7%) had re-interventions. Multivariable logistic regression analysis revealed peripheral arterial disease to be associated with the formation of IPT (OR 7.4, 95% CI 1.6-35.3, p = 0.02) and escalation of antithrombotic therapy was associated with regression or prevention of progression of IPT (OR 0.1, 95% CI 0.0-0.6, p = 0.01). Conclusion: PAD is associated with the formation of IPT after EVAR and warrants consideration of escalation of antithrombotic therapy to prevent further progression and complications.
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INTRODUCTION: Deep brain stimulation (DBS) surgery is an efficacious, underutilized treatment for Parkinson's disease (PD). Studies of DBS post-operative outcomes are often restricted to data from a single center and consider DBS in isolation. National estimates of DBS readmission and post-operative outcomes are needed, as are comparisons to commonly performed surgeries. METHODS: This study used datasets from the 2013 and 2014 Nationwide Readmissions Database (NRD). Our sample was restricted to PD patients discharged alive after hospitalization for DBS surgery. Descriptive analyses examined patient, clinical, hospital and index hospitalization characteristics. The all-cause, non-elective 30-day readmission rate after DBS was calculated, and logistic regression models were built to examine factors associated with readmission. Readmission rates for the most common surgical procedures were calculated and compared to DBS. RESULTS: There were 6058 DBS surgeries for PD in our sample, most often involving a male aged 65 and older, who lived in a high socioeconomic status zip code. DBS patients had an average of four comorbidities. With respect to outcomes, the majority of patients were discharged home (95.3%). Non-elective readmission was rare (4.9%), and was associated with socioeconomic status, comorbidity burden, and teaching hospital status. Much higher acute, non-elective readmission rates were observed for common procedures such as upper gastrointestinal endoscopy (16.2%), colonoscopy (14.0%), and cardiac defibrillator and pacemaker procedures (11.1%). CONCLUSION: Short-term hospitalization outcomes after DBS are generally favorable. Socioeconomic disparities in DBS use persist. Additional efforts may be needed to improve provider referrals for and patient access to DBS.
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Estimulação Encefálica Profunda/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Doença de Parkinson/epidemiologia , Doença de Parkinson/terapia , Readmissão do Paciente/estatística & dados numéricos , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Bases de Dados Factuais , Estimulação Encefálica Profunda/efeitos adversos , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Classe Social , Estados Unidos/epidemiologiaRESUMO
It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.
Assuntos
Vacinas contra a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , HIV-1/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Síndrome da Imunodeficiência Adquirida/patologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Colo/imunologia , Colo/patologia , Imunidade Celular , Mucosa Intestinal/patologia , Macaca mulatta , Reto/imunologia , Reto/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controleRESUMO
The one-step synthesis of a polyester family containing dihydroxyacetone is described along with a quantitative analysis of in vitro/in vivo degradation kinetics and initial biocompatibility. Polyesters were synthesized by combining dihydroxyacetone, which is a diol found in the eukaryotic glucose metabolic pathway, with even-carbon aliphatic diacids (adipic, suberic, sebacic) represented in the long-chain alpha carboxylic acid metabolic pathway, by SchÓ§tten-Baumann acylation. We show that by using a crystalline monomeric form of dihydroxyacetone, well-defined polyesters can be formed in one step without protection and deprotection strategies. Both diacid length and polyester molecular weight were varied to influence polymer physical and thermal properties. Polyesters were generated with number-averaged (Mn) molecular weights ranging from 2200-11,500. Polydispersities were consistent with step-growth polymerization and ranged from 2 to 2.6. The melting (Tm) and recrystallization (Tc) temperatures were impacted in an unpredictable manner. Thermal transitions for the polyesters were highest for the adipic acid followed by suberic acid and sebacic acid, respectively. It was shown that the thermal response of the DHA-based polyesters was influenced by both the diacid length and molecular weight. In vitro degradation studies revealed first-order weight loss kinetics, the molecular weight loss followed first order kinetics with 25%-40% of the original mass remaining after 8 weeks. In vivo testing over 16 weeks highlighted that mass loss ranged from â¼70% to â¼6% depending upon initial molecular weight and diacid length. Histological analysis revealed rapid resolution of both acute and chronic inflammatory responses, normal foreign body responses were observed and no inflammation was present after week 4. This one-step synthesis proved robust with unique copolymers warranting further study as potential biomaterials.
Assuntos
Materiais Biocompatíveis/síntese química , Di-Hidroxiacetona/química , Teste de Materiais/métodos , Poliésteres/síntese química , Animais , Materiais Biocompatíveis/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ácidos Carboxílicos/química , Feminino , Meia-Vida , Cinética , Poliésteres/química , Polimerização , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , TemperaturaRESUMO
INTRODUCTION: Phlegmasia caerulea dolens (PCD) is a clinical syndrome caused by venous obstruction leading to peripheral limb ischaemia. It can ultimately lead to venous gangrene, amputation or death in 25% of cases. PRESENTATION OF CASE: A 52-year-old man with a background of myeloma developed PCD secondary to an obstructing plasmacytoma and left femoral vein deep vein thrombosis (DVT). These were treated with combined radiotherapy and anticoagulation, with resolution of the patient's symptoms. His recovery was complicated by the development of heparin-induced thrombocytopenia (HIT) and cutaneous vasculitis. DISCUSSION: Both plasmacytoma and DVT are recognised complications of myeloma. This is, to our knowledge, the first description of these phenomena in combination causing PCD. The combination of venous stasis from the obstructing plasmacytoma and hypercoagulability from the underlying myeloma may have contributed to clot formation. A multifaceted treatment approach was required which aimed at improving venous flow via radiotherapy to the plasmacytoma and dissolving the obstructing clot with anticoagulant therapy. CONCLUSION: PCD has a high mortality and morbidity. Recognition is important to avoid an incorrect diagnosis of arterial occlusion and inappropriate surgical intervention. Treatment must be focused on removing the offending causes.
RESUMO
Neurofibromatosis type 1 (NF1) is a genetic condition, which affects 1 in every 3000 births. Patients with NF1 are at increased risk of a variety of vascular abnormalities. This report presents the case of a 60-year-old male with NF1 who suffered a left external iliac rupture and a right pseudoaneurysm following angioplasty. In addition, these were further complicated by previously undiagnosed, bilateral phaeochromocytomas. The inherent weakness in vessel wall architecture found in NF1 coupled with the hypertension evident during and after the procedure contributed to haemorrhage and pseudoaneurysm formation. Caution must be taken in such patients when considering vascular intervention.