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The American West in bronze, 1850-1925
Themes of the American West have been enduringly popular, and 'The American West in Bronze' features sixty-five iconic bronzes that display a range of subjects, from portrayals of the noble Indian to rough-and-tumble scenes of rowdy cowboys to tributes to the pioneers who settled the lands west of the Mississippi. Fascinating texts offer a fresh look at the roles that artists played in creating interpretations of the \"vanishing West\"--Whether based on fact, fiction or something in-between. These artists, including Charles M. Russell and Frederic Remington, embody a range of life experiences and artistic approaches.
Book
Accessible analysis of longitudinal data with linear mixed effects models
Longitudinal studies are commonly used to examine possible causal factors associated with human health and disease. However, the statistical models, such as two-way ANOVA, often applied in these studies do not appropriately model the experimental design, resulting in biased and imprecise results. Here, we describe the linear mixed effects (LME) model and how to use it for longitudinal studies. We re-analyze a dataset published by Blanton et al. in 2016 that modeled growth trajectories in mice after microbiome implantation from nourished or malnourished children. We compare the fit and stability of different parameterizations of ANOVA and LME models; most models found that the nourished versus malnourished growth trajectories differed significantly. We show through simulation that the results from the two-way ANOVA and LME models are not always consistent. Incorrectly modeling correlated data can result in increased rates of false positives or false negatives, supporting the need to model correlated data correctly. We provide an interactive Shiny App to enable accessible and appropriate analysis of longitudinal data using LME models.
Journal Article
Evaluation of the clinical utility of the PromarkerD in-vitro test in predicting diabetic kidney disease and rapid renal decline through a conjoint analysis
Early identification of patients at risk of developing diabetic kidney disease or rapid renal decline is imperative for appropriate patient management, but traditional methods of predicting renal decline are limited.
This study evaluated the impact of PromarkerD, a biomarker-based blood test predicting the risk of diabetic kidney disease (DKD) and rapid renal decline.
Conjoint analysis clarified the importance of PromarkerD and other patient attributes to physician decisions for type 2 diabetes patients. Forty-two patient profiles were generated, with varying levels of albuminuria, estimated glomerular filtration rate (eGFR), blood pressure, hemoglobin A1c (HbA1c), age, and PromarkerD result. A web-based survey asked each physician to make monitoring/treatment decisions about eight randomly selected profiles. Data were analyzed using multivariable logit models.
Two hundred three primary care physicians and 197 endocrinologists completed the survey. PromarkerD result was most important for increasing the frequency of risk factor monitoring. PromarkerD was second to HbA1c in importance for deciding to prescribe sodium/glucose cotransporter-2 inhibitors (SGLT2s) with a DKD indication, second to blood pressure for increasing the dose of lisinopril, and second to eGFR for replacing ibuprofen with a non-nephrotoxic medication. Compared with no PromarkerD results, a high-risk PromarkerD result was associated with significantly higher odds of increasing monitoring frequency (odds ratio [OR]: 2.56, 95% confidence interval: 1.90-3.45), prescribing SGLT2s (OR: 1.98 [1.56-2.52]), increasing lisinopril dose (OR: 1.48 [1.17-1.87]), and replacing ibuprofen (OR: 1.78 [1.32-2.40]). A low-risk PromarkerD result was associated with significantly lower odds of increasing monitoring frequency (OR: 0.48 [0.37-0.64]), prescribing SGLT2s (OR: 0.70 [0.56-0.88]), and replacing ibuprofen (OR: 0.75 [0.57-0.99]).
PromarkerD could increase adoption of renoprotective interventions in patients at high risk for renal decline and lower the likelihood of aggressive treatment in those at low risk. Further studies are needed to assess patient outcomes with PromarkerD in real-world practice.
Journal Article
Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
HER2
mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in
HER2
-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic
HER2
somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common
HER2
mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic
TP53
and
CDKN2A
alterations. Loss of amplified
HER2
S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring
HER2
mutations, the primary endpoint was not met and combinations may be explored.
In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.
Journal Article
Prospective comparison of transient, point shear wave, and magnetic resonance elastography for staging liver fibrosis
ObjectivesTo perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE).MethodsThis prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6 weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method.ResultsTE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85–0.93), 0.90 (95% CI 0.85–0.94), and 0.94 (95% CI 0.91–0.96).ConclusionMRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis.Trial registrationNCT02044523Key Points• The technical failure rate was similar between MRE and US-based elastography techniques.• Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis.• MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.
Journal Article
Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
Journal Article
Predicting amputation using machine learning: A systematic review
Amputation is an irreversible, last-line treatment indicated for a multitude of medical problems. Delaying amputation in favor of limb-sparing treatment may lead to increased risk of morbidity and mortality. This systematic review aims to synthesize the literature on how ML is being applied to predict amputation as an outcome. OVID Embase, OVID Medline, ACM Digital Library, Scopus, Web of Science, and IEEE Xplore were searched from inception to March 5, 2023. 1376 studies were screened; 15 articles were included. In the diabetic population, models ranged from sub-optimal to excellent performance (AUC: 0.6–0.94). In trauma patients, models had strong to excellent performance (AUC: 0.88–0.95). In patients who received amputation secondary to other etiologies (e.g.: burns and peripheral vascular disease), models had similar performance (AUC: 0.81–1.0). Many studies were found to have a high PROBAST risk of bias, most often due to small sample sizes. In conclusion, multiple machine learning models have been successfully developed that have the potential to be superior to traditional modeling techniques and prospective clinical judgment in predicting amputation. Further research is needed to overcome the limitations of current studies and to bring applicability to a clinical setting.
Journal Article
Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia
Background:
Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾5 mg l
−1
) and no cachexia (no cachexia and CRP: <5 mg l
−1
).
Methods:
A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software.
Results:
In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (
P
=0.005 and
P
=0.02, respectively), TGF
β
1 (
P
=0.042 and
P
<0.0001, respectively) and CRP (both
P
<0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (
P
=0.005), IL-8 (
P
=0.001) and absolute neutrophil counts (
P
=0.007).
Conclusions:
Ang II, TGF
β
1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia.
Journal Article
Trauma-Focused Tuning in to Kids: Evaluation in a Clinical Service
This study evaluated the Tuning in to Kids (TIK) parenting program delivered in a clinical setting with 77 parents and caregivers (hereafter referred to as “parents”) of children who had experienced complex trauma. The TIK program targets parent emotion socialization to improve children’s emotional and behavioral functioning. The study utilized a single-group design with pre- and post-intervention measures. Seventy-seven parents of children (aged 3–15 years) who had experienced complex trauma completed a ten-week version of the Trauma-Focused Tuning in to Kids program (TF-TIK). Measures examined parent reports of: emotion socialization; parent-child relationship; parent mental health; children’s emotional and behavioral functioning. Parents reported significantly improved emotion socialization, parent-child relationship, parent mental health, as well as child emotion regulation and behavior. This study provides initial support for the use of the TF-TIK parenting program in a clinical setting with parents of children who have experienced complex trauma in order to prevent or reduce problems.
Journal Article
Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression
Dysfunction of the proteins regulating synaptic function can cause synaptic plasticity imbalance that underlies neurological disorders such as intellectual disability. A study found that four distinct mutations within BRAG1, an Arf-GEF synaptic protein, each led to X-chromosome-linked intellectual disability (XLID). Although the physiological functions of BRAG1 are poorly understood, each of these mutations reduces BRAG1’s Arf-GEF activity. Here we show that BRAG1 is required for the activity-dependent removal of AMPA receptors in rat hippocampal pyramidal neurons. Moreover, we show that BRAG1 bidirectionally regulates synaptic transmission. On one hand, BRAG1 is required for the maintenance of synaptic transmission. On the other hand, BRAG1 expression enhances synaptic transmission, independently of BRAG1 Arf-GEF activity or neuronal activity, but dependently on its C-terminus interactions. This study demonstrates a dual role of BRAG1 in synaptic function and highlights the functional relevance of reduced BRAG1 Arf-GEF activity as seen in the XLID-associated human mutations.
BRAG1 mutations are linked to synaptic deficits and X-chromosome linked intellectual disability. Here, the authors show that BRAG1 mediates activity-dependent removal of synaptic AMPA receptors via Arf-GEF activity and PDZ interactions, and is required for maintaining AMPAR-mediated synaptic transmission.
Journal Article