ABSTRACT
The fungal infection causing white-nose disease in hibernating bats in North America has resulted in dramatic population declines of affected species, since the introduction of the causative agent Pseudogymnoascus destructans. The fungus is native to the Palearctic, where it also infects several bat species, yet rarely causes severe pathology or the death of the host. Pseudogymnoascus destructans infects bats during hibernation by invading and digesting the skin tissue, resulting in the disruption of torpor patterns and consequent emaciation. Relations among pathogen, host, and environment are complex, and individuals, populations, and species respond to the fungal pathogen in different ways. For example, the Nearctic Myotis lucifugus responds to infection by mounting a robust immune response, leading to immunopathology often contributing to mortality. In contrast, the Palearctic M. myotis shows no significant immunological response to infection. This lack of a strong response, resulting from the long coevolution between the hosts and the pathogen in the pathogen's native range, likely contributes to survival in tolerant species. After more than 15 years since the initial introduction of the fungus to North America, some of the affected populations are showing signs of recovery, suggesting that the fungus, hosts, or both are undergoing processes that may eventually lead to coexistence. The suggested or implemented management methods of the disease in North America have encompassed, for example, the use of probiotics and fungicides, vaccinations, and modifying the environmental conditions of the hibernation sites to limit the growth of the pathogen, intensity of infection, or the hosts' responses to it. Based on current knowledge from Eurasia, policy makers and conservation managers should refrain from disrupting the ongoing evolutionary processes and adopt a holistic approach to managing the epizootic.
Vista paleártica de una enfermedad fúngica de murciélagos Resumen La enfermedad fúngica que produce el síndrome de nariz blanca en murciélagos en hibernación en Norte América ha resultado en declinaciones poblacionales dramáticas en las especies afectadas desde la introducción del agente causante, Pseudogymnoascus destructans. El hongo es nativo del Paleártico, donde también infecta a varias especies de murciélagos; sin embargo, raramente causa patología severa o la muerte del hospedero. Pseudogymnoascus destructans infecta a los murciélagos durante la hibernación invadiendo y digiriendo el tejido de la piel, lo que resulta en la disrupción de los patrones de torpor y la consecuente emaciación. Las relaciones entre el patógeno, el huésped y el ambiente son complejas, y los individuos, las especies y poblaciones responden al patógeno fúngico de distintas maneras. Por ejemplo, Myotis lucifugus, especie del Neártico, responde a la infección montando una respuesta inmune robusta, produciendo una inmunopatología que a menudo contribuye a la mortalidad. En contraste, M. myotis del Paleártico no presenta respuesta inmunológica significativa a la infección. La falta de una fuerte respuesta, resultado de la larga coevolución entre hospederos y el patógeno en el rango nativo de distribución del patógeno, probablemente contribuye a la supervivencia en especies tolerantes. Después de más de 15 años desde la introducción del hongo en Norte América, algunas de las poblaciones afectadas están mostrando señales recuperación, lo que sugiere que el hongo, hospederos, o ambos, están pasando por procesos que eventualmente pueden conducir a la coexistencia. Los métodos de manejo de la enfermedad sugeridos o implementados en Norte América han abarcado, por ejemplo, el uso de probióticos y fungicidas, vacunaciones y modificación de las condiciones ambientales de los sitios de hibernación para limitar el crecimiento del patógeno, la intensidad de la infección o las respuestas de los hospederos. Con base en conocimiento actual de Eurasia, los formuladores de políticas y los manejadores de la conservación deberían abstenerse de alterar los procesos evolutivos en curso y adoptar un enfoque holístico para gestionar la epizootia.
ABSTRACT
Arbuscular mycorrhizal (AM) fungi associate with the roots of many plant species, enhancing their hosts access to soil nutrients whilst obtaining their carbon supply directly as photosynthates. AM fungi often face competition for plant carbon from other organisms. The mechanisms by which plants prioritise carbon allocation to mutualistic AM fungi over parasitic symbionts remain poorly understood. Here, we show that host potato plants (Solanum tuberosum cv. Désirée) selectively allocate carbon resources to tissues interacting with AM fungi rather than those interacting with phytophagous parasites (the nematode Globodera pallida). We found that plants reduce the supply of hexoses but maintain the flow of plant-derived fatty acids to AM fungi when concurrently interacting with parasites. Transcriptomic analysis suggest that plants prioritise carbon transfer to AM fungi by maintaining expression of fatty acid biosynthesis and transportation pathways, whilst decreasing the expression of mycorrhizal-induced hexose transporters. We also report similar findings from a different plant host species (Medicago truncatula) and phytophagous pest (the aphid Myzus persicae). These findings suggest a general mechanism of plant-driven resource allocation in scenarios involving multiple symbionts.
Subject(s)
Mycorrhizae , Mycorrhizae/metabolism , Carbon/metabolism , Symbiosis , Fungi/metabolism , Plant Roots/metabolism , Plants/metabolismABSTRACT
Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.
Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Bevacizumab/therapeutic use , Brain Neoplasms/complications , Brain Neoplasms/diagnosis , Brain Neoplasms/drug therapy , Carboplatin , Disease Progression , Glioblastoma/diagnosis , Glioblastoma/drug therapy , HumansABSTRACT
AIMS: To compare decay profiles of ruminant- and cattle-associated molecular markers for faecal contamination and Escherichia coli, facilitating their correct application in water quality studies. METHODS AND RESULTS: We generated decay profiles for cultivable E. coli, a general Bacteroidales genetic marker (GenBac3), ruminant markers (CF128, Rum2Bac) and cattle markers (CowM2, CowM3) using faeces-seeded mesocosms, and selected best fitting models for each decay profile. Global model fitting tested for differences between decay profiles. After normalizing for initial concentration, decay curves differed significantly between E. coli and all genetic markers except CowM3. Decay curves for CF128 differed from GenBac3 and Rum2Bac, but Rum2Bac and GenBac3 decay profiles did not differ. Despite similar survival profiles for some markers, highly varied initial concentrations affected time to nondetection. CONCLUSIONS: Decay curves and time until nondetection differed among markers from the same host. However, the Rum2Bac and GenBac3 markers had similar decay profiles and could potentially be investigated further for source allocation using the ratio method. SIGNIFICANCE AND IMPACT OF THE STUDY: As the use of genetic markers for microbial source tracking becomes increasingly common, caution is necessary. Both the shape of decay curves and time to nondetect may differ depending on the marker selected, resulting in possible misinterpretation of results and precluding application of a 'ratio method' of source allocation.
Subject(s)
Environmental Monitoring/methods , Fresh Water/chemistry , Water Quality , Animals , Bacteria/genetics , Bacteroidetes/genetics , Cattle , Escherichia coli/genetics , Feces/microbiology , Fresh Water/microbiology , Genetic Markers , Models, Theoretical , Polymerase Chain Reaction/methods , Quality Control , Ruminants , Water MicrobiologyABSTRACT
White-nose syndrome (WNS) is a fungal disease responsible for decimating many bat populations in North America. Pseudogymnoascus destructans (Pd), the psychrophilic fungus responsible for WNS, prospers in the winter habitat of many hibernating bat species. The immune response that Pd elicits in bats is not yet fully understood; antibodies are produced in response to infection by Pd, but they may not be protective and indeed may be harmful. To understand how bats respond to infection during hibernation, we studied the effect of Pd inoculation on the survival and gene expression of captive hibernating Myotis lucifugus with varying pre-hibernation antifungal antibody titres. We investigated gene expression through the transcription of selected cytokine genes (Il6, Il17a, Il1b, Il4 and Ifng) associated with inflammatory, Th1, Th2 and Th17 immune responses in wing tissue and lymph nodes. We found no difference in survival between bats with low and high anti-Pd titres, although anti-Pd antibody production during hibernation differed significantly between infected and uninfected bats. Transcription of Il6 and Il17a was higher in the lymph nodes of infected bats compared with uninfected bats. Increased transcription of these cytokines in the lymph node suggests that a pro-inflammatory immune response to WNS is not restricted to infected tissues and occurs during hibernation. The resulting Th17 response may be protective in euthermic bats, but because it may disrupt torpor, it could be detrimental during hibernation.
Subject(s)
Chiroptera/immunology , Hibernation/immunology , Mycoses/veterinary , Animals , Ascomycota , Chiroptera/microbiology , Cytokines/immunology , Mycoses/immunology , North America , Th17 Cells/immunologyABSTRACT
This manuscript describes the systematic development of pyridine-type ligands, which promote the Pd catalyzed, non-directed amination of benzene in combination with novel, hydroxylamine-based electrophilic amination reagents. DFT calculations and mechanistic experiments provide insights into the factors influencing the arene C-H amination protocol.
ABSTRACT
BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. METHODS: Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. RESULTS: We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). CONCLUSIONS: Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , Early Detection of Cancer/mortality , Aged , Australia/epidemiology , Early Detection of Cancer/methods , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Survival Rate/trendsABSTRACT
Following the widely publicized presentation of the Radiation Therapy Oncology Group (RTOG) 9802 data, we sought to understand how these data had been translated to the management of low grade gliomas (LGG) by Australian neuro-oncology clinicians. The de novo management of LGG is transitioning to include postoperative radiotherapy and chemotherapy after the RTOG 9802 study results demonstrated a survival benefit in this setting. In 2014, neurosurgeons, radiation oncologists and neuro-oncologists who were members of the Australian Cooperative Trials Group for Neuro-oncology (COGNO), as well as additional attendants of the COGNO annual scientific meeting, were surveyed. The survey presented six LGG clinical scenarios and asked respondents to select their preferred management strategy. Some additional questions included the respondents' approach to 1p/19q testing and chemotherapy preferences. The response rate was 30.2% (61/202), with the majority (77%) working in tertiary referral neuro-oncology centers. There was no consensus regarding the management approach for each scenario, with postsurgery observation alone remaining a popular strategy. Only 25% of respondents reported that their institution routinely tests for 1p/19q status in LGG, although 69% were of the opinion that all LGG patients should be tested. The majority (81%) preferred to use temozolomide rather than the procarbazine, lomustine, and vincristine combination as the first line chemotherapy for LGG, but only 44% would actually use it in this setting. Up front chemotherapy, prior to radiotherapy, would be considered by 52% of respondents for certain LGG patients. This survey assessed the management strategies for LGG since the updated RTOG 9802 data were presented. It demonstrates no consensus in the postoperative treatment approaches for LGG.
Subject(s)
Brain Neoplasms/therapy , Consensus , Disease Management , Glioma/therapy , Physicians/trends , Adult , Australia/epidemiology , Brain Neoplasms/diagnosis , Brain Neoplasms/epidemiology , Cohort Studies , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Female , Glioma/diagnosis , Glioma/epidemiology , Humans , Male , Middle Aged , Neoplasm Grading/trends , Surveys and Questionnaires , TemozolomideABSTRACT
PURPOSE OF INVESTIGATION: Embolisation of the internal iliac artery has been described as an effective and safe method of treating massive vaginal haemorrhage in small series of advanced uterine cancer and case reports of cervical cancer. Selective embolization of the bleeding vessel is potentially less morbid. The aim of this study was to assess the efficacy of selective arterial embolisation (SAE) in controlling intractable haemorrhage due to gynaecological malignancy. MATERIALS AND METHODS: This retrospective observational study comes from in a tertiary cancer center with 300 new gynecologic cancers per annum. The authors reviewed all gynecology cancer patients who had intractable major vaginal haemorrhage in the first five years following the introduction of selective arterial embolisation at their unit. The outcomes measured were the control of acute haemorrhage and discharge to planned pathway of treatment. RESULTS: SAE was successful in all cases. Identification of the bleeding point facilitated highly selective embolisation in more than half of the patients. The uterine arteries were embolised in the remaining cases. Bleeding stopped immediately. The expedient control of haemorrhage facilitated early discharge to commencement/continuation of radiation treatment or palliative care as appropriate. CONCLUSIONS: Since the introduction of SAE the authors have avoided emergency radiotherapy, surgery, and repeat vaginal packing in patients with intractable vaginal bleeding due to gynaecological cancer. Patients were discharged to their appropriate treatment pathways in a timely manner. The authors recommend the application of SAE.
Subject(s)
Embolization, Therapeutic , Genital Neoplasms, Female/complications , Uterine Hemorrhage/therapy , Adult , Aged , Female , Humans , Middle Aged , Retrospective Studies , Uterine ArteryABSTRACT
STUDY QUESTION: Is a history of three or more miscarriages associated with adverse perinatal outcomes in a subsequent pregnancy? SUMMARY ANSWER: Recurrent miscarriage is associated with an increased risk of adverse perinatal outcomes, including preterm birth, very preterm birth and perinatal death, in a subsequent pregnancy. WHAT IS KNOWN ALREADY: Published data are conflicting with some studies reporting an increase in adverse perinatal outcomes in association with prior recurrent miscarriage while others report little or no increase. Large-scale population-based studies have been lacking. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of 30 053 women with a singleton pregnancy who booked for antenatal care and delivery between January 2008 and July 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women who attended a university affiliated hospital in Ireland had a detailed obstetric history taken, recording the outcome of all previous pregnancies. We compared the obstetric and perinatal outcomes of 2030 women (6.8%) who had a history of three or more miscarriages (recurrent miscarriage) with the outcomes of 28 023 women (93.2%) who did not. Logistic regression analyses were performed, adjusting for potential confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: Women with a history of recurrent miscarriage were more likely to be obese, to have undergone assisted conception, to have had a previous perinatal death, and to be delivered by scheduled Caesarean section. Recurrent miscarriage was associated with an increased incidence of preterm birth (<37 weeks gestation, 8.1 versus 5.5%, adjOR 1.54; 95% CI 1.29-1.84), very preterm birth (<32 weeks gestation, 2.2 versus 1.2%, adjOR 1.80; 95% CI 1.28-2.53), and perinatal death (1.2 versus 0.5%, adjOR 2.66; 95% CI 1.70-4.14). The results were similar for both primary and secondary recurrent miscarriage. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, they were only confirmed to be consecutive in the primary RM group. The affected women have not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes differ according to aetiological subgroup. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, particularly in relation to the risk of preterm delivery. STUDY FUNDING/COMPETING INTERESTS: There was no specific funding obtained for this study and there are no conflict of interests.
Subject(s)
Abortion, Habitual/epidemiology , Pregnancy Outcome , Adolescent , Adult , Cesarean Section/adverse effects , Delivery, Obstetric , Female , Humans , Infant, Newborn , Ireland , Perinatal Death , Pregnancy , Premature Birth , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia. AIMS: To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres. METHODS: Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009. RESULTS: Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0-1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates. CONCLUSIONS: Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.
Subject(s)
Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Private Practice/standards , Universal Health Insurance/standards , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Australia/epidemiology , Colorectal Neoplasms/economics , Female , Humans , Male , Middle Aged , Private Practice/economics , Prospective Studies , Registries , Survival Rate/trends , Treatment Outcome , Universal Health Insurance/economics , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Histologic grading of intracranial astrocytomas is affected by sampling error and substantial inter- and intraobserver variability. We proposed that incorporating MR imaging into grading will predict patient survival more accurately than histopathology alone. MATERIALS AND METHODS: Patients with a new diagnosis of World Health Organization grades II-IV astrocytoma or mixed oligoastrocytoma diagnosed between September 2007 and December 2010 were identified. Two hundred forty-five patients met the inclusion criteria. Preoperative MRIs were independently reviewed by 2 readers blinded to the histologic grade, and an MR imaging grade was given. The MR imaging and histopathologic grades were compared with patient survival. RESULTS: Patients with grade II or III astrocytomas on histology but evidence of necrosis on MR imaging (consistent with a grade IV tumor) had significantly worse survival than patients with the same histology but no evidence of necrosis on MR imaging (P = .002 for grade II histology and P = .029 for grade III). Their survival was not significantly different from that in patients with grade IV tumors on histology (P = .164 and P = .385, respectively); this outcome suggests that all or most are likely to have truly been grade IV tumors. MR imaging evidence of necrosis was less frequent in grade II and III oligoastrocytomas, preventing adequate subgroup analysis. CONCLUSIONS: MR imaging can improve grading of intracranial astrocytomas by identifying patients suspected of being undergraded by histology, with high interobserver agreement. This finding has the potential to optimize patient management, for example, by encouraging more aggressive treatment earlier in the patient's course.
Subject(s)
Astrocytoma/pathology , Brain Neoplasms/pathology , Neoplasm Grading/methods , Neuroimaging/methods , Adult , Aged , Astrocytoma/mortality , Brain Neoplasms/mortality , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Observer Variation , World Health OrganizationABSTRACT
BACKGROUND: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. AIMS: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. METHODS: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. RESULTS: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. CONCLUSIONS: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.
Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/therapy , Databases, Factual/trends , Adult , Aged , Aged, 80 and over , Australia/epidemiology , Colorectal Neoplasms/diagnosis , Disease Management , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. Having a second or subsequent operation at recurrence may be a positive prognostic factor for survival. Recent studies suggest that socio-demographic variables may influence survival, raising the question whether surgical care differs based on these variables. We examined the relationship between selected socio-demographic variables and the number of repeat operations undergone by patients with recurrent GBM. Data from all patients diagnosed with GBM between 2001 and 2011 was obtained from a clinical database maintained across two institutions (one public, one private). The clinical and socio-demographic factors for patients who received one operation were compared to those who had two or more operations, using chi-squared analyses to determine statistical differences between groups. Socioeconomic status was measured using the Index of Relative Socioeconomic Advantage and Disadvantage scores. Of 553 patients, 449 (81%) had one operation and 104 (19%) had ≥2 operations. Patients who had ≥2 operations were significantly younger (median 55 years versus 64 years, p<0.001), less likely to have multifocal (p=0.043) or bilateral (p=0.037) disease and more likely to have initial macroscopic resection (p=0.006), than those who had only one operation. Socioeconomic status did not significantly differ between the groups (p=0.31). Similarly, there was no significant difference between the number of operations in patients from regional versus city residence and public versus private hospital. This is reassuring as it suggests similar surgical management options are available for patients regardless of socio-demographic background.
Subject(s)
Brain Neoplasms/surgery , Glioblastoma/surgery , Neoplasm Recurrence, Local/surgery , Neurosurgical Procedures/methods , Aged , Australia , Brain Neoplasms/epidemiology , Demography , Female , Glioblastoma/epidemiology , Humans , Longitudinal Studies , Male , Middle Aged , Prognosis , Statistics, NonparametricABSTRACT
Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.
Subject(s)
Bronchiolitis Obliterans/chemically induced , Cyclosporine/toxicity , Graft Rejection/chemically induced , Interleukin-17/physiology , Lung Transplantation/adverse effects , Th2 Cells/immunology , Trachea/transplantation , Animals , Blotting, Western , Bronchiolitis Obliterans/immunology , Bronchiolitis Obliterans/pathology , Cytokines/metabolism , Flow Cytometry , Graft Rejection/immunology , Graft Rejection/pathology , Immunoenzyme Techniques , Immunosuppressive Agents/toxicity , Interferon-gamma/physiology , Interleukin-4/physiology , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Trachea/drug effects , Trachea/immunology , Transplantation, Heterotopic , Transplantation, HomologousABSTRACT
Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS(+) Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade.
Subject(s)
Graft Rejection/immunology , Histocompatibility Antigens Class II/immunology , Immunoconjugates/administration & dosage , Interleukin-2/administration & dosage , T-Lymphocytes, Regulatory/immunology , Abatacept , Animals , CD28 Antigens/metabolism , Histocompatibility Testing , Interleukin-2/pharmacology , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , Signal Transduction , T-Lymphocytes, Regulatory/drug effectsABSTRACT
BACKGROUND/AIM: The complexity and cost of treating cancer patients is escalating rapidly and increasingly difficult decisions are being made regarding which interventions provide value for money. BioGrid Australia supports collection and analysis of comprehensive treatment and outcome data across multiple sites. Here, we use preliminary data regarding the National Bowel Cancer Screening Program (NBCSP) and stage-specific treatment costs for colorectal cancer (CRC) to demonstrate the potential value of real world data for cost-effectiveness analyses (CEA). METHODS: Data regarding the impact of NBCSP on stage at diagnosis were combined with stage-specific CRC treatment costs and existing literature. An incremental CEA was undertaken from a government healthcare perspective, comparing NBCSP with no screening. The 2008 invited population (n= 681,915) was modelled in both scenarios. Effectiveness was expressed as CRC-related life years saved (LYS). Costs and benefits were discounted at 3% per annum. RESULTS: Over the lifetime and relative to no screening, NBCSP was predicted to save 1265 life years, prevent 225 CRC cases and cost an additional $48.3 million, equivalent to a cost-effectiveness ratio of $38,217 per LYS. A scenario analysis assuming full participation improved this to $23,395. CONCLUSIONS: This preliminary CEA based largely on contemporary real world data suggests population-based faecal occult blood test screening for CRC is attractive. Planned ongoing data collection will enable repeated analyses over time, using the same methodology in the same patient populations, permitting an accurate analysis of the impact of new therapies and changing practice. Similar CEA using real world data related to other disease types and interventions appears desirable.
Subject(s)
Colorectal Neoplasms/economics , Colorectal Neoplasms/therapy , Databases, Factual/economics , Early Detection of Cancer/economics , Early Detection of Cancer/methods , Aged , Australia/epidemiology , Colorectal Neoplasms/epidemiology , Cost-Benefit Analysis/economics , Female , Humans , Male , Middle AgedABSTRACT
Multidisciplinary Team (MDT) meetings are critical in the management of complex cancer cases. There are limited data regarding the effectiveness of neuro-oncology MDT meetings and the impact of documenting and disseminating the recommended patient management. We established a weekly neuro-oncology MDT meeting and developed a standard electronic communication process. A survey was issued to participating clinicians to assess their level of satisfaction. The survey revealed that 100% felt the meeting and its documentation was very or extremely important, and 94% (n=15) felt the meeting was effective in documentation and communication of plans. There was a mixed response regarding which patients should be discussed: 44% (n=7) thought all patients should be discussed and 56% (n=9) thought only those patients with complex management issues should be discussed. We have developed an efficient method of documenting and disseminating patient information arising from our neuro-oncology MDT meeting. Clinician satisfaction was high.
Subject(s)
Central Nervous System Neoplasms/therapy , Group Processes , Interprofessional Relations , Job Satisfaction , Medical Oncology/methods , Patient Care Team , Data Collection/methods , Humans , PhysiciansABSTRACT
To demonstrate whether the use of videophone technology is an effective alternative method to direct observation of tuberculosis (TB) medication administration, a retrospective chart review and data analysis were performed on records for 57 patients with active TB in two Washington state counties who utilized videophone technology for the administration of medications from 2002 through 2006. A total of US$139,546 was saved in staff salaries, benefits and travel costs. The average cost savings per patient was US$2448. The use of videophone technology is a cost-effective alternative to in-home directly observed administration of TB medication.
Subject(s)
Antitubercular Agents/administration & dosage , Delivery of Health Care/methods , Observation/methods , Telephone/statistics & numerical data , Tuberculosis/drug therapy , Video Recording/statistics & numerical data , Cost-Benefit Analysis , Humans , Retrospective Studies , Telephone/economics , Telephone/instrumentation , Tuberculosis/economics , Video Recording/economics , Video Recording/instrumentation , WashingtonABSTRACT
BACKGROUND: Varying amounts of data related to cancer diagnosis, treatment and/or outcome are routinely collected by many disparate groups. Routinely combining data from these sources could improve data quality and utility for audit and research purposes. The aim of this study is to demonstrate the benefits of linkage between oncology databases. METHODS: We examined colorectal cancer (CRC) data recorded by the Victorian Cancer Registry and two hospital clinical databases between January 2000 and December 2005. Where data were in common, the completeness and accuracy of each dataset were examined. Where content differed, the potential value of making this additional data available to the other database was examined. RESULTS: Of the 831 cases recorded at the hospitals, 822 (98.9%) were also recorded on the cancer registry. Eight of the 913 cases (0.87%) recorded as having CRC by the registry did not have CRC. Errors in recording of tumour site and tumour or nodal stage were frequent in both databases. Metastasis stage was recorded in only 29 of 822 (3.5%) registry cases examined. Discordance for diagnosis date and death date was also frequent, although the difference was typically minor. Adding additional death data from the registry to the clinical database significantly altered stage-specific and overall survival figures. CONCLUSION: A multidirectional flow of data between hospital and registry databases provides multiple opportunities to improve data quality and utility. While issues around data ownership and usage need to be considered, the advantages of routine data linkage are readily apparent.