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1.
Neurology ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666352

RESUMO

OBJECTIVE: To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development. METHODS: A total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69-71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and ß-amyloid (Aß) positivity (determined from Aß-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4. RESULTS: Childhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aß positivity and WMHV were independently associated with lower PACC scores, and Aß positivity was associated with poorer nonverbal reasoning. Aß positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aß-negative participants are provided. CONCLUSIONS: This study adds to emerging evidence that subtle cognitive differences associated with Aß deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.

2.
Intern Med J ; 49(10): 1221-1228, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31602772

RESUMO

Recent trials within the past few years have influenced not only how we treat patients immediately after acute ischaemic stroke, but also how we investigate for aetiology. With the advent of improved medications, procedures and monitoring devices, modern stroke prevention strategies are more individualised, but the decision-making process is more complex. We provide an approach to navigating these management options.

3.
World Neurosurg ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31568915

RESUMO

OBJECTIVE: The middle fossa craniotomy for tegmen defect repair provides wide access. This approach often requires temporal lobe manipulation, lumbar drain placement, and longer recovery. We describe a keyhole middle fossa approach with a simple titanium skull base repair that allows for wide access with no temporal lobe manipulation and does not require lumbar drain placement, which results in a dramatic reduction in hospital length of stay. METHODS: A retrospective review was performed on 14 consecutive patients with spontaneous cerebrospinal fluid (CSF) otorrhea. Each patient underwent a keyhole middle fossa approach followed by multilayer dural repair with titanium mesh "gull wing" skull base reconstruction. Postoperative measures included operative time, length of hospital stay, CSF leak recurrence, and surgical complications (seizures, hemorrhage, aphasia, infection). RESULTS: The average age of the patients was 60.7 ± 12.7 years old, and average body mass index was 32.8 ± 7.9 kg/m2. Nine of the patients were female. The average operative time was 103 ± 32.8 minutes. The average hospital length of stay was 1.4 days. There were no cases of postoperative CSF otorrhea, meningitis, aphasia, or seizures. There were no recurrences over a mean follow-up of 20.3 months (range: 5-48 months). CONCLUSIONS: A minimally invasive keyhole middle fossa approach with a multilayer dural reconstruction including titanium mesh "gull wing" skull base repair provides a quick, effective treatment for a broad spectrum of tegmen defects and meningoencephaloceles. This exposure and reconstruction technique do not require the use of a lumbar drain and result in minimal hospitalization.

4.
Neurobiol Aging ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31582231

RESUMO

The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

5.
PLoS One ; 14(10): e0224030, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622410

RESUMO

BACKGROUND: The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral ß-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited. METHODS: Using cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of ß-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume. RESULTS: Compared to ß-amyloid negative participants (n = 334), ß-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes. CONCLUSION: These data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and ß-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the ß-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31630156

RESUMO

BACKGROUND: DNA methylation (DNAm) age acceleration (AgeAccel) has been shown to be predictive of all-cause mortality but it is unclear what functional aspect/s of ageing it captures. We examine associations between four measures of AgeAccel in adults aged 45-87 years and physical and cognitive performance and their age-related decline. METHODS: AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno and AgeAccelGrim were calculated in the Medical Research Council National Survey of Health and Development (NSHD), National Child Development Study (NCDS) and TwinsUK. Three measures of physical (grip strength, chair rise speed and forced expiratory volume in one second[FEV1]) and two measures of cognitive (episodic memory and mental speed) performance were assessed. RESULTS: AgeAccelPheno and AgeAccelGrim, but not AgeAccelHannum and AgeAccelHorvath were related to performance in random effects meta-analyses (n=1388-1685). For example, a one year increase in AgeAccelPheno/AgeAccelGrim was associated with a 0.01ml[95%CI:0.01,0.02]/0.03ml[95%CI:0.01,0.05] lower mean FEV1. In NSHD, AgeAccelPheno and AgeAccelGrim at 53 years were associated with age-related decline in performance between 53 and 69 years as tested by linear mixed models (p<0.05). In a subset of NSHD participants(n=482), there was little evidence that change in any AgeAccel measure was associated with change in performance conditional on baseline performance. CONCLUSIONS: We found little evidence to support associations between the first generation of DNAm-based biomarkers of ageing and age-related physical or cognitive performance in mid-life to early old age. However, there was evidence that the second generation biomarkers, AgeAccelPheno and AgeAccelGrim, could act as makers of an individual's health-span as proposed.

7.
JAMA Netw Open ; 2(9): e1911528, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31532517

RESUMO

Importance: Social media campaigns have been successfully implemented in nontherapeutic trials. However, evidence to support their utility in cancer therapeutic trials is limited. Objective: To examine physician attitudes toward and perceptions of social media use for therapeutic trial recruitment of patients with cancer. Design, Setting, and Participants: This qualitative study engaged 44 physicians (24 academic based and 20 community based) at the main academic and 6 affiliated community sites of City of Hope in Duarte, California. Semistructured interviews were conducted in person or by telephone from March to June 2018. An interview guide was developed to explore perceptions of social media use for accrual of cancer therapeutic trials. Responses were recorded digitally and transcribed. Data were analyzed using qualitative content analysis. Main Outcomes and Measures: Physicians' perceptions of the advantages and disadvantages of using social media for clinical trial recruitment, strategies to improve uptake of social media in clinical trials, and the barriers and facilitators to social media use for professional purposes in general. Results: Of the 44 participants, 16 (36%) were women, 30 (68%) had more than 10 years of practice experience, 24 (55%) practiced in academia, and 20 (45%) practiced in the community. Physicians most commonly cited increased trial awareness and visibility as an advantage of using social media for trial recruitment. Cited disadvantages were increased administrative burden and risk of misinformation. Physicians also reported a need for institutional-level interventions (eg, restructuring of clinical trial offices to include personnel with social media expertise), increased evidence-based approaches to social media use, and more physician training on the use of social media. Perceived facilitators to professional social media use were networking and education; barriers included lack of time and lack of evidence of benefit. Conclusions and Relevance: In this qualitative study, physicians recognized the benefits of using social media for clinical trial recruitment but noted that barriers, including increased administrative burden, increased time, and the risk of misinformation, remain. Future interventions to address these concerns are a required first step in increasing digital engagement for clinical trial accrual purposes.

8.
Lancet Neurol ; 18(10): 942-952, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444142

RESUMO

BACKGROUND: Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition. METHODS: Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69-71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London (London, UK); all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60-64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-ß positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score-the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60-64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-ß status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders. FINDINGS: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants (238 [51%] men; mean age 70·7 years [SD 0·7]; 83 [18%] amyloid-ß-positive) were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69-71 years of age (increase in mean WMHV per 10 mm Hg greater SBP 7%, 95% CI 1-14, p=0·024; increase in mean WMHV per 10 mm Hg greater DBP 15%, 4-27, p=0·0057; increase in mean WMHV per one SD change in SBP 15%, 3-29, p=0·012; increase in mean WMHV per 1 SD change in DBP 15%, 3-30, p=0·017). Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69-71 years of age (-6·9 mL per 10 mm Hg greater DBP, -11·9 to -1·9, p=0·0068), as were greater increases in DBP between 36 and 43 years of age (-6·5 mL per 1 SD change, -11·1 to -1·9, p=0·0054). Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69-71 years of age (-0·03 mL per 1 SD change, -0·06 to -0·001, p=0·043). Neither absolute blood pressure nor change in blood pressure predicted amyloid-ß status or PACC score at 69-71 years of age. INTERPRETATION: High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69-71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-ß load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health. FUNDING: Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals.

9.
Stud Health Technol Inform ; 264: 158-162, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437905

RESUMO

Emergency department (ED) overcrowding has been a pain point in hospitals across the globe. "Frequent flyers," who visited the ED at a much higher rate than average, account for almost one third of ED visits even though they represent only a small proportion of all ED patients. In this study, we used data-mining methods to cluster ED frequent flyers at a large academic medical center in the US. The objective was to identify distinct types of frequent flyers, and the common characteristics associated with each type. The results show that the frequent flyers at the ED have three subgroups each exhibiting distinct characteristics: (1) the elderly with chronic health conditions, (2) middle-aged males with unhealthy behavior, and (3) adult females who are generally healthy. These findings may inform targeted interventional strategies for patients of each subgroup, who likely have distinct reasons for visiting the ED frequently, to reduce ED overcrowding.


Assuntos
Centros Médicos Acadêmicos , Serviço Hospitalar de Emergência , Análise por Conglomerados , Feminino , Humanos , Masculino , Dor
10.
BMJ Open ; 9(7): e029502, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31371298

RESUMO

OBJECTIVE: To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study. DESIGN: Prospective observational sub-study of a birth cohort. SETTING: Single-day assessment at a research centre in London, UK. PARTICIPANTS: 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female. OUTCOME MEASURES: Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated. RESULTS: 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11). CONCLUSIONS: In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings.

11.
J Geriatr Oncol ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31375399

RESUMO

OBJECTIVES: Oncologists can be one of the major barriers to older adult's participation in research. Multiple studies have described academic clinicians' concerns for not enrolling older adults onto trials. Although the majority of older adults receive their cancer care in the community, few studies have examined the unique challenges that community oncologists face and how they differ from oncologist-related barriers in academia. METHODS: Semi-structured interviews were conducted by telephone or face-to-face with 44 medical oncologists (24 academic-based and 20 community-based) at City of Hope from March to June 2018. Interviews explored oncologists' perceptions of barriers to clinical trial enrollment of older adults with cancer. Data were analyzed using qualitative content analysis. RESULTS: Of the 44 participants, 36% were women and 68% were in practice for >10 years. Among the entire sample, stringent eligibility criteria (n = 20) and oncologist concerns for treatment toxicities (n = 15) were the most commonly cited barriers. Compared to academic oncologists, community oncologists more often cited patient attitudes, beliefs, and understanding (n = 9 vs. n = 2) and caregiver burden (n = 6 vs. n = 0). In contrast, compared to community oncologists, academic oncologists more often cited oncologist bias (n = 10 vs. n = 3) and insufficient time/support (n = 4 vs. n = 1). CONCLUSIONS: Differences in perceptions among academic and community oncologists about trials suggest that barriers are multifaceted, complex, and vary by practice setting. Interventions to increase trial accrual among older adults with cancer may benefit from being tailored to address the unique barriers of different practice settings.

13.
World Neurosurg ; 131: 186-190, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421294

RESUMO

BACKGROUND: Rathke cleft cysts (RCCs) are benign cysts arising from the pars intermedia as a result of incomplete obliteration of the Rathke pouch during development of the pituitary gland. The most common presenting symptoms are headaches, visual disturbances, and endocrinopathies. Recurrence of RCCs after surgical treatment is a well-known phenomenon after surgery with reported recurrence rates as high as 30%. Various methods have been employed to reduce the rate of recurrence. Complete cyst wall resection has been associated with increased rates of perioperative cerebrospinal fluid leak, diabetes insipidus, and carotid injury, while inconsistently demonstrating reduced recurrence rates. Marsupialization, in which the cyst cavity is widely exposed and left open with or without a fat graft suspension, has similarly shown increased morbidity without clear improvement in outcomes. We report here the use of a steroid-eluting sinus stent to maintain patency of the cyst opening. CASE DESCRIPTION: A 39-year-old female presented with a symptomatic RCC. She underwent 4 different surgeries including cyst wall resection, marsupialization, and fat graft placement. She developed short-term symptomatic and radiographic recurrence within 3 months of each surgery. She then underwent placement of a steroid-eluting sinus stent. At 3 months, the patient remained symptom free, without radiographic recurrence and with patent cyst fenestration on nasal endoscopy. CONCLUSIONS: Recurrent RCCs are challenging to manage. Strategies to reduce recurrence are typically associated with higher risk and varying success. Stent placement represents a simple, low-risk method of potentially maintaining patency of cyst fenestration.

14.
Diabetologia ; 62(10): 1891-1900, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359084

RESUMO

AIMS/HYPOTHESIS: Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship. METHODS: From the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA1c) assessed at age 60-64 years, and cognitive state (Addenbrooke's Cognitive Examination III [ACE-III]) and verbal memory assessed at age 69 years. Earlier-life measures included socioeconomic position (SEP), cognition at age 8 years and educational attainment. Polygenic risk scores (PRSs) for type 2 diabetes were calculated. We first used a PRS approach with multivariable linear regression to estimate associations between PRSs and metabolic traits and later-life cognitive state. Second, using a path model approach, we estimated the interrelationships between earlier-life measures, features of mid-life type 2 diabetes and cognitive state at age 69 years. All models were adjusted for sex. RESULTS: The externally weighted PRS for type 2 diabetes was associated with mid-life metabolic traits (e.g. HOMA2-IR ß = 0.08 [95% CI 0.02, 0.16]), but not with ACE-III (ß = 0.04 [-0.02, 0.90]) or other cognitive outcomes. While there was an association between HOMA2-IR and subsequent ACE-III (ß = -0.09 [-0.15, -0.03]), path modelling showed no direct effect (ß = -0.01 [-0.06, 0.03]) after accounting for the association between childhood SEP and education with HOMA2-IR. The same pattern was observed for later-life verbal memory. CONCLUSIONS/INTERPRETATION: Associations between type 2 diabetes and mid-life metabolic traits with subsequent cognitive state do not appear causal, and instead they may be explained by SEP in early life, childhood cognition and educational attainment. Therefore, glucose-lowering medication may be unlikely to combat cognitive impairment in older age.

16.
J Cereb Blood Flow Metab ; 39(8): 1413-1432, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31208241

RESUMO

The metabolic demands of the brain are met by oxygen and glucose, supplied by a complex hierarchical network of microvessels (arterioles, capillaries, and venules). Transient changes in neural activity are accommodated by local dilation of arterioles or capillaries to increase cerebral blood flow and hence nutrient availability. Transport and communication between the circulation and the brain is regulated by the brain microvascular endothelial cells that form the blood-brain barrier. Under homeostatic conditions, there is very little turnover in brain microvascular endothelial cells, and the cerebrovascular architecture is largely static. However, changes in the brain microenvironment, due to environmental factors, disease, or trauma, can result in additive or subtractive changes in cerebrovascular architecture. Additions occur by angiogenesis or vasculogenesis, whereas subtractions occur by vascular pruning, injury, or endothelial cell death. Here we review the various processes that lead to changes in the cerebrovascular architecture, including sustained changes in the brain microenvironment, development and aging, and injury, disease, and repair.

17.
Genet Med ; 21(10): 2406-2407, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31043710

RESUMO

In the original version of this Article, the affiliation details for Drs. Jordan Lerner-Ellis and George Charames did not include the Department of Pathology and Laboratory Medicine at the University of Toronto. In addition, Drs. Jordan Lerner-Ellis and George Charames were incorrectly affiliated with the Institute of Health Policy, Management and Evaluation at the University of Toronto. These errors have now been corrected in both the PDF and HTML versions of the Article.

18.
Diabetes ; 68(8): 1681-1691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088856

RESUMO

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

19.
Sci Rep ; 9(1): 7390, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089155

RESUMO

ENMD-2076, an aurora-A kinase inhibitor with anti-angiogenic properties, has shown activity in solid and hematologic malignancies. We investigated oral ENMD-2076 in an open-label, single-arm phase II study using 275 mg daily on a 28-day cycle in patients with advanced soft-tissue sarcomas (STS) receiving ≤1 line of prior therapy. Primary endpoint was 6-month progression-free survival (PFS) with ≤15% indicating no interest, and ≥40% indicating further interest in ENMD-2076. Secondary/exploratory endpoints included clinical benefit (CBR ≥6-months) and objective response (ORR) rates, PFS, OS, safety, and whole-exome sequencing (WES) for potentially associated biomarkers. Overall, 23/25 (92%) patients receiving ENMD-2076 were efficacy evaluable with median follow-up of 14 months (range 2.2-39.5). Common subtypes were leiomyosarcoma (n = 10), undifferentiated pleomorphic sarcoma (n = 3), angiosarcoma (n = 3), and alveolar soft-part sarcoma (n = 3). The 6-month PFS was 20.8% (95% CI:3.2-38.4) with a CBR of 17% (95% CI:1.55-33.23) and ORR of 9% (95% CI:3.08-20.46). Median PFS was 2.5 months (95% CI:2.20-4.47) and OS was 14.1 months (95% CI:6.07-20.07). The most common high-grade treatment-related adverse event was hypertension (60%). WES identified PTPRB mutations in 3/4 patients (p = 0.018) benefiting from ENMD-2076. Although this study failed to meet its primary endpoint, occasional responses and prolonged stable disease was noted. ENMD-2076 evaluation in PTPRB mutated tumors and/or angiosarcoma is warranted.

20.
Clin Biomech (Bristol, Avon) ; 67: 90-95, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082636

RESUMO

BACKGROUND: Anterior cruciate ligament injuries are among the most common injuries in high impact sports, and reconstruction is the standard surgical procedure for these ruptures. Reconstructions are often performed using allografts rather than autografts on a case-by-case basis. Controversy exists as to whether or not age of donor tissue plays a factor in the mechanical properties of allografts. METHODS: 38 peroneus longus (PL) tendons were prepared using the two-strand graft technique and then subjected to a cyclic loading test regimen of 1000 cycles to determine material properties. Specimens were grouped based on age to ascertain whether donor age affects the material properties of PL tendons. FINDINGS: Secant modulus of the first cycle was determined to be 150.43 (SD 40.24) MPa. The average magnitude of the dynamic modulus was determined to be 82.81 (SD 24.65) MPa. Specimens were grouped into three distinct groups for analysis (x < 40 yo, 40 yo ≤ x < 60 yo, 60 yo < x). INTERPRETATION: The need for using intrinsic material properties is highlighted. There is no significant difference in any intrinsic material property with respect to age or the fatigue of the tendon as the cycle count increases. Conversely, the measured stiffness of a tendon decreased as function of age with a large effect size. Based on analysis of graft geometries, it was determined that PL tendons become significantly more slender with increased age which result in the observed decrease in stiffness.

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