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0000-0002-8825-8625
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Alfred Health
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Publisher: Wiley
Date: 27-02-2017
DOI: 10.1111/APT.13992
Abstract: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4-6, visit 2: day 7-9, trough: day 13-14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey-Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1-2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66-80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
Publisher: American Society of Hematology
Date: 09-05-2013
DOI: 10.1182/BLOOD-2012-10-462291
Abstract: Independent predictors of stable, undetectable BCR-ABL1 during first-line imatinib therapy were female sex and the BCR-ABL1 value at 3 months. Time to achieve an MMR influenced time to stable, undetectable BCR-ABL1, suggesting slower dynamics of BCR-ABL1 decline with delayed MMR.
Publisher: Oxford University Press (OUP)
Date: 29-06-2016
DOI: 10.1093/JAMIA/OCW085
Abstract: Objective: Our objective was to compare the change in research informed knowledge of health professionals and their intended practice following exposure to research information delivered by either Twitter or Facebook. Methods: This open label comparative design study randomized health professional clinicians to receive “practice points” on tendinopathy management via Twitter or Facebook. Evaluated outcomes included knowledge change and self-reported changes to clinical practice. Results: Four hundred and ninety-four participants were randomized to 1 of 2 groups and 317 responders analyzed. Both groups demonstrated improvements in knowledge and reported changes to clinical practice. There was no statistical difference between groups for the outcomes of knowledge change (P = .728), changes to clinical practice (P = .11) or the increased use of research information (P = .89). Practice points were shared more by the Twitter group (P & .001) attrition was lower in the Facebook group (P & .001). Conclusion: Research information delivered by either Twitter or Facebook can improve clinician knowledge and promote behavior change. No differences in these outcomes were observed between the Twitter and Facebook groups. Brief social media posts are as effective as longer posts for improving knowledge and promoting behavior change. Twitter may be more useful in publicizing information and Facebook for encouraging course completion.
Publisher: American Society of Hematology
Date: 05-06-2023
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 11-10-2011
Publisher: Elsevier BV
Date: 04-1997
DOI: 10.1016/S0093-691X(97)00054-X
Abstract: Various needle sizes (17- and 20-g) and aspiration pressures (25, 50, 75 and 100 mmHg) were used to aspirate a total of 5,827 ovarian follicles from bovine ovaries from a slaughterhouse source to assess the impact on the quantity and quality of recovered immature oocytes. The cumulus oocyte complexes (COC's) were graded according to the presence and consistency of cumulus cells surrounding the oocyte and the data analyzed using general linear models. Overall recovery rates and the recovery of oocytes considered viable for IVM/IVF procedures (Classes A, B and C) were both significantly higher using a 17-g needle than a 20-g needle (P < 0.01). As the vacuum pressure increased so did the recovery rate of the total number of oocytes, although the number of viable oocytes reached a maximum at a calculated vacuum pressure of 55 mmHg for the 17-g needle and 77 mmHg for the 20-g needle, with an increased incidence of denuded oocytes at higher vacuum pressures. In a second experiment conducted on 1, 473 follicles, no significant difference was found between 17-g double (flushing) and 17-g single lumen needles in the recovery rate of either the total number or number of viable oocytes when using a vacuum pressure of 50 mmHg.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2012
DOI: 10.1038/LEU.2012.305
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/SR9890161
Abstract: The influence of the soil moisture regime on the tolerance of the soil micro-organisms to increased osmotic stress was examined by laboratory tests with a range of New Zealand soils. Soils from various climatic regions (moist, intermediate and dry) were amended with glucose-NaCl solutions, incubated for 0.5 h, and the respiration rate over the following 2 h was used as a measure of the response of the microbial biomass to the changed osmotic potential. Osmotic potentials were varied between -4 and -80 bar by altering the concentration of NaCl. Air-drying the soils at 25�C decreased the respiration response of the microbial biomass by 3-60% but had little effect on the tolerance of the surviving populations to decreased osmotic potentials. In general, the soils showed the same patterns: an osmotic potential of -23 bar decreased the respiration response by 28-45% (18-44% after air-drying) and a -80 bar potential decreased it by 64-86% (52-84% after air-drying). For the majority of soils, a consistent relationship was obtained between the respiration rate of the moist soils and the osmotic potential applied. A reasonable prediction of the respiration response after air-drying could be obtained from the respiration response of moist soils at -25 bar osmotic potential.
Publisher: Public Library of Science (PLoS)
Date: 16-12-2014
Publisher: Public Library of Science (PLoS)
Date: 26-07-2016
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.IJROBP.2009.06.032
Abstract: Positron emission tomography/computed tomography (PET/CT) is increasingly used for delineating gross tumor volume (GTV) in non-small-cell lung cancer (NSCLC). The methodology for contouring tumor margins remains controversial. We developed a rigorous visual protocol for contouring GTV that uses all available clinical information and studied its reproducibility in patients from a prospective PET/CT planning trial. Planning PET/CT scans from 6 consecutive patients were selected. Six "observers" (two radiation oncologists, two nuclear medicine physicians, and two radiologists) contoured GTVs for each patient using a predefined protocol and subsequently recontoured 2 patients. For the estimated GTVs and axial distances, least-squares means for each observer and for each case were calculated and compared, using the F test and pairwise t-tests. In five cases, tumor margins were also autocontoured using standardized uptake value (SUV) cutoffs of 2.5 and 3.5 and 40% SUV(max). The magnitude of variation between observers was small relative to the mean (coefficient of variation [CV] = 3%), and the total variation (intraclass correlation coefficient [ICC] = 3%). For estimation of superior/inferior (SI), left/right (LR), and anterior osterior (AP) borders of the GTV, differences between observers were also small (AP, CV = 2%, ICC = 0.4% LR, CV = 6%, ICC = 2% SI, CV 4%, ICC = 2%). GTVs autocontoured generated using SUV 2.5, 3.5, and 40% SUV(max) differed widely in each case. An SUV contour of 2.5 was most closely correlated with the mean GTV defined by the human observers. Observer variation contributed little to total variation in the GTV and axial distances. A visual contouring protocol gave reproducible results for contouring GTV in NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
Publisher: Springer Science and Business Media LLC
Date: 13-02-2023
Publisher: Wiley
Date: 08-05-2017
DOI: 10.1111/APT.14124
Abstract: Discriminative drug level thresholds for disease activity endpoints in patients with Crohn's disease. have been consistently demonstrated with infliximab, but not adalimumab. To identify threshold concentrations for infliximab and adalimumab in Crohn's disease according to different disease endpoints, and factors that influence drug levels. We performed a cross-sectional service evaluation of patients receiving maintenance infliximab or adalimumab for Crohn's disease. Serum drug levels were at trough for infliximab and at any time point for adalimumab. Endpoints included Harvey-Bradshaw index, C-reactive protein and faecal calprotectin. 6-tioguanine nucleotide (TGN) concentrations were measured in patients treated with thiopurines. A total of 191 patients (96 infliximab, 95 adalimumab) were included. Differences in infliximab levels were observed for clinical (P=.081) and biochemical remission (P=.003) and faecal calprotectin normalisation (P<.0001) with corresponding thresholds identified on ROC analysis of 1.5, 3.4 and 5.7 μg/mL. Adalimumab levels were similar between active disease and remission regardless of the endpoint assessed. Modelling identified that higher infliximab dose, body mass index and colonic disease independently accounted for 31% of the variation in infliximab levels, and weekly dosing, albumin and weight accounted for 23% of variation in adalimumab levels. TGN levels did not correlate with drug levels. Infliximab drug levels are associated with the depth of response/remission in patients with Crohn's disease, but no such relationship was observed for adalimumab. More data are needed to explain the variation in drug levels.
Publisher: JMIR Publications Inc.
Date: 03-04-2019
DOI: 10.2196/12531
Publisher: Springer Science and Business Media LLC
Date: 14-08-2015
DOI: 10.1007/S00420-015-1085-3
Abstract: Physical work and sleep restriction are two stressors faced by firefighters, yet the combined impact these demands have on firefighters' acute stress responses is poorly understood. The purpose of the present study was to assess the effect firefighting work and sleep restriction have on firefighters' acute cortisol and heart rate (HR) responses during a simulated 3-day and 2-night fire-ground deployment. Firefighters completed multiple days of simulated physical work separated by either an 8-h (control condition n = 18) or 4-h sleep opportunity (sleep restriction condition n = 17). Salivary cortisol was s led every 2 h, and HR was measured continuously each day. On day 2 and day 3 of the deployment, the sleep restriction condition exhibited a significantly higher daily area under the curve cortisol level and an elevated cortisol profile in the afternoon and evening when compared with the control condition. Firefighters' HR decreased across the simulation, but there were no significant differences found between conditions. Findings highlight the protective role an 8-h sleep opportunity between shifts of firefighting work has on preserving normal cortisol levels when compared to a 4-h sleep opportunity which resulted in elevated afternoon and evening cortisol. Given the adverse health outcomes associated with chronically high cortisol, especially later in the day, future research should examine how prolonged exposure to firefighting work (including restricted sleep) affects firefighters' cortisol levels long term. Furthermore, monitoring cortisol levels post-deployment will determine the minimum recovery time firefighters need to safely return to the fire-ground.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 05-10-2017
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.JSAMS.2013.11.012
Abstract: The study aim was to assess rater agreement of the Resistance Training Skills Battery (RTSB) for adolescents. The RTSB provides an assessment of resistance training skill competency and includes six exercises. The RTSB can be used to assess performance and progress in adolescent resistance training programmes and to provide associated feedback to participants. In idual skill scores are based on the number of performance criteria successfully demonstrated and an overall resistance training skill quotient (RTSQ) is created by summing the six skill scores. The eight raters had varying experience in movement skill assessment and resistance training and completed a 2-3h training session in how to assess resistance training performance using the RTSB. The raters then completed an assessment on six skills for 12 adolescents (mean age=15.1 years, SD=1.0, six male and six female) in a randomised order. Agreement between seven of the eight raters was high (20 of the 21 pairwise correlations were greater than 0.7 and 13 of the 21 were greater than 0.8). Correlations between the eighth rater and each of the other seven raters were generally lower (0.45-0.78). Most variation in the assigned RTSB scores (67%) was between cases, a relatively small amount of the variation (10%) was between raters and the remainder (23%) was between periods within raters. The between-raters coefficient of variation was approximately 5%. The RTSB can be used reliably by those with experience in movement skill assessment and resistance training to assess the resistance skill of adolescents.
Publisher: Informa UK Limited
Date: 02-09-2023
Publisher: Informa UK Limited
Date: 31-10-2021
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.2165/00002512-200724060-00004
Abstract: To evaluate the efficacy of a flexible low-intensity combination chemotherapy (FLICC) protocol in a multicentre, phase II study of elderly patients with acute myeloid leukaemia (AML). Twenty-five patients aged 61-78 years (median 70 years) with de novo (n = 17) or secondary (n = 8) AML (cytogenetic risk: favourable 2, intermediate 18, adverse 2, unknown 3) from eight Australian centres were enrolled. Treatment comprised mitoxantrone 6 mg/m(2) intravenously daily for 3 days, cytarabine 10mg/m(2) subcutaneously every 12 hours for 7-14 days and etoposide 100mg orally for 7-14 days. The treatment was generally well tolerated, and 13 patients (52%) achieved a complete remission (CR). One patient achieved a partial remission but died on day 28 due to pneumonia. Five patients (20%) had no response, whilst six (24%) died on or before day 30 and so were not evaluable. The median overall survival (OS) was 6.5 months, and the median remission duration was 7.7 months. Estimated 1-year survival was 32%, but patients achieving CR had an estimated 1-year survival of 64%, whereas none in the non-CR group survived to 1 year. Two of the CR patients have survived beyond 2 years. OS was significantly shorter in the adverse cytogenetic risk group of patients compared with the favourable- and intermediate-risk groups, with the rates of death relative to the adverse group being 0.02 and 0.08 in the favourable- and intermediate-risk groups, respectively. There was no significant association between CR rate and pre-existing myelodysplasia or the presence of multilineage dysplasia. The median durations of significant neutropenia (<0.5 x 10(9)/L) and thrombocytopenia (<20 x10(9)/L) with the first course of treatment in the 19 evaluable patients were 19 days (range 12-26) and 11 days (range 1-25), respectively. The median duration of stay in the hospital was 27 days (range 14-42). These values were much shorter for the second course of treatment: 6 days, 5 days and 15 days, respectively. The findings of this multicentre, phase II study validate the previously reported single-institution experience with the FLICC protocol in elderly patients with AML. The clinical outcome with this protocol is comparable to those reported with more aggressive anti-leukaemia protocols.
Publisher: Springer Science and Business Media LLC
Date: 12-1980
DOI: 10.1038/HDY.1980.77
Publisher: Wiley
Date: 15-05-2021
DOI: 10.1111/BJH.17504
Abstract: We evaluated the efficacy and tolerability of continuous ixazomib‐thalidomide‐dexamethasone (ITd: 4 mg, day 1, 8, 15 100 mg daily and 40 mg weekly). A total of 39 patients with relapsed/refractory multiple myeloma (RRMM) aged ≥18 years with one to three prior lines of therapy were enrolled from two tertiary centres in Victoria and South Australia, Australia. The overall response rate (ORR) was 56·4% with a clinical benefit rate of 71·8%. The median progression‐free survival was 13·8 months [95% confidence interval (CI) 8·2–22·2] and median overall survival was not reached. The median time to best response and duration of response was 3·7 months (95% CI 2·8–10·5) and 18·4 months (95% CI 10·2–31·0) respectively. Prior immunomodulatory drug (IMID) exposure was associated with a lower ORR (40% vs. 73·7%, P = 0·03). Survival outcomes in patients with prior proteasome inhibitor (PI) and/or IMID exposure were similar. Patients received a median (range) of 11 (1–31) cycles of therapy and six patients (15%) remained on therapy at the time of final analysis. Grade 3/4 haematological and non‐haematological adverse events were reported in 7·7% and 20·6% of patients respectively. ITd dose reductions were required in 15·4%, 48·7% and 35·9% of patients respectively. The present study demonstrates promising effectiveness and tolerability of ITd as an affordable all‐oral PI‐IMID approach for RRMM.
Publisher: Informa UK Limited
Date: 11-06-2019
DOI: 10.1080/10428194.2019.1571201
Abstract: In preclinical studies, oral azacitidine (CC-486), a hypomethylating agent, has been shown to have a direct anti-MM effect and in vitro anti-MM synergism when combined with lenalidomide (LEN). We present a phase 1b, single center, 3 × 3 dose escalation study with planned expansion at maximum tolerated dose (MTD), which assessed the safety and efficacy of combining CC-486 with LEN (25 mg d1-21/28) and dexamethasone (DEX) (40 mg weekly) in patients with relapsed/refractory MM who had previously failed LEN. Twenty-four patients were enrolled. The MTD of CC-486 was 150 mg d1-21 recommended expansion dose was 100 mg d1-21. Adverse events were predictable and manageable. ORR was 37.5% clinical benefit rate was 50%. Median OS was 10.3 m median PFS was 2.6 m. Correlative proteomics demonstrated that higher MM tumor cell cereblon expression (pretreatment, C1D5) was associated with superior PFS/OS. CC-486, LEN and DEX produced meaningful clinical responses in heavily treated LEN refractory MM patients. Proteomics may have utility in predicting clinical outcomes.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2014
Publisher: Wiley
Date: 11-2015
DOI: 10.14814/PHY2.12604
Publisher: Springer Science and Business Media LLC
Date: 23-12-2015
DOI: 10.1007/S10484-015-9329-2
Abstract: This study examined how changes in wildland firefighters' mood relate to cytokine and cortisol levels in response to simulated physical firefighting work and sleep restriction. Firefighters completed 3 days of simulated wildfire suppression work separated by an 8-h (control condition n = 18) or 4-h sleep opportunity (sleep restriction condition n = 17) each night. Firefighters' mood was assessed daily using the Mood Scale II and Samn-Perelli fatigue scale. Participants also provided s les for the determination of salivary cortisol and pro- (IL-6, IL-8, IL-1β, TNF-α) and anti-inflammatory (IL-4, IL-10) cytokine levels. An increase in the positive mood dimension Happiness was related to a rise in IL-8 and TNF-α in the sleep restriction condition. A rise in the positive mood dimension Activation among sleep restricted firefighters was also related to higher IL-6 levels. An increase in the negative mood dimension Fatigue in the sleep restriction condition was associated with increased IL-6, TNF-α, IL-10 and cortisol levels. In addition, an increase in Fear among sleep restricted firefighters was associated with a rise in TNF-α. Elevated positive mood and immune activation may reflect an appropriate response by the firefighters to these stressors. To further understand this relationship, subsequent firefighting-based research is needed that investigates whether immune changes are a function of affective arousal linked to the expression of positive moods. Positive associations between negative mood and inflammatory and cortisol levels to physical work and restricted sleep provide useful information to fire agencies about subjective fire-ground indicators of physiological changes.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Wiley
Date: 09-1995
DOI: 10.1111/J.1751-0813.1995.TB07540.X
Abstract: Three groups of 8, 4-month-old male Jersey or Jersey-cross calves were infected with 2400 Dictyocaulus viviparus L3 larvae and either left untreated or injected subcutaneously with 200 micrograms/kg doramectin 5 or 25 days after infection (DAI). Lungworms were found in all untreated cattle (geometric mean = 49) at necropsy 39 or 40 DAI. None was found in any of the treated cattle. In a second experiment, groups of 6, 8-month-old calves were untreated or injected with 200 micrograms/kg doramectin 28, 21 or 14 days before each calf was challenged with 2700 D viviparus larvae. Lungworms were recovered at necropsy 32 to 34 DAI. The geometric mean worm burden in the untreated cattle was 550. This was reduced by 100%, 99.5% and 94.1% in calves treated with doramectin 14, 21 or 28 days, respectively, before infection. It was concluded that doramectin is a highly effective anthelmintic against D viviparus adult or L4 infections of cattle, and that reinfection of treated cattle will be significantly reduced for at least 28 days after treatment.
Publisher: Oxford University Press (OUP)
Date: 20-12-2022
Abstract: Wide variation exists globally in the treatment and outcomes of stage III patients with non–small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public rivate status of notifying institution, and multidisciplinary meeting discussion. A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were & years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required.
Publisher: Georg Thieme Verlag KG
Date: 27-10-2017
Abstract: Background and study aims The evidence for efficacy and safety of cold snare polypectomy is limited. The aim of this study was to assess the completeness of resection and safety of cold snare polypectomy, using either traditional or dedicated cold snares. Patients and methods This was a prospective, non-randomized study performed at a single tertiary hospital. Adult patients with at least one colorectal polyp (size ≤ 10 mm) removed by cold snare were included. In the first phase, all patients had polyps removed by traditional snare without diathermy. In the second phase, all patients had polyps removed by dedicated cold snare. Complete endoscopic resection was determined from histological examination of quadrantic polypectomy margin biopsies. Immediate or delayed bleeding within 2 weeks was recorded. Results In total, 181 patients with 299 eligible polyps (n = 93 (173 polyps) traditional snare group, n = 88 (126 polyps) dedicated cold snare group) were included. Patient demographics and procedure indications were similar between groups. Mean polyp size was 6 mm in both groups (P = 0.25). Complete polyp resection was 165 /173 (95.4 % 95 %CI 90.5 – 97.6 %) in the traditional snare group and 124/126 (98.4 % 95 %CI 93.7 – 99.6 %) in the dedicated cold snare group (P = 0.16). Serrated polyps, compared with adenomatous polyps, had a higher rate of incomplete resection (7 % vs. 2 %, P = 0.03). There was no statistically significant difference in the rate of immediate bleeding (3 % vs. 1 %, P = 0.41) and there were no delayed hemorrhages or perforations. Conclusions Cold snare polypectomy is effective and safe for the complete endoscopic resection of small (≤ 10 mm) colorectal polyps with either traditional or dedicated cold snares.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.EJCA.2015.06.129
Abstract: The aims of this analysis were to examine levels of unmet needs and depression among carers of people newly diagnosed with cancer and to identify groups who may be at higher risk, by examining relationships with demographic characteristics. One hundred and fifty dyads of people newly diagnosed with cancer and their carers, aged 18 years and older, were recruited from four Australian hospitals. People with cancer receiving adjuvant cancer treatment with curative intent, were eligible to participate. Carers completed the Supportive Care Needs Survey-Partners & Caregivers (SCNS-P&C45), and both carers and patients completed the Centre of Epidemiologic-Depression Scale (CES-D). Overall, 57% of carers reported at least one, 37% at least three, 31% at least five, and 15% at least 10 unmet needs the most commonly endorsed unmet needs were in the domains of information and health care service needs. Thirty percent of carers and 36% of patients were at risk of clinical depression. A weak to moderate positive relationship was observed between unmet needs and carer depression (r=0.30, p<0.001). Carer levels of unmet needs were significantly associated with carer age, hospital type, treatment type, cancer type, living situation, relationship status (in both uni- and multi-factor analysis) person with cancer age and carer level of education (in unifactor analysis only) but not with carer gender or patient gender (in both uni- and multi-factor analyses). Findings highlight the importance of developing tailored programmes to systematically assist carers who are supporting patients through the early stages of cancer treatment.
Publisher: American Society of Hematology
Date: 15-11-2008
DOI: 10.1182/BLOOD-2008-06-161737
Abstract: We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.
Publisher: Elsevier BV
Date: 04-2015
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/SR9890377
Abstract: The elements Al, Fe and Si were extracted with acid oxalate and acid (HCl) hydroxylamine by using 36 s les from eight different soils, and the results for each extractant were compared. Parent materials were largely volcanic in nature, but eight s les were from soils derived from quartzo-feldspathic materials. Oxalate extracted significantly greater amounts of Fe from most s les than hydroxylamine. Results for Al and Si were less consistent. Compared with oxalate, hydroxylamine (soil : solution, 1:250) extracted significantly greater amounts of Al and Si from some s les and less from others. Taken over all s les, however, there was no significant difference between the two methods in the amounts of Al and Si each extracted. A decrease in the soil:solution ratio for hydroxylamine from 1:250 to 1:400 had little effect of Fe and Si values, but it did increase the amount of Al extracted in several cases. Soil mineralogy appeared to bear little relationship to observed differences, although the presence of magnetite probably contributed to higher oxalate-Fe values. Although statistically significant, differences between in idual values were generally small. Results are compatible with previous studies which indicated that hydroxylamine provides an approximation of oxalate values for Al and Fe. Unlike previous work, however, the present results also suggest that approximate values can be obtained for Si.
Publisher: BMJ
Date: 11-04-2019
DOI: 10.1136/BMJQS-2018-008975
Abstract: Patient participation in care is a fundamental element of safe and high-quality healthcare with the potential to enhance health outcomes and improve patient satisfaction. To test the efficacy of a clinician-facilitated, bedside multimedia ( MyStay ) intervention designed to support patient participation in their recovery after total knee replacement surgery. The primary outcome was patients’ reported worst pain intensity on postoperative day 3. Secondary outcomes were patient activation, length of hospital stay, knee function and satisfaction with care. Unmasked, cluster randomised, four-period cross-over trial with a simultaneous process evaluation within in a large private, not-for-profit, metropolitan teaching hospital. Statistical analyses used linear mixed models with random effects for wards, cohorts within wards and patients within cohorts and fixed effects for treatment and period. 241 patients were recruited between March 2014 and June 2015. Patients were admitted to intervention (104) or control (137) clusters. Intervention group patients reported significantly lower mean pain intensity scores on postoperative day 3 (6.1 vs 7.1, 95% CI −1.94 to −0.08, p=0.04). The percentages of patients who reported severe pain (score ≥7) were 43.7% and 64.2% in the intervention and control groups, respectively (χ 2 9.89, p=0.002 generalised linear mixed model Wald test, p=0.05). Intervention group patients on average stayed in hospital one less day (5.3 vs 6.3, 95% CI 0.05 to 1.94, p=0.04), reported higher activation (45.1% vs 27.1% at level 4 activation) (p=0.04) and higher overall satisfaction with care (9.3 vs 8.6, 95% CI 1.09 to 0.219, p=0.01), and were more likely to refer family or friends to the health service (9.3 vs 8.7, 95% CI 1.07 to 0.13, p=0.02). The clinician-facilitated, MyStay bedside multimedia intervention enhanced patients’ activation and participation in their care after surgery pain intensity and length of stay in hospital were reduced and patients were more satisfied with their care. ACTRN12614000340639 ( www.anzctr.org.au/default.aspx ).
Publisher: Elsevier BV
Date: 2015
Publisher: The Endocrine Society
Date: 10-2006
DOI: 10.1210/JC.2006-0684
Abstract: Rapid bone loss occurs from the proximal femur after allogeneic stem cell transplantation (alloSCT). The objective of the study was to evaluate effects of high-dose pamidronate therapy on bone loss (BMD) after alloSCT. This was a randomized, multicenter, open-label, 12-month prospective study of iv pamidronate (90 mg/month) beginning before conditioning vs. no pamidronate. All 116 patients also received calcitriol (0.25 microg/d) and calcium (1000 mg/d), which were continued for another year. Primary objectives were to compare changes in BMD 12 months after alloSCT at the femoral neck, lumbar spine, and total hip between the treatment arms and assess influences of glucocorticoid and cyclosporin therapy on these changes. Pamidronate reduced bone loss at the spine, femoral neck, and total hip by 5.6, 7.7, and 4.9% (all P < or = 0.003), respectively, at 12 months. However, BMD of the femoral neck and total hip was still 2.8 and 3.5% lower than baseline, respectively (P < 0.05) with pamidronate. Only differences at the total hip remained significant between the two groups at 24 months. Benefits were restricted to patients receiving an average daily prednisolone dose greater than 10 mg and cyclosporin therapy for more than 5 months within the first 6 months of alloSCT. Pamidronate markedly reduced but did not completely prevent postallogeneic bone marrow transplantation bone loss. BMD benefits were greatest in patients on higher doses of immunosuppressive therapy, but most were lost 12 months after stopping pamidronate. Studies of more potent bisphosphonates or anabolic therapy with PTH after alloSCT are warranted with the aim of durable maintenance of bone mass.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2018
DOI: 10.1038/S41467-018-06021-7
Abstract: Pre-leukemic stem cells (pre-LSCs) give rise to leukemic stem cells through acquisition of additional gene mutations and are an important source of relapse following chemotherapy. We postulated that cell-cycle kinetics of pre-LSCs may be an important determinant of clonal evolution and therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia to study cell cycle in vivo, we show that self-renewal, clonal evolution and therapeutic resistance are limited to a rare population of pre-LSCs with restricted cell cycle. We show that proliferative pre-LSCs are unable to return to a cell cycle-restricted state. Cell cycle-restricted pre-LSCs have activation of p53 and its downstream cell-cycle inhibitor p21. Furthermore, absence of p21 leads to proliferation of pre-LSCs, with clonal extinction through loss of asymmetric cell ision and terminal differentiation. Thus, inducing proliferation of pre-LSCs represents a promising strategy to increase cure rates for acute leukemia.
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 10-02-2020
DOI: 10.1038/S41598-020-59009-Z
Abstract: Pre-operative discrimination of malignant masses is crucial for accurate diagnosis and prompt referral to a gynae oncology centre for optimal surgical intervention. HGSOC progression is correlated with local and systemic inflammation. We hypothesised that inclusion of inflammatory biomarkers in sera may improve diagnostic tests. In the training cohort, we tested four existing clinical tests (RMI score and ROMA, CA125 and HE4) and a panel of 28 immune soluble biomarkers in sera from 66 patients undergoing surgery for suspected ovarian cancer. Six promising immune biomarkers alone, or in combination with conventional tests, were subsequently analysed in an independent validation cohort (n = 69). IL-6 was identified as the main driver of variability followed closely by conventional diagnostic tests. Median sera IL-6 was higher in HGSOC patients compared to those with a benign mass or controls with normal ovaries (28.3 vs 7.3 vs 1.2 pg/ml, p 0.0001). The combination of IL-6 further improved the overall predictive probability of the conventional tests. Modelling a two-step triage of women with a suspicious ovarian mass, with IL-6 3.75 pg/ml as primary triage followed by conventional tests (CA125 or RMI score) identified ovarian cancer in patients with a misclassification rate of 4.54–3.03%, superior to the use of CA125 or RMI alone (9.09 to 10.60). The validation cohort demonstrated a similar improvement in the diagnostic sensitivity following addition of IL-6. IL-6 in combination with conventional tests may be a useful clinical biomarker for triage of patients with a suspected malignant ovarian mass.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2015
DOI: 10.1038/LEU.2014.247
Abstract: The BTK (Bruton's tyrosine kinase) inhibitor ibrutinib is associated with an increased risk of bleeding. A previous study reported defects in collagen- and adenosine diphosphate (ADP)-dependent platelet responses when ibrutinib was added ex vivo to patient s les. Whereas the collagen defect is expected given the central role of BTK in glycoprotein VI signaling, the ADP defect lacks a mechanistic explanation. In order to determine the real-life consequences of BTK platelet blockade, we performed light transmission aggregometry in 23 patients receiving ibrutinib treatment. All patients had reductions in collagen-mediated platelet aggregation, with a significant association between the degree of inhibition and the occurrence of clinical bleeding or bruising (P=0.044). This collagen defect was reversible on drug cessation. In contrast to the previous ex vivo report, we found no in vivo ADP defects in subjects receiving standard doses of ibrutinib. These results establish platelet light transmission aggregometry as a method for gauging, at least qualitatively, the severity of platelet impairment in patients receiving ibrutinib treatment.
Publisher: Wiley
Date: 27-03-2019
DOI: 10.1111/BJH.15894
Publisher: Frontiers Media SA
Date: 08-09-2017
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0309-1740(99)00051-0
Abstract: Cryo-scanning electron microscopy was used to study the ultrastructure of small s les (approximately 6 g) of pork. Combinations of six freezing rates, two storage times and three thawing rates were used. Cavities created after sublimation of the ice crystals were quantitatively analysed using an image analysis software package. The cross-sectional areas of cavities of meat s les in the frozen state were approximately ten times the areas of the cavities of the fresh and thawed s les. The large cavities in the frozen state grossly distorted the muscle cell structures. Upon thawing, the meat structure had almost completely recovered. No significant freezing rate effects were observed, however, trends were evident. Significant storage time effects were observed. In the frozen state, at the 90th percentile level, the hole area fraction was greater in stored s les for intermediate cavity areas. In thawed s les, hole area fractions of stored s les were greater than in s les without storage.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-10-2020
DOI: 10.1200/JCO.20.00572
Abstract: The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose r -up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m 2 on days 1-5 and idarubicin 12 mg/m 2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72% it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.EJCA.2005.11.020
Abstract: This multicentre study examined uptake of bilateral risk-reducing mastectomy (BRRM) and bilateral risk-reducing oophorectomy (BRRO) in women at increased risk for breast and/or ovarian cancer who had attended a familial cancer clinic (FCC) between January 1999 and June 2000. Eligible women (N=396), were mailed a questionnaire assessing: BRRM and BRRO details risk perception and anxiety. Family history, genetic testing and risk assessment were abstracted from medical records. Surgery was cross-tabulated with demographics, risk perception and anxiety with either Fisher's exact test or the exact form of the Mantel-Haenszel test (for ordinal factors) used to investigate for associations. Ordinal logistic regression was used with continuous-scale covariates. In total, 130 women were lost to follow-up leaving 266 of these 182 (68.4%) responded. Mean follow-up time was 3.73 years. The BRRM rate was 4.4% with no difference found between moderate and high-risk groups. BRRM was associated with increasing numbers of affected relatives (P=0.025). BRRO was undertaken by 17.3%, more commonly in women older than 40 years of age (P=0.023) and with a BRCA1/2 mutation (P=0.017). Women who underwent BRRM (P=0.052) or BRRO (P<0.001) had a lower post-procedure risk perception than those who did not. During the timeframe of this study, risk-reducing surgery was undertaken by a small percentage of Australian women at increased risk for breast and/or ovarian cancer who attended FCCs. Family cancer history and mutation status were associated with uptake.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
Publisher: American Medical Association (AMA)
Date: 02-2021
Publisher: Public Library of Science (PLoS)
Date: 14-08-2017
Publisher: American Society of Hematology
Date: 24-05-2019
DOI: 10.1182/BLOODADVANCES.2019000195
Abstract: In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR EMR failure: BCR-ABL1 & % on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood s les from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5% P & .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2010
DOI: 10.1007/S00520-010-0829-6
Abstract: Partially presented in poster format at the 40th and 41st Annual Meetings of the American Society of Clinical Oncology, held in 2004 in New Orleans, Louisiana and in 2005 in Orlando, Florida. We aimed to: (a) assess patient knowledge about cancer clinical trials (CCT) and satisfaction with their decision to participate, (b) determine whether satisfaction correlates with objective understanding, or other factors, and (c) identify correlates of increased understanding. A convenience s le of 100 patients were recruited. Instruments assessed quality of informed consent (QuIC), quality of life (EORTC QLQ C-30), anxiety and depression (HADS), and preferences for information and involvement in decision making. Measures were completed within 2 weeks of clinical trial enrollment. One hundred two patients (68 male) with a median age of 58.4 years (29-85) were registered in 27 of the 33 therapeutic cancer clinical trials approved for the Consent Study. Mean QuIC objective knowledge (QuIC-A) was 77.6 (/100) (95% CI, 75.7-79.4) and perceived (subjective) understanding (QuIC-B) 91.5 (95% CI, 89.6-93.3). There was low but significant correlation between QuIC-A and B (R = 0.26, p = 0.008). Satisfaction was very high. Correlation between QuIC-B and satisfaction was moderate (0.430, p < 0.001). QuIC-B, but not QuIC-A was associated with QOL scores. Preferences regarding participation in decision making and whether these preferences were achieved did not impact upon knowledge, understanding or satisfaction. Patient knowledge regarding CCT is similar to published US data, and satisfaction is high. Satisfaction correlates with perceived but not objective understanding of CCT. Strategies to further improve the consent process need to be developed.
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.BBMT.2006.12.449
Abstract: The role of allogeneic transplantation in patients with de novo acute myeloid leukemia in first complete remission (AML-CR1) is controversial. Aiming to preserve a graft-versus-leukemia effect, but minimize morbidity and mortality from conditioning-related toxicity and graft-versus-host disease (GVHD), we conducted a prospective multicenter study of reduced-intensity conditioning (RIC) as preparation for peripheral blood stem cell sibling allografts in patients with intermediate or poor risk AML-CR1. Conditioning consisted of fludarabine 125 mg/m(2) and cyclophosphamide 120 mg/kg. Thirty-four patients were transplanted with a median age of 45 years 85% had intermediate risk cytogenetics. Early toxicity was minimal. The overall incidence of grade II-IV acute GVHD was low (21%), but the 3 patients (9%) who developed grade IV GVHD died. Donor T cell chimerism was rapid and generally complete, but complete myeloid chimerism was delayed. Thirteen patients (38%) relapsed, 12 within a year of transplant. The estimated disease-free survival (DFS) and overall survival at 2 years was 56% (95% confidence interval [CI] 39%-71%) and 68% (95% CI 50%-81%), respectively. The incidence of extensive chronic GVHD (cGVHD) was low (24% of surviving patients at 12 months) and most survivors had an excellent performance status. These observations justify a prospective comparison of RIC versus myeloablative conditioning allografts for AML-CR1.
Publisher: Informa UK Limited
Date: 14-02-2011
DOI: 10.3109/10428194.2010.547155
Abstract: In this prospective, multicenter, non-randomized study for patients with stage I-II Hodgkin lymphoma, group 1 (without risk-factors [RF]) had three cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and group 2 (any of bulk, extranodal site, >3 regions, raised erythrocyte sedimentation rate [ESR]) and group 3 (B-symptoms) received four cycles. Involved field radiotherapy (IFRT) 30 Gy was given after adequate chemotherapy response. Five-year overall survival and freedom from progression (FFP) were 96% (95% confidence interval [CI] 91-98%) and 90% (84-94%), respectively. Five-year FFP was 97% (90-99%), 89% (75-95%), and 73% (52-86%) for groups 1, 2, and 3, respectively. In patients with RF, chemotherapy responses of complete response unconfirmed (CRu), partial response (PR), and stable disease (SD) were associated with FFP of 90%, 86%, and 62% (p=0.17), and CR/no CR on functional imaging with FFP of 90%/67%, respectively (p=0.05). The 97% FFP in group 1 compares favorably with previously reported results from cooperative trial groups. Intensification of therapy warrants study in patients with RF and a poor chemotherapy response.
Publisher: Springer Science and Business Media LLC
Date: 09-1988
DOI: 10.1007/BF02182044
Publisher: MDPI AG
Date: 29-06-2019
Abstract: Mutational characterisation utilising plasma (PL)-derived circulating tumour DNA (ctDNA) in multiple myeloma (MM) has been recently described. Mutational analyses of paired bone marrow (BM) MM cell DNA and ctDNA from 76 patients (n = 24, new diagnosis (ND), n = 52, relapsed/refractory (RR)) for (ras/raf signaling pathway) and tumour protein p53 (TP53) mutations using the OnTarget™ Mutation Detection (OMD) platform was performed. The total number and proportions of mutations in each of the compartments (BM-specific, PL-specific or shared) was significantly higher in RR patients compared to ND patients (p = 0.0002 and p 0.0001, respectively). Patients with 2 mutations or 1% fractional abundance (FA) in the PL had significantly shorter overall survival (OS) (p = 0.04 and p = 0.0006, respectively). Patients with PL-specific TP53 mutations had significantly shorter OS compared to patients with no PL-TP53 mutations (p = 0.003), while no differences were observed in patients with (K-ras) KRAS mutations. Targeted deep licon sequencing (TAS) of matched PL and BM s les from 36 MM patients for DNA-repair and RAS-RAF pathway genes found that DNA-repair genes were present at significantly higher levels in the PL when compared to RAS-RAF mutations (p = 0.0095). We conclude that ctDNA analysis identifies a higher prevalence of potentially actionable DNA-repair gene mutated subclones than BM analysis.
Publisher: American Society of Hematology
Date: 31-07-2017
DOI: 10.1182/BLOODADVANCES.2017006825
Abstract: Germ line variants in ASXL1 and BIM are strong biomarkers of response to imatinib in chronic phase CML. A combined Sokal risk and ASXL1 and BIM variant model identified a subgroup of patients with the greatest risk of treatment failure.
Publisher: Elsevier BV
Date: 02-1990
DOI: 10.1016/0040-5809(90)90038-W
Abstract: The variance of s le heterozygosity, averaged over several loci, is studied in a variety of situations. The variance depends on the s ling implicit in the mating system as well as on that explicit in the loci scored and in iduals s led. There are also effects of allelic distributions over loci and of linkage or linkage disequilibrium between pairs of loci. Results are obtained for populations in drift and mutation balance, for infinite populations undergoing mixed self and random mating, and for finite monoecious populations with or without selfing. For unlinked loci in drift/mutation balance, variances appear to be lessened more by increasing the number of loci scored than by increasing the number of in iduals s led. For infinite populations under the mixed self and random mating system, however, the reverse is true. Methods for estimating the variance of s le heterozygosity are discussed, with attention being paid to unbalanced data where not all loci are scored in all in iduals.
Publisher: JMIR Publications Inc.
Date: 26-10-2015
DOI: 10.2196/JMIR.4763
Publisher: Public Library of Science (PLoS)
Date: 25-11-2013
Publisher: CSIRO Publishing
Date: 1992
DOI: 10.1071/SR9920209
Abstract: The changes in microbial biomass C, soil respiration, microbial activity (respiration/microbial C) and the content of oxidizable organic C extracted by 0-5 M K2SO4, were measured in four soils of contrasting characteristics (a sand, two silt loam soils and a peat) which were air-dried at 22�C at three different rates in the laboratory. Respiration was also measured on s les of the drying soils rewetted with water. The rates of drying were: h (fast), h (medium) and h (slow) drying was carried out for 6 h on consecutive days, with overnight storage. Measurements were also made on soils stored at field-moisture content over the 15 day duration of the experiment. Respiration and activity declined continuously and in a generally linear manner as the volumetric water content (W,) decreased. The decline in respiration in relation to water content W, was similar for all four soils and for the three rates of drying. Microbial biomass C also declined but generally only after a considerable initial period of drying (after the soils had reached Wv of 0-1-0.3). Extractable C values increased, but only after an initial drying period (Wv below 0.06-0.12). The increases in extractable C were approximately coincident with the decreases in microbial C, but only part of the increase in extractable C could be accounted for by the decrease in microbial C. Rewetting of dried soils caused a marked increase in respiration, particularly when the rewetted soils had reached Wv values where extractable C had begun to increase. The relationship between microbial activity and extractable C was similar for all four soils and was not affected by the rate of drying. The similarity of the microbial responses in these contrasting soils, and the absence of any detectable differences between rates of drying suggest that the microbial communities had similar survival strategies to resist desiccation, and occupied comparable physical niches in the soils, despite these soils having widely differing textures, organic matter content, and soil moisture characteristics.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2022
DOI: 10.1038/S41375-022-01571-8
Abstract: Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1–5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA G17V mutations associated with improved PFS (median 5.47 vs . 1.35 months Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2019
Publisher: Wiley
Date: 20-03-2017
DOI: 10.1002/AJH.24704
Abstract: RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort n = 295) and Dusseldorf registry (Germany validation cohort n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000369854
Abstract: b i Background: /i /b To determine the effect of adiposity in males aged 50-70 years on cardiovascular responses to acute psychological stress. b i Methods: /i /b Lean (BMI 20-25 kg/m sup /sup ) (n = 21) and overweight/obese (BMI 27-35 kg/m sup /sup ) (n = 21) men aged 50-70 years were subjected to psychological stress. Systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output were measured by a Finometer during resting (60 min), stress (30 min), and recovery (90 min). b i Results: /i /b The lean group had a significantly higher SBP stress reactivity when compared to the overweight/obese group (51.5 ± 3.7% vs. 41.0 ± 2.9% (mean ± SEM) p 0.05). A significant effect of time was observed for systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output (p 0.0001 for all). There were significant time × body type interactions for systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output (p 0.05 for all). Total peripheral resistance during recovery was higher in the lean compared to the overweight/obese group (p 0.05). In the lean group, systolic and diastolic blood pressure variability remained elevated after stress (p 0.05) but returned to resting levels in the overweight/obese group (p 0.05). b i Conclusion: /i /b Moderate adiposity in men was associated with reduced systolic blood pressure % reactivity, total peripheral resistance, and blood pressure variability after psychological stress. Overweight/obese men appear to be at no greater risk of unfavorable cardiovascular responses to stress.
Publisher: Elsevier BV
Date: 05-2009
Publisher: Oxford University Press (OUP)
Date: 19-07-2016
DOI: 10.1093/CID/CIW492
Abstract: Vaccines can have nontargeted heterologous effects that manifest as increased protection against nonvaccine infections, as described for measles vaccine (MV), or increased susceptibility to infections and death, as described following diphtheria-tetanus-whole cell pertussis (DTP) vaccination. The mechanisms are unknown, and high-quality immunological studies are lacking. This study was designed to investigate the heterologous effects of MV and DTP in 302 Gambian infants. The results support a sex-differential immunosuppressive effect of DTP on innate proinflammatory responses and T-cell immunity. Males but not females receiving MV had enhanced proinflammatory innate responses. The results point to modified signaling via Toll-like receptor 4 (TLR4) as a possible mechanism for the effects on innate immunity. When both vaccines were administered together, purified protein derivative responses were enhanced in females but downregulated in males. Collectively, these data indicate immunological effects that could account for heterologous effects of MV and DTP, to take forward into prospective trials.
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/10428190400013076
Abstract: Forty-three fit elderly patients with de novo acute myeloid leukemia (AML) received chemotherapy with mitoxantrone and intermediate dose cytarabine (MIDAC) in a phase II clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. The main aim of the study was to evaluate the tolerability and efficacy of MIDAC in inducing durable remissions. While the chemotherapy was generally well tolerated, less than half the patients achieved complete remission (CR) after induction and many of those in CR could not receive planned consolidation cycles. The median overall survival for all patients was 6.5 months and the median disease-free survival for those achieving CR was 8.3 months. Only 2 patients survived beyond 4 years. Factors significantly associated with shorter survival were adverse cytogenetics, marrow dysplasia and increasing age. These results suggest that only selected elderly patients with AML are likely to benefit from aggressive chemotherapy and that novel therapies are required to improve the poor prognosis of this group.
Publisher: Informa UK Limited
Date: 15-07-2021
DOI: 10.1080/10428194.2021.1948030
Abstract: LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS (
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 09-2015
Publisher: Wiley
Date: 21-02-2018
DOI: 10.1111/APT.14571
Abstract: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10 Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.
Publisher: Springer Science and Business Media LLC
Date: 20-03-2017
DOI: 10.1038/BMT.2017.37
Abstract: High-risk (HR) multiple myeloma (MM) has poor outcomes with conventional therapy. Tandem autologous-non-myeloablative (NMA) allogeneic stem cell transplantation (autologous stem cell transplantation (ASCT)-NMA allogeneic SCT) is potentially curative secondary to graft-versus-myeloma effect. We retrospectively analysed ASCT-NMA allogeneic SCT outcomes of 59 HR and relapsed MM patients. At a median follow-up of 35.8 months, the outcomes for HR-MM upfront tandem ASCT-NMA allogeneic SCT and standard-risk (SR) MM upfront ASCT alone were comparable (median PFS 1166 days versus 1465 days, P=0.36 median overall survival (OS) not reached in both cohorts, P=0.31). The 5-year PFS and OS of patients who had ASCT-NMA allogeneic SCT after relapsing from previous ASCT were 30% and 48% respectively. High CD3+ cell dose (>3 × 10
Publisher: BMJ
Date: 02-03-2019
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.IJPSYCHO.2016.10.015
Abstract: Physical work and sleep loss are wildland firefighting demands that elicit psychological and physiological stress responses. Research shows that these responses are statistically related which presents an opportunity to use subjective psychological questionnaires to monitor physiological changes among firefighters an approach used extensively in sport settings. The aim of the present study was to investigate if changes in self-reported psychological factors on the multi-component training distress scale (MTDS), relate to cytokines and cortisol levels among firefighters completing three days of simulated physical firefighting work separated by an 8-h or restricted 4-h sleep each night. Each day firefighters completed the MTDS in the morning and salivary cortisol and inflammatory cytokines were measured throughout the day. When sleep restricted, firefighters demonstrated increases in MTDS factors of general fatigue, perceived stress and depressed mood that were related to elevated cytokines (TNF-α, IL-8, IL-10). Conversely, firefighters who had an 8-h sleep demonstrated a positive relationship between physical signs and symptoms and elevated IL-6, while depressed mood was inversely related to decreasing cortisol and cytokines (IL-6, TNF-α, IL-10). Findings highlight the utility of the MTDS to detect psychological changes that reflect physiological responses among firefighters. Future research that establishes thresholds for specific factors which predict health-related physiological changes, will allow fire agencies implement multi-component measures to monitor and manage the health of personnel on the fire-ground.
Publisher: Elsevier BV
Date: 1990
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-04-2009
Abstract: Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival. Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability. After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P .001 hazard ratio [HR], 0.5 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004 HR, 0.41 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77% P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events. Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2016
DOI: 10.1038/LEU.2016.34
Abstract: Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma s les to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission s les. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be in idualized early according to the cytokine-risk profile of the patient.
Publisher: BMJ
Date: 10-2015
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
Publisher: MDPI AG
Date: 21-01-2023
Abstract: We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood s les from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2+ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2+ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2+ Treg is likely to be mediated via the STAT3 signalling pathway.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0309-1740(99)00050-9
Abstract: The effects of six freezing rates, two storage times and three thawing rates on the drip loss from small s les (approximately 6 g) of pork were studied. Drip was collected by centrifugal extraction. Protein denaturation of the meat s le was analysed by differential scanning calorimetry. At fast freezing rates, drip losses obtained were not significantly different from that of fresh s les. At the slower freezing rates studied, drip losses were greater than that from fresh s les. After four weeks storage, drip losses were significantly greater at the slow freezing rates compared to the s les without storage. However, for the stored s les, there were no differences in drip losses with respect to the initial freezing rates. Furthermore, the drip losses from stored s les were not significantly different from drip losses of s les at the slow freezing rates without storage. No differences in denaturation profiles of the meat s les, composition of drip or total protein concentrations in the drip s les were observed.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2006
DOI: 10.1007/S10689-006-0006-8
Abstract: This multicenter study examined the adherence of high-risk women to screening recommendations for breast and ovarian cancer following consultation at a familial cancer clinic (FCC). Self-report questionnaires assessing recall of screening advice, tests undertaken, risk perception, anxiety (Impact of Events Scale) and demographics were mailed to 396 consecutive eligible women who had attended one of six FCCs a median of 3.6 years prior. Family history, genetic test results and screening recommendations were abstracted from medical records. 182/266 (68.4%) women responded with 130 lost to follow-up. The proportions of women undertaking at least the recommended frequency of screening tests were: breast self examination (BSE) 50.4%, clinical breast examination (CBE) 66.0%, mammography 82.2%, transvaginal ultrasound (TVUS) 70.0%, CA125 84.0%. Factors associated with adherence to screening were: higher anxiety for BSE and CBE, being BRCA1/2 positive for CBE, older age, method of arrangement and having at least one affected first degree relative for mammography. Factors significantly associated with over-adherence were higher scores for anxiety for BSE and CBE and younger age (< 40 years) for TVUS. Between 41.3% (BSE) and 57.6% (CBE) of women incorrectly recalled their screening recommendations. A substantial minority of high-risk women do not adhere to screening advice. Strategies to improve the accuracy of recall of recommendations and the uptake of recommended screening are required.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2019
DOI: 10.1038/S41375-019-0469-X
Abstract: Monitoring tumour burden and therapeutic response through analyses of circulating cell-free tumour DNA (ctDNA) and extracellular RNA (exRNA) in multiple myeloma (MM) patients were performed in a Phase Ib trial of 24 relapsed/refractory patients receiving oral azacitidine in combination with lenalidomide and dexamethasone. Mutational characterisation of paired BM and PL s les at study entry identified that patients with a higher number of mutations or a higher mutational fractional abundance in PL had significantly shorter overall survival (OS) (p = 0.005 and p = 0.018, respectively). A decrease in ctDNA levels at day 5 of cycle 1 of treatment (C1D5) correlated with superior progression-free survival (PFS) (p = 0.017). Evaluation of exRNA transcripts of candidate biomarkers indicated that high CRBN levels coupled with low levels of SPARC at baseline were associated with shorter OS (p = 0.000003). IKZF1 fold-change <0.05 at C1D5 was associated with shorter PFS (p = 0.0051) and OS (p = 0.0001). Furthermore, patients with high baseline CRBN coupled with low fold-change at C1D5 were at the highest risk of progression (p = 0.0001). In conclusion, this exploratory analysis has provided the first demonstration in MM of ctDNA for predicting disease outcome and of the utility of exRNA as a biomarker of therapeutic response.
Publisher: Elsevier BV
Date: 11-2007
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0309-1740(99)00052-2
Abstract: The effects of combinations of freezing, thawing and frozen storage on the drip loss and ultrastructure of small s les (approximately 6 g) of pork were studied. S les were stored for up to 12 weeks at -20°C or for up to 4 weeks at temperatures fluctuating between -10 and -3°C. Drip was collected by centrifugal extraction. Cryo-scanning electron microscopy was used to study the ultrastructure of the meat. Sizes of cavities created after sublimation of the ice crystals were quantitatively analysed using an image analysis software package. Freezing rate by storage time interactions were observed in drip loss analyses. No differences were observed in the drip protein concentration or electrophoretic patterns. Ultrastructural differences were only observed after thawing s les stored at the higher temperatures. The effects being investigated were subtle.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Informa UK Limited
Date: 1997
Publisher: Elsevier BV
Date: 05-2016
Abstract: Low folate status is associated with an increased risk of colorectal carcinogenesis. Optimal folate status may be genoprotective by preventing uracil misincorporation into DNA and DNA hypomethylation. Adenomatous polyps have low folate status compared with normal colonic mucosa, and they are surrounded by histologically normal mucosa that also is of low folate status. In a randomized controlled trial conducted at a single Dublin hospital between April 2002 and March 2004, we assessed the effect of folic acid supplementation on tissue folate, uracil misincorporation into DNA, and global DNA hypomethylation in colonocytes isolated from sites of adenomatous polyps and from histologically normal tissue adjacent and 10-15 cm distal to them. Twenty patients with adenomatous polyps on initial colonoscopy and polypectomy were randomly assigned to receive either 600 μg folic acid/d [n = 12, 38% men, mean age 64.3 y, and body mass index (BMI, in kg/m(2)) 26.6] or placebo (n = 8, 50% men, mean age 68.4 y, and BMI 27.2) for 6 mo, and then repeat the colonoscopy. Blood and colonocyte tissue folate concentrations were measured with the use of a microbiological assay. Uracil misincorporation and global DNA hypomethylation were measured in colonocytes with the use of modified comet assays. Over time, folic acid supplementation, compared with placebo, increased tissue folate (mean ± SEM) from 15.6 ± 2.62 pg/10(5) cells to 18.1 ± 2.12 pg/10(5) cells (P < 0.001) and decreased the global DNA hypomethylation ratio from 1.7 ± 0.1 to 1.0 ± 0.1 (P < 0.001). The uracil misincorporation ratio decreased by 0.5 ± 0.1 for the site adjacent to the polyp over time (P = 0.05). A response to folic acid supplementation, which increased colonocyte folate and improved folate-related DNA biomarkers of cancer risk, was seen in the participants studied. Exploratory analysis points toward the area formerly adjacent to polyps as possibly driving the response. That these areas persist after polypectomy in the absence of folate supplementation is consistent with a potentially carcinogenic field's causing the appearance of the polyp.
Publisher: Oxford University Press (OUP)
Date: 10-02-2016
Abstract: Previous studies suggest overrepresentation of particular polymorphisms within the Helicobacter pylori CagL hypervariable motif (CagLHM) in gastric cancer-associated isolates. However, these disease correlations were geographically variable and ambiguous. We compared the disease correlation of several hundred geographically erse CagL sequences and identified 33 CagLHM sequence combinations with disparate geographical distribution, revealing substantial worldwide CagLHM ersity, particularly within Asian countries. Notably, polymorphisms E59 and I60 were significantly overrepresented, whereas D58 and E62 were underrepresented, in gastric cancer-associated H. pylori isolates worldwide. Thus, CagLHM regional ersity may contribute to the varied prevalence of H. pylori-related gastric cancer observed in erse populations.
Publisher: Wiley
Date: 06-2008
DOI: 10.1111/J.1440-1673.2008.01957.X
Abstract: This study evaluated the variability among six radiation therapy planners in planning radiation treatment for four patients with lung cancer using two treatment protocols. The interplanner variability for target conformity and homogeneity was smaller than the variability among the patients and planning approaches. The same was found for the dose volume indices achieved for most critical structures, indicating that interplanner variability is not likely to be an important source of variation in radiotherapy studies if concise treatment protocols are followed.
No related grants have been discovered for John Reynolds.