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1.
Asia Pac J Clin Oncol ; 20(1): 25-31, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36722413

RESUMO

AIM: Lung cancer is the leading cause of cancer-related deaths in Australia with poor long-term survival outcomes. Stage III non-small cell lung cancer (NSCLC) is a highly heterogenous group with diverse tumor characteristics and multiple, possible treatment options. We present retrospective data on patient characteristics, treatment patterns, and long-term outcomes in stage III NSCLC patients treated at a single cancer center in New South Wales, Australia. METHODS: Stage III NSCLC patients were identified from the 'Nepean Cancer Research Biobank'. Patient demographics, cancer-related information, and long-term follow-up data were collected and analyzed. RESULTS: A total of 88 patients were eligible for analysis with 61% of them diagnosed as stage IIIA, 35% IIIB, and 4% IIIC. Induction chemotherapy was administered in 20% of the patients. Overall, 48% of the study population underwent surgery, and 38% underwent concurrent chemoradiotherapy (CCRT). Both median progression-free survival and overall survival (OS) were superior in stage IIIA patients in comparison to stage IIIB (and IIIC) patients (22 vs. 11 months, p = .018; and 58 vs. 19 months, p = .048, respectively). Patients who were younger (<65 years old), good Eastern Cooperative Oncology Group performance status (ECOG PS <2), and females had better prognosis on univariate analysis. There was a nonstatistically significant trend toward better median OS with CCRT in comparison to surgery (58 vs. 37 months, p = .87). CONCLUSIONS: Long-term outcomes remain poor, and hence better treatment strategies are urgently needed in stage III NSCLC. Equally, more robust, prospective studies would help delineate the optimal treatment modality in these patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Estudos Prospectivos , Estadiamento de Neoplasias , Quimiorradioterapia
2.
Behav Pharmacol ; 33(6): 377-394, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35947066

RESUMO

Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.


Assuntos
Analgésicos Opioides , Dor , Analgésicos Opioides/efeitos adversos , Animais , Isoquinolinas , Naltrexona/análogos & derivados , Dor/tratamento farmacológico , Fenilpropionatos , Ratos , Receptores Opioides/agonistas , Receptores Opioides mu/agonistas
3.
Age Ageing ; 51(2)2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35150584

RESUMO

INTRODUCTION: Mechanical thrombectomy (MT) can improve outcomes following ischaemic stroke. Patient selection for MT is predominantly based on physiological and imaging parameters. We assessed whether people living with pre-stroke frailty had differing outcomes following MT. METHODS: We included consecutive patients undergoing MT at a UK comprehensive stroke centre. We calculated a cumulative deficits frailty index to identify pre-stroke frailty in those patients presenting directly to the centre. Frailty was defined as an index score ≥ 0.24. We assessed univariable and multivariable association between pre-stroke frailty and stroke outcomes. Our primary outcomes were modified Rankin Scale (mRS) and mortality at 90 days. RESULTS: Of 175 patients who underwent MT (2014-2018), we identified frailty in 49 (28%). Frail and non-frail patients had similar rates of thrombolysis administration, successful recanalization and onset to recanalization times. Those with pre-stroke frailty had higher 24 hour National Institutes of Health Stroke Scale (12(IQR: 8-17) versus 3(IQR: 2-13); P = 0.001); were less likely to be independent (mRS 0-2: 18% versus 61%; P < 0.001) and more likely to die (47% versus 14%; P < 0.001) within 90 days. Adjusting for age, baseline NIHSS and thrombolysis, frailty remained a strong, independent predictor of poor clinical outcome at 90 days (Death OR: 3.12 (95% CI: 1.32-7.4); dependency OR: 3.04 (95%CI: 1.10-8.44). Age was no longer a predictor of outcome when adjusted for frailty. CONCLUSION: Pre-stroke frailty is prevalent in real-world patients eligible for MT and is an important predictor of poor outcomes. Routine assessment of pre-stroke frailty could help decision-making around patient selection for MT.


Assuntos
Isquemia Encefálica , Fragilidade , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/terapia , Estudos de Coortes , Fragilidade/complicações , Fragilidade/diagnóstico , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Trombectomia/efeitos adversos , Trombectomia/métodos , Resultado do Tratamento
4.
Appl Environ Microbiol ; 87(8)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33579688

RESUMO

Microbial communities within the animal digestive tract often provide important functions for their hosts. The composition of eukaryotes' gut bacteria can be shaped by host diet, vertical bacterial transmission, and physiological variation within the digestive tract. In several ant taxa, recent findings have demonstrated that nitrogen provisioning by symbiotic bacteria makes up for deficiencies in herbivorous diets. Using 16S rRNA amplicon sequencing and qPCR, this study examined bacterial communities at a fine scale across one such animal group, the turtle ant genus Cephalotes We analyzed the composition and colonization density across four portions of the digestive tract to understand how bacterial diversity is structured across gut compartments, potentially allowing for specific metabolic functions of benefit to the host. In addition, we aimed to understand if caste differentiation or host relatedness influences the gut bacterial communities of Cephalotes ants. Microbial communities were found to vary strongly across Cephalotes gut compartments in ways that transcend both caste and host phylogeny. Despite this, caste and host phylogeny still have detectable effects. We demonstrated microbial community divergence across gut compartments, possibly due to the varying function of each gut compartment for digestion.IMPORTANCE Gut compartments play an important role in structuring the microbial community within individual ants. The gut chambers of the turtle ant digestive tract differ remarkably in symbiont abundance and diversity. Furthermore, caste type explains some variation in the microbiome composition. Finally, the evolutionary history of the Cephalotes species structures the microbiome in our study, which elucidates a trend in which related ants maintain related microbiomes, conceivably owing to co-speciation. Amazingly, gut compartment-specific signatures of microbial diversity, relative abundance, composition, and abundance have been conserved over Cephalotes evolutionary history, signifying that this symbiosis has been largely stable for over 50 million years.

7.
Exp Appl Acarol ; 82(4): 515-527, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33206311

RESUMO

Ticks (Chelicerata, Ixodida) are blood-feeding ectoparasites believed to have evolved at least about 120 millions of years ago and found worldwide. However, many aspects of their unique life cycle and anatomy, including their mechanical properties, remain to be understood. Here, we compared the mechanical properties of the cuticle of the argasid tick Ornithodoros moubata to those of two species of ixodid tick, Amblyomma hebraeum and Ixodes pacificus that we explored in our earlier studies of the tick exoskeleton. Significant differences were expected given the substantial difference in life cycle, including a five-fold increase during the repeated adult blood meal for female O. moubata vs. 70- to 120-fold during the single feeding of the adult female A. hebraeum and I. pacificus. We demonstrate here that the layered structure and mechanical properties (stiffness and viscosity) of the cuticle show minor differences, but the difference in cuticle thickness is substantial. Ductility is lost during feeding; reduced pH restores ductility. Previous work suggests that this occurs in vivo in engorged ixodid ticks; there is no evidence of this occurring in vivo in O. moubata. Thinning of cuticle in O. moubata fed females is consistent with the predicted stretch of cuticle due to the blood meal; there is no evidence of cuticle synthesis during the short feeding period. Dimensional analysis suggests that the soft feel of argasid ticks is related to cuticle thickness, not cuticle stiffness. Relative to argasid ticks, the hard ixodid ticks accommodate a ca. 20-fold higher size of blood meal by starting with a thicker cuticle and growing much additional cuticle during engorgement.


Assuntos
Argasidae , Ixodes , Ixodidae , Ornithodoros , Amblyomma , Animais , Feminino
8.
Clin Med (Lond) ; 20(3): e40-e45, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32414740

RESUMO

INTRODUCTION: The clinical efficacy and cost-effectiveness of mechanical thrombectomy (MT) for the treatment of large vessel occlusion stroke is well established, but uncertainty remains around the true cost of delivering this treatment within the NHS. The aim of this study was to establish the cost of providing MT within the hyperacute phase of care and to explore differences in resources used and costs across different neuroscience centres in the UK. METHOD: This was a multicentre retrospective study using micro-costing methods to enable a precise assessment of the costs of MT from an NHS perspective. Data on resources used and their costs were collected from five UK neuroscience centres between 2015 and 2018. RESULTS: Data were collected on 310 patients with acute ischaemic stroke treated with MT. The mean total cost of providing MT and inpatient care within 24 hours was £10,846 (95% confidence interval (CI) 10,527-11,165) per patient. The main driver of cost was MT procedure costs, accounting for 73% (£7,943; 95% CI 7,649-8,237) of the total 24-hour cost. Costs were higher for patients treated under general anaesthesia (£11,048; standard deviation (SD) 2,654) than for local anaesthesia (£9,978; SD 2,654), mean difference £1,070 (95% CI 381-1,759; p=0.003); admission to an intensive care unit (ICU; £12,212; SD 3,028) against for admission elsewhere (£10,179; SD 2,415), mean difference £2,032 (95% CI 1,345-2,719; p<0001).The mean cost within 72 hours was £12,440 (95% CI 10,628-14,252). The total costs for the duration of inpatient care before discharge from a thrombectomy centre was £14,362 (95% CI 13,603-15,122). CONCLUSIONS: Major factors contributing to costs of MT for stroke include consumables and staff for intervention, use of general anaesthesia and ICU admissions. These findings can inform the reimbursement, provision and strategic planning of stroke services and aid future economic evaluations.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Isquemia Encefálica/cirurgia , Humanos , Estudos Retrospectivos , Medicina Estatal , Acidente Vascular Cerebral/terapia , Trombectomia , Reino Unido
10.
J Pharmacol Exp Ther ; 372(2): 205-215, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31748404

RESUMO

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the µ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at µ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.


Assuntos
Buprenorfina/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos Opioides/metabolismo , Animais , Técnicas de Observação do Comportamento , Pressão Sanguínea/efeitos dos fármacos , Buprenorfina/efeitos adversos , Buprenorfina/farmacocinética , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Interações Alimento-Droga , Frequência Cardíaca/efeitos dos fármacos , Heroína/metabolismo , Humanos , Macaca mulatta , Masculino , Morfina/metabolismo , Naltrexona/efeitos adversos , Naltrexona/farmacocinética , Canais de Potássio/metabolismo , Receptores Opioides mu/metabolismo , Remifentanil/farmacologia , Prevenção Secundária , Autoadministração , Resultado do Tratamento
11.
J Am Chem Soc ; 141(41): 16450-16460, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31538776

RESUMO

The recent report of RBS-Seq to map simultaneously the epitranscriptomic modifications N1-methyladenosine, 5-methylcytosine, and pseudouridine (Ψ) via bisulfite treatment of RNA provides a key advance to locate these important modifications. The locations of Ψ were found by a deletion signature generated during cDNA synthesis after bisulfite treatment for which the chemical details of the reaction are poorly understood. In the present work, the bisulfite reaction with Ψ was explored to identify six isomers of bisulfite adducted to Ψ. We found four of these adducts involved the heterocyclic ring, similar to the reaction with other pyrimidines. The remaining two adducts were bonded to the 1' carbon, which resulted in opening of the ribose ring. The utilization of complementary 1D- and 2D-NMR, Raman, and electronic circular dichroism spectroscopies led to the assignment of the two ribose adducts being the constitutional isomers of an S- and an O-adduct of bisulfite to the ribose, and these are the final products after heating. A mechanistic proposal is provided to rationalize chemically the formation and stereochemistries of all six isomeric bisulfite adducts to Ψ; conversion of intermediate adducts to the two final products is proposed to involve E2, SN2', and [2,3]-sigmatropic shift reactions. Lastly, a synthetic RNA template with Ψ at a known location was treated with bisulfite, leading to a deletion signature after reverse transcription, supporting the RBS-Seq report. This classical bisulfite reaction used for epigenomic and epitranscriptomic sequencing diverges from the C nucleoside Ψ to form stable bisulfite end products that yield signatures for next-generation sequencing.


Assuntos
Pseudouridina/química , RNA/química , Sulfitos/química , Conformação de Ácido Nucleico
13.
Cerebrovasc Dis ; 47(5-6): 231-237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212294

RESUMO

BACKGROUND: Mechanical thrombectomy has revolutionised the treatment of acute ischaemic stroke due to large vessel occlusion. It is well recognised that patients are more likely to benefit when reperfusion happens quickly, however, there is uncertainty as to how best to deliver this service. OBJECTIVES: To compare outcomes of patients in Northern -Ireland who underwent thrombectomy via direct admission to the single endovascular centre (mothership [MS]) with those transferred from primary stroke centres (drip-and-ship [DS]). METHODS: Analysis was conducted on the records of all patients who underwent thrombectomy from January 2014 to December 2017 inclusive. The primary outcome measure was 3 months functional independence (modified Rankin Score [mRS] 0-2). Secondary outcome measures were full recovery (mRS 0) at 3 months, symptomatic intracranial haemorrhage (sICH) rates and mortality rates. RESULTS: Two hundred fourteen patients underwent thrombectomy (MS 124, DS 90). Patients in the MS group were older (median 73 vs. 70 years, p = 0.026), but there was no significant difference in baseline National Institutes of Health Stroke Scale (median 15 MS vs. 16.5 DS, p = 0.162) or thrombolysis rates (41.9% MS vs. 54.4% DS, p = 0.070) between the groups. Time from stroke onset to arrival at thrombectomy centre was shorter in the MS group (median 71 vs. 218 min, p < 0.001) but door to groin puncture time was shorter in the DS group (median 30 vs. 60 min, p < 0.001). There was no significant difference in 3 months functional independence (51.6% MS vs. 62.2% DS, p = 0.123), or in the secondary outcome measures of full recovery (21.8% MS vs. 12.2% DS, p = 0.071), sICH (MS 0.8%, DS 4.4%, p = 0.082) and mortality (MS 24.2%, DS 20.0%, p = 0.468). CONCLUSIONS: Our analysis showed similar outcomes after thrombectomy in the MS and DS groups. For patients potentially eligible for thrombectomy, rapid access to the endovascular centre is essential to optimise both the number of patients treated and the outcomes achieved.


Assuntos
Isquemia Encefálica/terapia , Procedimentos Endovasculares , Admissão do Paciente , Transferência de Pacientes , Acidente Vascular Cerebral/terapia , Trombectomia , Terapia Trombolítica , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/mortalidade , Isquemia Encefálica/fisiopatologia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Irlanda do Norte , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Trombectomia/efeitos adversos , Trombectomia/mortalidade , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/mortalidade , Fatores de Tempo , Resultado do Tratamento
14.
Front Microbiol ; 10: 1139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191479

RESUMO

Endogenous viral elements (EVEs) can play a significant role in the evolution of their hosts and have been identified in animals, plants, and fungi. Additionally, EVEs potentially provide an important snapshot of the evolutionary frequency of viral infection. The purpose of this study is to take a comparative host-centered approach to EVE discovery in ant genomes to better understand the relationship of EVEs to their ant hosts. Using a comprehensive bioinformatic pipeline, we screened all nineteen published ant genomes for EVEs. Once the EVEs were identified, we assessed their phylogenetic relationships to other closely related exogenous viruses. A diverse group of EVEs were discovered in all screened ant host genomes and in many cases are similar to previously identified exogenous viruses. EVEs similar to ssRNA viral proteins are the most common viral lineage throughout the ant hosts, which is potentially due to more chronic infection or more effective endogenization of certain ssRNA viruses in ants. In addition, both EVEs similar to viral glycoproteins and retrovirus-derived proteins are also abundant throughout ant genomes, suggesting their tendency to endogenize. Several of these newly discovered EVEs are found to be potentially functional within the genome. The discovery and analysis of EVEs is essential in beginning to understand viral-ant interactions over evolutionary time.

15.
Vaccine ; 37(1): 80-89, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478007

RESUMO

Current acellular-pertussis (aP) vaccines appear inadequate for long-term pertussis control because of short-lived efficacy and the increasing prevalence of pertactin-negative isolates which may negatively impact vaccine efficacy. In this study, we added fimbriae (FIM)2 and FIM3 protein to licensed 2-, 3- or 5-component aP vaccines (Pentavac®, Boostrix®, Adacel®, respectively) to assess whether an aP vaccine with enhanced FIM content demonstrates enhanced efficacy. Vaccine-induced protection was assessed in an intranasal mouse challenge model. In addition, potential reactogenicity was measured by biomarkers in a human whole blood assay (WBA) in vitro and benchmarked the responses against licensed whole cell pertussis (wP) and aP vaccines including Easyfive®, Pentavac® and Pentacel®. The results show that commercial vaccines demonstrated reduced efficacy against pertactin-negative versus pertactin-positive strains. However, addition of higher amounts of FIM2/3 to aP vaccines reduced lung colonization and increased vaccine efficacy against a pertactin-negative strain in a dose-dependent manner. Improvements in efficacy were similar for FIM2 and FIM3-expressing strains. Increasing the amount of FIM2/3 proteins in aP formulations did not alter vaccine-induced biomarkers of potential reactogenicity including prostaglandin E2, cytokines and chemokines in human newborn cord and adult peripheral blood tested in vitro. These results suggest that increasing the quantity of FIM proteins in current pertussis vaccine formulations may further enhance vaccine efficacy against B. pertussis infection without increasing the reactogenicity of the vaccine.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Fímbrias/imunologia , Vacina contra Coqueluche/imunologia , Fatores de Virulência de Bordetella/imunologia , Coqueluche/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/imunologia , Biomarcadores/sangue , Bordetella pertussis , Quimiocinas/imunologia , Citocinas/imunologia , Dinoprostona/imunologia , Feminino , Proteínas de Fímbrias/genética , Humanos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Acelulares/imunologia , Fatores de Virulência de Bordetella/genética , Coqueluche/imunologia
16.
Ann Thorac Surg ; 107(5): 1507-1514, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30579847

RESUMO

BACKGROUND: To investigate the risk and predictors of reintervention (surgery or radiotherapy) after limited resection for lung cancer. METHODS: A population-based, all-inclusive study using linked data from the New South Wales Admitted Patient Data Collection and Death Register included all patients undergoing limited resection for lung cancer between July 1, 2002, and March 31, 2014. Univariate and adjusted competing risk analyses were used to estimate the effect of potential factors for risk of reintervention within 6 months and 24 months of the initial surgery. RESULTS: The overall 5-year survival for lung cancer patients undergoing limited lung resection was 52% (49% to 54%); for patients aged 70 years or more, the survival rate was 44% (40% to 47%). Reintervention occurred in 6.2% by 6 months and 11.3% by 24 months after the surgery. Younger age, surgery in private hospitals, and fewer comorbidities were independently associated with increased risk of reintervention. Patients who had the surgery performed in high surgical volume hospitals had 49% lower risk of reintervention within the first 6 months (95% confidence interval: 0.30 to 0.85). The effect of hospital surgical volume was attenuated by 24 months (hazard ratio 0.87, 95% confidence interval: 0.60 to 1.28). Patients undergoing reintervention within 6 months or 24 months had a twofold (1.52 to 2.57) and 2.3-fold (1.89 to 2.83) increased risk of death, respectively. CONCLUSIONS: The reintervention rate within 6 or 24 months of initial limited lung cancer resection was modest, but there was considerable variation among hospitals. Reintervention was not a benign event and was associated with lower survival in an Australian population.


Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , New South Wales , Reoperação , Retratamento , Estudos Retrospectivos , Taxa de Sobrevida
17.
Front Immunol ; 9: 2634, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524426

RESUMO

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naïve and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates.


Assuntos
Envelhecimento/imunologia , Vacina BCG/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/imunologia , Vacinas contra Hepatite B/imunologia , Monócitos/imunologia , Adjuvantes Imunológicos , Adulto , Feminino , Humanos , Imunização , Memória Imunológica , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Tecidos
18.
Exp Appl Acarol ; 76(3): 365-380, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30306503

RESUMO

The mechanical properties of the cuticle of Ixodes pacificus (Ip) are compared to those of Amblyomma hebraeum (Ah) from our earlier work. The 10-fold size difference between the species is expected to lead to significant differences in mechanical properties, because cuticular stretch depends on high internal hydrostatic pressure during the rapid phase of engorgement. We demonstrate here: (1) The cuticle of partially fed Ip is less stiff and viscous than that of Ah. (2) A stretch-recoil cycle in both ticks consists of recoverable deformation (ESv) and permanent deformation (ESp); ESp is higher in Ip, and increases sharply during the slow phase of engorgement, but not in Ah. (3) Injected dopamine (DA) increases ESp and reduces all measures of stiffness and viscosity, suggesting that a catecholaminergic neurotransmitter plays a fundamental role in modulating mechanical properties of the cuticle. However, unlike Ah, DA's effect was not different from that of the control (1.2% NaCl). Mere insertion of the needle may have punctured the gut, causing the release of perhaps a catecholamine that increases ESp, an hypothesis supported by the fact that inserting a needle without any injection also caused an increase in ESp. (4) Stretch reduces ESp, but subjecting loops to pH 6.5 in vitro restores it. (5) Despite the smaller size of Ip, later onset of the rapid phase of engorgement, a thinner cuticle and different mechanical properties all reduce the internal pressure needed for stretch.


Assuntos
Exoesqueleto/fisiologia , Ixodes/fisiologia , Exoesqueleto/crescimento & desenvolvimento , Animais , Fenômenos Biomecânicos , Tamanho Corporal , Comportamento Alimentar , Feminino , Ixodes/crescimento & desenvolvimento , Ixodidae/crescimento & desenvolvimento , Ixodidae/fisiologia
19.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29875243

RESUMO

A diverse range of DNA sequences derived from circoviruses (family Circoviridae) has been identified in samples obtained from humans and domestic animals, often in association with pathological conditions. In the majority of cases, however, little is known about the natural biology of the viruses from which these sequences are derived. Endogenous circoviral elements (CVe) are DNA sequences derived from circoviruses that occur in animal genomes and provide a useful source of information about circovirus-host relationships. In this study, we screened genome assemblies of 675 animal species and identified numerous circovirus-related sequences, including the first examples of CVe derived from cycloviruses. We confirmed the presence of these CVe in the germ line of the elongate twig ant (Pseudomyrmex gracilis), thereby establishing that cycloviruses infect insects. We examined the evolutionary relationships between CVe and contemporary circoviruses, showing that CVe from ants and mites group relatively closely with cycloviruses in phylogenies. Furthermore, the relatively random interspersion of CVe from insect genomes with cyclovirus sequences recovered from vertebrate samples suggested that contamination might be an important consideration in studies reporting these viruses. Our study demonstrates how endogenous viral sequences can inform metagenomics-based virus discovery. In addition, it raises doubts about the role of cycloviruses as pathogens of humans and other vertebrates.IMPORTANCE Advances in DNA sequencing have dramatically increased the rate at which new viruses are being identified. However, the host species associations of most virus sequences identified in metagenomic samples are difficult to determine. Our analysis indicates that viruses proposed to infect vertebrates (in some cases being linked to human disease) may in fact be restricted to arthropod hosts. The detection of these sequences in vertebrate samples may reflect their widespread presence in the environment as viruses of parasitic arthropods.


Assuntos
Circovirus/genética , Genoma , Especificidade de Hospedeiro , Animais , Circovirus/fisiologia
20.
BMJ Support Palliat Care ; 8(3): 335-339, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29914968

RESUMO

OBJECTIVE: To evaluate the outcomes of tracheobronchial stenting in patients with malignant central airway obstruction and assist practitioners in palliative settings in understanding the indications, contraindications and management of tracheobronchial stents. METHODS: This retrospective study involved a consecutive case series of palliative patients with central airway obstruction secondary to inoperable cancers who underwent tracheobronchial stenting at a single institution. The European Cooperative Oncology Group (ECOG) scale was used to evaluate patient functional status before and after tracheobronchial stenting. RESULTS: Twenty-three patients underwent tracheobronchial stenting for malignant central airway obstruction. The majority of patients presented with symptoms of worsening dyspnoea (21 of 23; 91%). Postoperatively, there was a significant improvement in mean ECOG performance status from 2.88±0.34 to 1.58±0.50 (p<0.01). There was no intraoperative mortality resulting from tracheobronchial stenting. Five patients (21.74%) re-presented to hospital due to worsening symptoms and required emergency bronchoscopy. Two patients had stent migration, requiring stent replacement. One patient restenosed from tumour granulation, requiring microdebrider to debulk the mass. Two patients had stent failure secondary to external tumour compression, leading to death. CONCLUSION: Tracheobronchial stenting is a safe and effective procedure that offers rapid palliation of symptoms and improvement in patient functional status.


Assuntos
Obstrução das Vias Respiratórias/cirurgia , Broncoscopia/métodos , Cuidados Paliativos/métodos , Stents , Traqueotomia/métodos , Idoso , Obstrução das Vias Respiratórias/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias do Sistema Respiratório/complicações , Neoplasias do Sistema Respiratório/terapia , Estudos Retrospectivos , Traqueia/cirurgia , Resultado do Tratamento
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