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1.
J Cell Biochem ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31907974

RESUMO

Ductal carcinoma in situ (DCIS) is a nonobligate precursor to invasive breast cancer. Only a small percentage of DCIS cases are predicted to progress; however, there is no method to determine which DCIS lesions will remain innocuous from those that will become invasive disease. Therefore, DCIS is treated aggressively creating a current state of overdiagnosis and overtreatment. There is a critical need to identify functional determinants of progression of DCIS to invasive ductal carcinoma (IDC). Interrogating biopsies from five patients with contiguous DCIS and IDC lesions, we have shown that expression of the long noncoding RNA BHLHE40-AS1 increases with disease progression. BHLHE40-AS1 expression supports DCIS cell proliferation, motility, and invasive potential. Mechanistically, BHLHE40-AS1 modulates interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) activity and a proinflammatory cytokine signature, in part through interaction with interleukin enhancer-binding factor 3. These data suggest that BHLHE40-AS1 supports early breast cancer progression by engaging STAT3 signaling, creating an immune-permissive microenvironment.

2.
Pharmacoeconomics ; 38(2): 135-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31840216

RESUMO

Although probabilistic analysis has become the accepted standard for decision analytic cost-effectiveness models, deterministic one-way sensitivity analysis continues to be used to meet the need of decision makers to understand the impact that changing the value taken by one specific parameter has on the results of the analysis. The value of a probabilistic form of one-way sensitivity analysis has been recognised, but the proposed methods are computationally intensive. Deterministic one-way sensitivity analysis provides decision makers with biased and incomplete information whereas, in contrast, probabilistic one-way sensitivity analysis (POSA) can overcome these limitations, an observation supported in this study by results obtained when these methods were applied to a previously published cost-effectiveness analysis to produce a conditional incremental expected net benefit curve. The application of POSA will provide decision makers with unbiased information on how the expected net benefit is affected by a parameter taking on a specific value and the probability that the specific value will be observed.

3.
J Clin Oncol ; 38(5): 423-433, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31841354

RESUMO

PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations, tumor response, and safety. RESULTS: Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION: Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.

4.
Infect Control Hosp Epidemiol ; 40(12): 1374-1379, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619300

RESUMO

BACKGROUND: Surgical site infections (SSIs) are common surgical complications that lead to increased costs. Depending on payer type, however, they do not necessarily translate into deficits for every hospital. OBJECTIVE: We investigated how surgical site infections (SSIs) influence the contribution margin in 2 reimbursement systems based on diagnosis-related groups (DRGs). METHODS: This preplanned observational health cost analysis was nested within a Swiss multicenter randomized controlled trial on the timing of preoperative antibiotic prophylaxis in general surgery between February 2013 and August 2015. A simulation of cost and income in the National Health Service (NHS) England reimbursement system was conducted. RESULTS: Of 5,175 patients initially enrolled, 4,556 had complete cost and income data as well as SSI status available for analysis. SSI occurred in 228 of 4,556 of patients (5%). Patients with SSIs were older, more often male, had higher BMIs, compulsory insurance, longer operations, and more frequent ICU admissions. SSIs led to higher hospital cost and income. The median contribution margin was negative in cases of SSI. In SSI cases, median contribution margin was Swiss francs (CHF) -2045 (IQR, -12,800 to 4,848) versus CHF 895 (IQR, -2,190 to 4,158) in non-SSI cases. Higher ASA class and private insurance were associated with higher contribution margins in SSI cases, and ICU admission led to greater deficits. Private insurance had a strong increasing effect on contribution margin at the 10th, 50th (median), and 90th percentiles of its distribution, leading to overall positive contribution margins for SSIs in Switzerland. The NHS England simulation with 3,893 patients revealed similar but less pronounced effects of SSI on contribution margin. CONCLUSIONS: Depending on payer type, reimbursement systems with DRGs offer only minor financial incentives to the prevention of SSI.

5.
Med Decis Making ; 39(7): 857-866, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31556806

RESUMO

Diagnostic tests are expensive and time-consuming to develop. Early economic evaluation using decision modeling can reduce commercial risk by providing early evidence on cost-effectiveness. The National Institute for Health Research Diagnostic Evidence Co-operatives (DECs) was established to catalyze evidence generation for diagnostic tests by collaborating with commercial developers; DEC researchers have consequently made extensive use of early modeling. The aim of this article is to summarize the experiences of the DECs using early modeling for diagnostics. We draw on 8 case studies to illustrate the methods, highlight methodological strengths and weaknesses particular to diagnostics, and provide advice. The case studies covered diagnosis, screening, and treatment stratification. Treatment effectiveness was a crucial determinant of cost-effectiveness in all cases, but robust evidence to inform this parameter was sparse. This risked limiting the usability of the results, although characterization of this uncertainty in turn highlighted the value of further evidence generation. Researchers evaluating early models must be aware of the importance of treatment effect evidence when reviewing the cost-effectiveness of diagnostics. Researchers planning to develop an early model of a test should also 1) consult widely with clinicians to ensure the model reflects real-world patient care; 2) develop comprehensive models that can be updated as the technology develops, rather than taking a "quick and dirty" approach that may risk producing misleading results; and 3) use flexible methods of reviewing evidence and evaluating model results, to fit the needs of multiple decision makers. Decision models can provide vital information for developers at an early stage, although limited evidence mean researchers should proceed with caution.

6.
Health Technol Assess ; 23(40): 1-194, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31397263

RESUMO

BACKGROUND: Delirium is a common and serious neuropsychiatric syndrome, usually triggered by illness or drugs. It remains underdetected. One reason for this is a lack of brief, pragmatic assessment tools. The 4 'A's test (Arousal, Attention, Abbreviated Mental Test - 4, Acute change) (4AT) is a screening tool designed for routine use. This project evaluated its usability, diagnostic accuracy and cost. METHODS: Phase 1 - the usability of the 4AT in routine practice was measured with two surveys and two qualitative studies of health-care professionals, and a review of current clinical use of the 4AT as well as its presence in guidelines and reports. Phase 2 - the 4AT's diagnostic accuracy was assessed in newly admitted acute medical patients aged ≥ 70 years. Its performance was compared with that of the Confusion Assessment Method (CAM; a longer screening tool). The performance of individual 4AT test items was related to cognitive status, length of stay, new institutionalisation, mortality at 12 weeks and outcomes. The method used was a prospective, double-blind diagnostic test accuracy study in emergency departments or in acute general medical wards in three UK sites. Each patient underwent a reference standard delirium assessment and was also randomised to receive an assessment with either the 4AT (n = 421) or the CAM (n = 420). A health economics analysis was also conducted. RESULTS: Phase 1 found evidence that delirium awareness is increasing, but also that there is a need for education on delirium in general and on the 4AT in particular. Most users reported that the 4AT was useful, and it was in widespread use both in the UK and beyond. No changes to the 4AT were considered necessary. Phase 2 involved 785 individuals who had data for analysis; their mean age was 81.4 (standard deviation 6.4) years, 45% were male, 99% were white and 9% had a known dementia diagnosis. The 4AT (n = 392) had an area under the receiver operating characteristic curve of 0.90. A positive 4AT score (> 3) had a specificity of 95% [95% confidence interval (CI) 92% to 97%] and a sensitivity of 76% (95% CI 61% to 87%) for reference standard delirium. The CAM (n = 382) had a specificity of 100% (95% CI 98% to 100%) and a sensitivity of 40% (95% CI 26% to 57%) in the subset of participants whom it was possible to assess using this. Patients with positive 4AT scores had longer lengths of stay (median 5 days, interquartile range 2.0-14.0 days) than did those with negative 4AT scores (median 2 days, interquartile range 1.0-6.0 days), and they had a higher 12-week mortality rate (16.1% and 9.2%, respectively). The estimated 12-week costs of an initial inpatient stay for patients with delirium were more than double the costs of an inpatient stay for patients without delirium (e.g. in Scotland, £7559, 95% CI £7362 to £7755, vs. £4215, 95% CI £4175 to £4254). The estimated cost of false-positive cases was £4653, of false-negative cases was £8956, and of a missed diagnosis was £2067. LIMITATIONS: Patients were aged ≥ 70 years and were assessed soon after they were admitted, limiting generalisability. The treatment of patients in accordance with reference standard diagnosis limited the ability to assess comparative cost-effectiveness. CONCLUSIONS: These findings support the use of the 4AT as a rapid delirium assessment instrument. The 4AT has acceptable diagnostic accuracy for acute older patients aged > 70 years. FUTURE WORK: Further research should address the real-world implementation of delirium assessment. The 4AT should be tested in other populations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53388093. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 40. See the NIHR Journals Library website for further project information. The funder specified that any new delirium assessment tool should be compared against the CAM, but had no other role in the study design or conduct of the study.

7.
Clin Chem ; 65(11): 1363-1374, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31444309

RESUMO

BACKGROUND: For medical tests that have a central role in clinical decision-making, current guidelines advocate outcome-based analytical performance specifications. Given that empirical (clinical trial-style) analyses are often impractical or unfeasible in this context, the ability to set such specifications is expected to rely on indirect studies to calculate the impact of test measurement uncertainty on downstream clinical, operational, and economic outcomes. Currently, however, a lack of awareness and guidance concerning available alternative indirect methods is limiting the production of outcome-based specifications. Therefore, our aim was to review available indirect methods and present an analytical framework to inform future outcome-based performance goals. CONTENT: A methodology review consisting of database searches and extensive citation tracking was conducted to identify studies using indirect methods to incorporate or evaluate the impact of test measurement uncertainty on downstream outcomes (including clinical accuracy, clinical utility, and/or costs). Eighty-two studies were identified, most of which evaluated the impact of imprecision and/or bias on clinical accuracy. A common analytical framework underpinning the various methods was identified, consisting of 3 key steps: (a) calculation of "true" test values; (b) calculation of measured test values (incorporating uncertainty); and (c) calculation of the impact of discrepancies between (a) and (b) on specified outcomes. A summary of the methods adopted is provided, and key considerations are discussed. CONCLUSIONS: Various approaches are available for conducting indirect assessments to inform outcome-based performance specifications. This study provides an overview of methods and key considerations to inform future studies and research in this area.

9.
Lancet ; 393(10191): 2599-2612, 2019 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-31178152

RESUMO

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Resultado do Tratamento , Reino Unido , Adulto Jovem
10.
Brain Stimul ; 12(5): 1253-1260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088732

RESUMO

BACKGROUND: Prior studies have found that continuous theta burst stimulation (cTBS) targeting the left dlPFC results in reliable increases in consumption of calorie-dense food items. However, it is not known to what extent such effects are modified by cues in the immediate eating environment. Tempting environments (i.e., those saturated with appetitive eating cues) may lead to more reliance on cognitive control networks involving the dlPFC, thereby enhancing cTBS effects on indulgent eating. OBJECTIVE/HYPOTHESIS: The objective was to examine the extent to which cTBS effects on indulgent eating would be modified by contextual cues. It was hypothesized that cTBS effects would be stronger in the presence of facilitating cues. METHODS: Using a single-blinded between-subjects factorial design, 107 TMS-naïve adults were randomly assigned to one of four conditions: 1) active cTBS + facilitating cues, 2) sham cTBS + facilitating cues, 3) active cTBS + inhibiting cues, 4) sham cTBS + inhibiting cues. Following stimulation participants completed a flanker paradigm and a taste test during which quantity consumed was assessed surreptitiously. RESULTS: Findings revealed a significant interaction between stimulation and cue type (F(1,102) = 6.235, p = .014), such that cTBS resulted in increased food consumption (compared to sham) in the presence of the facilitating cue but not in the presence of the inhibiting cue. Moderated mediational analyses showed selective mediation of cTBS effects on consumption through cTBS attenuation of flanker interference scores. CONCLUSIONS: The effects of cTBS on indulgent eating are strengthened in the presence of facilitating cues. Methodologically speaking, facilitating cues may be a functional prerequisite for exploring cTBS effects on eating in the laboratory. Substantively, the findings also suggest that facilitating cues in the eating environment may amplify counter-intentional food indulgence in everyday life via cognitive control failure.


Assuntos
Fissura/fisiologia , Sinais (Psicologia) , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Estimulação Luminosa/métodos , Ritmo Teta/fisiologia , Adolescente , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Córtex Pré-Frontal/fisiologia , Método Simples-Cego , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
11.
Trends Cogn Sci ; 23(4): 349-361, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30824229

RESUMO

In the modern obesogenic environment, limiting calorie-dense food consumption is partially dependent on the capacity of individuals to override visceral reactions to hyperpalatable and rewarding food cues. In the current review, we employ a health neuroscience framework to outline: (i) how individual variations in prefrontal cortical structure and functionality, and by extension, executive functions, may predispose an individual to the overconsumption of appetitive calorie-dense foods via differences in dietary self-regulation; (ii) how obesity may result in changes to cortical structure and functionality; and (iii) how the relationship between the structure and function of the prefrontal cortex and obesity may be best described as reciprocal in nature.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30867655

RESUMO

Background: Breast cancer is the second most common cancer worldwide, the most common among women, and the most frequent cause of death among women in less developed regions. Trastuzumab is a humanized monoclonal antibody that downregulates the extracellular domain of the HER2 protein. Using trastuzumab to treat women with localized HER2-positive breast cancer has been shown to improve survival. The objective of this study is to explore the cost-effectiveness of adjuvant trastuzumab, from a societal perspective, in 11 African countries. In addition, we aimed to establish value-based prices for trastuzumab based on the gross domestic product per capita in each country. Methods: We developed a Markov model in order to assess the costs and benefits associated with trastuzumab treatment over a lifetime horizon. A probabilistic sensitivity analysis was performed in order to estimate the impact of uncertainty of parameter-values on the results. Efficacy inputs were derived using clinical trial data from non-African countries. Results: In the base case analysis, trastuzumab yielded a gain ranging from 0.92 LYs in Nigeria to 1.07 LYs in South Africa, and 0.9 QALYs in Nigeria to 1.02 QALYs in South Africa. The incremental cost ranged from 19,561 USD in Nigeria to 19,997 USD in Congo, and an incremental cost-effectiveness ratio ranging from 19,534 USD/QALY in South Africa to 21,697 USD/QALY in Nigeria. Using willingness to pay estimates based on World Health Organization recommendations, trastuzumab appear to not be cost-effective in all countries analyzed. Cost-effectiveness estimates were most sensitive to the discount rate, trastuzumab cost, and the hazard ratio. Conclusions: Trastuzumab does not appear to be cost effective in the African countries analyzed. In order for trastuzumab to be cost-effective, the costs of treatment would require significant discounts.

13.
Eur Urol Focus ; 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30738795

RESUMO

BACKGROUND: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). OBJECTIVE: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. INTERVENTION: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. RESULTS AND LIMITATIONS: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design. CONCLUSIONS: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. PATIENT SUMMARY: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.

14.
Clin Cancer Res ; 25(9): 2708-2716, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796035

RESUMO

PURPOSE: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. PATIENTS AND METHODS: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. RESULTS: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). CONCLUSIONS: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

15.
Sleep ; 42(5)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30805652

RESUMO

Poor sleep is common following stroke, limits stroke recovery, and can contribute to further cognitive decline post-stroke. However, it is unclear what aspects of sleep are different in older adults with stroke compared with those without, and whether the relationship between sleep and cognitive function differs by stroke history. We investigated whether older adults with stroke experience poorer sleep quality than older adults without stroke, and whether poor sleep quality attenuates cognitive performance among older adults with a history of stroke. Thirty-five age- and sex-matched older adults with stroke (age: 69.86 ± 1.13 years; 51.43% female) and without stroke (age: 69.83 ± 1.12; 51.43% female) were compared with respect to sleep quality using the MotionWatch8 (MW8) and Pittsburgh Sleep Quality Index (PSQI). Cognitive performance was indexed using the Alzheimer's Disease Assessment Scale Plus (ADAS-Cog Plus). Additionally, we examined whether poor sleep quality is associated with poorer cognitive performance among older adults with stroke. Older adults with stroke had longer MW8 measured sleep duration (27.82 ± 12.17 min; p = 0.03) and greater fragmentation (6.44 ± 2.24; p < 0.01), but did not differ in PSQI from their nonstroke peers. There was a significant group x sleep quality interaction for fragmentation (ß = 0.02; p < 0.01) and efficiency (ß = -0.03; p = 0.02) on ADAS-Cog Plus performance, whereby differences in cognitive performance between older adults with and without stroke were accentuated in the presence of poor sleep quality. Older adults with stroke have poorer sleep quality than their nonstroke counterparts, and older adults with stroke and poor sleep quality experience larger deficits in cognitive performance. Clinical Trial Registration: Vitality: Promoting Cognitive Function in Older Adults With Chronic Stroke (Vitality); https://clinicaltrials.gov/ct2/show/NCT01916486; NCT01916486.

16.
J Clin Epidemiol ; 109: 125-132, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30711490

RESUMO

OBJECTIVE: Evidence-based guidelines recommend adjuvant chemotherapy in early stage breast cancer whenever treatment benefit is considered sufficient to outweigh the associated risks. However, many groups of patients were either excluded from or underrepresented in the clinical trials that form the evidence base for this recommendation. This study aims to determine whether using administrative health care data-real world data-and econometric methods for causal analysis to provide "real world evidence" (RWE) are feasible methods for addressing this gap. METHODS: Cases of primary breast cancer in women from 2001 to 2015 were extracted from the Scottish cancer registry (SMR06) and linked to other routine health records (inpatient and outpatient visits). Four methods were used to estimate the effect of adjuvant chemotherapy on disease-specific and overall mortality: (1) regression with adjustment for covariates, (2) propensity score matching, (3) instrumental variables analysis, and (4) regression discontinuity design. Hazard ratios for breast cancer mortality and all-cause mortality were compared to those from a meta-analysis of randomized trials. RESULTS: A total of 39,805 cases were included in the analyses. Regression adjustment, propensity score matching, and instrumental variables were feasible, whereas regression discontinuity was not. Effectiveness estimates were similar between RWE and randomized trials for breast cancer mortality but not for all-cause mortality. CONCLUSIONS: RWE methods are a feasible means to generate estimates of effectiveness of adjuvant chemotherapy in early stage breast cancer. However, such estimates must be interpreted in the context of the available randomized evidence and the potential biases of the observational methods.

17.
Ann Behav Med ; 53(5): 486-492, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29947728

RESUMO

BACKGROUND: Long-term future thinking has been associated with a range of favorable health behaviors. However, it is currently unclear whether this translates into an effect on morbidity and mortality. PURPOSE: The goal of this study was to study the relationship between time perspective and all-cause mortality and to examine the role of health behavior in explaining this association. METHODS: Participants (N = 9,949) aged 50 and over from the English Longitudinal Study of Ageing, a representative cohort of older English adults, estimated the length of their time horizon for financial planning (time perspective). Two thousand ninety-two deaths were recorded over a 9-year follow-up period (2002/2003-2012). Smoking, physical activity, and alcohol consumption were examined as factors that may underlie the time perspective-mortality link. RESULTS: Our prospective survival analyses showed that those who tend to plan for longer periods experienced a significantly reduced risk of all-cause mortality (HR = 0.83; 95% confidence interval [CI]: [0.80, 0.87], p < .001 per 1 SD increase in future time perspective). This association remained after adjusting for baseline socioeconomic status and health (HR = 0.92; 95% CI: [0.88, 0.97], p < .001). The link between time perspective and mortality was observed across the gradient of financial circumstances and did not appear to be due to reverse causality. Healthy behavior among the more future orientated explained 34% of the link between time perspective and mortality. CONCLUSIONS: Using a simply administered indicator of time perspective, this study suggests that a future-orientated time perspective may be an important predictor of reduced risk of death.

18.
PLoS Med ; 16(12): e1003006, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31891574

RESUMO

BACKGROUND: Adjuvant chemotherapy in early stage breast cancer has been shown to reduce mortality in a large meta-analysis of over 100 randomised trials. However, these trials largely excluded patients aged 70 years and over or with higher levels of comorbidity. There is therefore uncertainty about whether the effectiveness of adjuvant chemotherapy generalises to these groups, hindering patient and clinician decision-making. This study utilises administrative healthcare data-real world data (RWD)-and econometric methods for causal analysis to estimate treatment effectiveness in these trial-underrepresented groups. METHODS AND FINDINGS: Women with early breast cancer aged 70 years and over and those under 70 years with a high level of comorbidity were identified and their records extracted from Scottish Cancer Registry (2001-2015) data linked to other routine health records. A high level of comorbidity was defined as scoring 1 or more on the Charlson comorbidity index, being in the top decile of inpatient stays, and/or having 5 or more visits to specific outpatient clinics, all within the 5 years preceding breast cancer diagnosis. Propensity score matching (PSM) and instrumental variable (IV) analysis, previously identified as feasible and valid in this setting, were used in conjunction with Cox regression to estimate hazard ratios for death from breast cancer and death from all causes. The analysis adjusts for age, clinical prognostic factors, and socioeconomic deprivation; the IV method may also adjust for unmeasured confounding factors. Cohorts of 9,653 and 7,965 were identified for women aged 70 years and over and those with high comorbidity, respectively. In the ≥70/high comorbidity cohorts, median follow-up was 5.17/6.53 years and there were 1,935/740 deaths from breast cancer. For women aged 70 years and over, the PSM-estimated HR was 0.73 (95% CI 0.64-0.95), while for women with high comorbidity it was 0.67 (95% CI 0.51-0.86). This translates to a mean predicted benefit in terms of overall survival at 10 years of approximately3% (percentage points) and 4%, respectively. A limitation of this analysis is that use of observational data means uncertainty remains both from sampling uncertainty and from potential bias from residual confounding. CONCLUSIONS: The results of this study, as RWD, should be interpreted with caution and in the context of existing and emerging randomised data. The relative effectiveness of adjuvant chemotherapy in reducing mortality in patients with early stage breast cancer appears to be generalisable to the selected trial-underrepresented groups.

19.
Am J Dent ; 31(5): 227-233, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30346667

RESUMO

PURPOSE: To evaluate in vitro enamel sample discoloration following exposure to a scientific reference cigarette (3R4F) or emissions from next generation tobacco and nicotine products (NGPs) such as electronic cigarettes (EC) and tobacco heating products (THP). METHODS: Bovine enamel blocks (6.5 × 6.5 mm) were prepared and pre-incubated with human or artificial saliva, to form a pellicle layer before exposure to either particulate matter (PM) or whole aerosols. PM was prepared by capturing 3R4F cigarette smoke (CS), a commercial THP (THP1.0) or a novel vapor product (NVP)/next generation e-cigarette aerosols on Cambridge filter pads followed by elution with dimethyl sulfoxide (DMSO). Ten enamel samples were exposed to each PM for 14 days. For aerosol exposure, 12 enamel samples were exposed (200 puffs per day, for 5 consecutive days) to 3R4F CS or THP1.0 and NVP aerosols. Control samples were incubated with DMSO (PM study) or phosphate buffered saline (PBS, aerosol study). Individual enamel sample color readings (L*, a*, b*) were measured at baseline and on each exposure day. Mean ΔL*, Δa*, Δb* and ΔE values were calculated for each product or control. A one-way ANOVA was used to assess the differences between the products and controls. The Tukey procedure for pairwise comparisons was also used. RESULTS: At all timepoints, 3R4F PM and CS induced enamel discoloration that was statistically significant (< 0.0001) when compared to THP1.0 or NVP. After 14-day PM exposure, mean ΔE values were 29.4± 3.6, 10.5 ± 2.3, 10.7 ± 2.6 and 12.6 ± 2.0 for 3R4F, THP1.0, NVP and DMSO control respectively. After 5-day CS or aerosol exposure, mean ΔE values were 26.2 ± 3.2, 3.6 ± 1.9, 3.4 ± 1.3, 5.3 ± 0.8 for 3R4F CS, THP1.0, NVP or PBS control, respectively. Both exposure methods demonstrated that THP1.0 and NVP induced minimal staining, mean ΔL* , Δa* , Δb* and ΔE values were comparable to DMSO or PBS controls. CLINICAL SIGNIFICANCE: For the first time, diverse NGPs across the risk continuum were assessed in vitro for their impact on enamel staining. CS exposure significantly increased the level of bovine enamel sample discoloration, whereas THP1.0 or NVP exposure resulted in values comparable to the controls.


Assuntos
Esmalte Dentário , Sistemas Eletrônicos de Liberação de Nicotina , Descoloração de Dente , Aerossóis , Animais , Bovinos , Esmalte Dentário/efeitos dos fármacos , Calefação , Humanos , Fumar , Tabaco
20.
Neurosci Lett ; 687: 280-284, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30267851

RESUMO

Despite the increasing use of continuous theta burst (cTBS) protocols targeting the prefrontal cortex in clinical and research settings, very little is known regarding the interindividual factors that influence the magnitude and duration of cTBS aftereffects. The few existing studies have predominantly focussed on motor and corticospinal excitability, and the applicability of such findings to prefrontal modulation remains unclear. The current investigation aggregated published data from our laboratory to (1) assess the reproducibility of the effects of cTBS targeting the left dorsolateral prefrontal cortex (dlPFC) on executive function task performance, and (2) determine which factors are associated with individual differences in cTBS responsivity. Data from 76 healthy young adult female participants aged 19-26 (M = 20.6; SD = 1.6) were included in the analyses. Significant attenuations in executive function task performance from baseline were observed following active cTBS. However, these effects were not totally universal in that cTBS-induced attenuation of executive functions was observed in 61.8% of participants (i.e., responders). In addition, baseline task performance was a significant predictor of the magnitude of the cTBS-induced change in task performance in that cTBS effect was larger for individuals with higher baseline executive control abilities than those with lower abilities. Together, these data provide a quantitative estimate of the degree to which healthy participants may vary in the responsiveness to prefrontal cTBS, and potential moderating factors.


Assuntos
Atenção/fisiologia , Córtex Motor/fisiologia , Córtex Pré-Frontal/fisiologia , Ritmo Teta/fisiologia , Adulto , Função Executiva/fisiologia , Feminino , Humanos , Estudos Longitudinais , Reprodutibilidade dos Testes , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
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