Constant Curvature Coefficients and Exact Solutions in Fractional Gravity and Geometric Mechanics

We study fractional configurations in gravity theories and Lagrange mechanics. The approach is based on Caputo fractional derivative which gives zero for actions on constants. We elaborate fractional geometric models of physical interactions and we formulate a method of nonholonomic deformations to other types of fractional derivatives. The main result of this paper consists in a proof that for corresponding classes of nonholonomic distributions a large class of physical theories are modelled as nonholonomic manifolds with constant matrix curvature. This allows us to encode the fractional dynamics of interactions and constraints into the geometry of curve flows and solitonic hierarchies.Comment: latex2e, 11pt, 27 pages, the variant accepted to CEJP; added and up-dated reference

Anticholinergic burden in older women: not seeing the wood for the trees?

Objectives: To identify medicines contributing to and describe predictors of anticholinergic burden among community-dwelling older Australian women. Design, setting and participants: Retrospective longitudinal analysis of data from the Australian Longitudinal Study on Women's Health linked to Pharmaceutical Benefits Scheme medicines data from 1 January 2008 to 30 December 2010; for 3694 women born in 1921–1926. Main outcome measures: Anticholinergic burden calculated from Anticholinergic Drug Scale (ADS) scores derived from ADS levels (0 to 3) for all medicines used by each woman, summed over each 6-month period (semester), medicines commonly used by women with high semester ADS scores (defined as 75th percentile of scores). Results: 1126 women (59.9%) used at least one medicine with anticholinergic properties. The median ADS score was 4 or 5 across all semesters. Most anticholinergic medicines used by women who had a high anticholinergic burden (ADS score, = 9) had a low anticholinergic potency (ADS level 1). Increasing age, cardiovascular disease, and number of other medicines used were predictive of a higher anticholinergic burden. Conclusions: A high anticholinergic medicines burden in this group was driven by the use of multiple medicines with lower anticholinergic potency rather than the use of medicines with higher potency. This is a novel and important finding for clinical practice as doctors would readily identify the risk of a high anticholinergic burden for patients using high potency medicines, but may be less likely to identify this risk for users of multiple medicines with low anticholinergic potency

Numerical investigation of three types of space and time fractional Bloch-Torrey equations in 2D

Recently, the fractional Bloch-Torrey model has been used to study anomalous diffusion in the human brain. In this paper, we consider three types of space and time fractional Bloch-Torrey equations in two dimensions: Model-1 with the Riesz fractional derivative; Model-2 with the one-dimensional fractional Laplacian operator; and Model-3 with the two-dimensional fractional Laplacian operator. Firstly, we propose a spatially second-order accurate implicit numerical method for Model-1 whereby we discretize the Riesz fractional derivative using a fractional centered difference. We consider a finite domain where the time and space derivatives are replaced by the Caputo and the sequential Riesz fractional derivatives, respectively. Secondly, we utilize the matrix transfer technique for solving Model-2 and Model-3. Finally, some numerical results are given to show the behaviours of these three models especially on varying domain sizes with zero Dirichlet boundary conditions

The International comparison of Systems of care and patient outcomes In minor Stroke and Tia (InSIST) study: A community-based cohort study

This is the author accepted manuscript. The final version is available from Sage Publications via the DOI in this record.Rationale: Rapid response by health-care systems for transient ischemic attack and minor stroke (TIA/mS) is recommended to maximize the impact of secondary prevention strategies. The applicability of this evidence to Australian non-hospital-based TIA/mS management is uncertain. Aims: Within an Australian community setting we seek to document processes of care, establish determinants of access to care, establish attack rates and determinants of recurrent vascular events and other clinical outcomes, establish the performance of ABC2-risk stratification, and compare the processes of care and outcomes to those in the UK and New Zealand for TIA/mS. Sample size estimates: Recruiting practices containing approximately 51 full-time-equivalent general practitioners to recruit 100 TIA/mS per year over a four-year study period will provide sufficient power for each of our outcomes. Methods and design: An inception cohort study of patients with possible TIA/mS recruited from 16 general practices in the Newcastle-Hunter Valley-Manning Valley region of Australia. Potential TIA/mS will be ascertained by multiple overlapping methods at general practices, after-hours collaborative, and hospital in-patient and outpatient services. Participants’ index and subsequent clinical events will be adjudicated as TIA/mS or mimics by an expert panel. Study outcomes: Process outcomes—whether the patient was referred for secondary care; time from event to first patient presentation to a health professional; time from event to specialist acute-access clinic appointment; time from event to brain and vascular imaging and relevant prescriptions. Clinical outcomes—recurrent stroke and major vascular events; and health-related quality of life. Discussion: Community management of TIA/mS will be informed by this study.Nationale Health and Medical Research Council (NHMRC

The characteristics of patients with possible Transient Ischemic Attack and Minor Stroke in the Hunter and Manning Valley regions, Australia (the INSIST Study)

This is the final version. Available on open access from the American Academy of Neurology via the DOI in this record. Background: Transient ischemic attack (TIA) and minor stroke (TIAMS) are risk factors for stroke recurrence. Some TIAMS may be preventable by appropriate primary prevention. We aimed to recruit “possible-TIAMS” patients in the INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study. Methods: A prospective inception cohort study performed across 16 Hunter–Manning region, Australia, general practices in the catchment of one secondary-care acute neurovascular clinic. Possible-TIAMS patients were recruited from August 2012 to August 2016. We describe the baseline demographics, risk factors and pre-event medications of participating patients. Results: There were 613 participants (mean age; 69 ± 12 years, 335 women), and 604 (99%) were Caucasian. Hypertension was the most common risk factor (69%) followed by hyperlipidemia (52%), diabetes mellitus (17%), atrial fibrillation (AF) (17%), prior TIA (13%) or stroke (10%). Eighty-nine (36%) of the 249 participants taking antiplatelet therapy had no known history of cardiovascular morbidity. Of 102 participants with known AF, 91 (89%) had a CHA2DS2-VASc score ≥ 2 but only 47 (46%) were taking anticoagulation therapy. Among 304 participants taking an antiplatelet or anticoagulant agent, 30 (10%) had stopped taking these in the month prior to the index event. Conclusion: This study provides the first contemporary data on TIAMS or TIAMS-mimics in Australia. Community and health provider education is required to address the under-use of anticoagulation therapy in patients with known AF, possibly inappropriate use of antiplatelet therapy and possibly inappropriate discontinuation of antiplatelet or anticoagulation therapy.National Health and Medical Research Counci

Psychiatry out-of-hours: a focus group study of GPs' experiences in Norwegian casualty clinics

Background: For Norwegian general practitioners (GPs), acute treatment of mental illness and substance abuse are among the most commonly experienced emergency situations in out-of-hours primary healthcare. The largest share of acute referrals to emergency psychiatric wards occurs out-of-hours, and out-of-hours services are responsible for a disproportionately high share of compulsory referrals. Concerns exist regarding the quality of mental healthcare provided in the out-of-hours setting. The aim of this study was to explore which challenges GPs experience when providing emergency care out-of-hours to patients presenting problems related to mental illness or substance abuse. Methods: We conducted a qualitative study based on two individual interviews and six focus groups with purposively sampled GPs (totally 45 participants). The interviews were analysed successively in an editing style, using a thematic approach based on methodological descriptions by Charmaz and Malterud. Results: Safety and uncertainty were the dominating themes in the discussions. The threat to personal safety due to unpredictable patient behaviour was a central concern, and present security precautions in the out-of-hours services were questioned. The GPs expressed high levels of uncertainty in their work with patients presenting problems related to mental illness or substance abuse. The complexity of the problems presented, shortage of time, limited access to reliable information and limited range of interventions available during out-of-hours contributed to this uncertainty. Perceived access to second opinion seemed to have a major impact on subjectively experienced work stress. Conclusions: The GPs experienced out-of-hours psychiatry as a field with high levels of uncertainty and limited support to help them meet the experienced challenges. This might influence the quality of care provided. If the current organisation of emergency mental healthcare is to be kept, we need to provide GPs with a better support framework out-of-hours

One-year risk of stroke after transient ischemic attack or minor stroke in Hunter New England, Australia (INSIST Study)

Background: One-year risk of stroke in transient ischemic attack and minor stroke (TIAMS) managed in secondary care settings has been reported as 5–8%. However, evidence for the outcomes of TIAMS in community care settings is limited. Methods: The INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study was a prospective inception cohort community-based study of patients of 16 general practices in the Hunter–Manning region (New South Wales, Australia). Possible-TIAMS patients were recruited from 2012 to 2016 and followed-up for 12 months post-index event. Adjudication as TIAMS or TIAMS-mimics was by an expert panel. We established 7-days, 90-days, and 1-year risk of stroke, TIA, myocardial infarction (MI), coronary or carotid revascularization procedure and death; and medications use at 24 h post-index event. Results: Of 613 participants (mean age; 70 ± 12 years), 298 (49%) were adjudicated as TIAMS. TIAMS-group participants had ischemic strokes at 7-days, 90-days, and 1-year, at Kaplan-Meier (KM) rates of 1% (95% confidence interval; 0.3, 3.1), 2.1% (0.9, 4.6), and 3.2% (1.7, 6.1), respectively, compared to 0.3, 0.3, and 0.6% of TIAMS-mimic-group participants. At one year, TIAMS-group-participants had twenty-five TIA events (KM rate: 8.8%), two MI events (0.6%), four coronary revascularizations (1.5%), eleven carotid revascularizations (3.9%), and three deaths (1.1%), compared to 1.6, 0.6, 1.0, 0.3, and 0.6% of TIAMS-mimic-group participants. Of 167 TIAMS-group participants who commenced or received enhanced therapies, 95 (57%) were treated within 24 h post-index event. For TIAMS-group participants who commenced or received enhanced therapies, time from symptom onset to treatment was median 9.5 h [IQR 1.8–89.9]. Conclusion: One-year risk of stroke in TIAMS participants was lower than reported in previous studies. Early implementation of antiplatelet/anticoagulant therapies may have contributed to the low stroke recurrence

Fractional dynamics pharmacokinetics–pharmacodynamic models

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multisubstrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structureguided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of similar to 500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A

Keratin 8 expression in colon cancer associates with low faecal butyrate levels

<p>Abstract</p> <p>Background</p> <p>Butyrate has been implicated in the mechanistic basis of the prevention of colorectal cancer by dietary fibre. Numerous in vitro studies have shown that butyrate regulates cell cycle and cell death. More recently we have shown that butyrate also regulates the integrity of the intermediate filament (IF) cytoskeleton <it>in vitro</it>. These and other data suggest a link between the role of diet and the implication of a central role for the keratin 8 (K8) as guardian of the colorectal epithelium.</p> <p>Methods</p> <p>In this cross-sectional study possible links between butyrate levels, field effects and keratin expression in cancer were addressed directly by analysing how levels of expression of the IF protein K8 in tumours, in adjacent fields and at a distant landmark site may be affected by the level of butyrate in the colon microenvironment. An immunohistochemical scoring protocol for K8 was developed and applied to samples, findings were further tested by immunoblotting.</p> <p>Results</p> <p>Levels of K8 in colorectal tumours are lower in subjects with higher levels of faecal butyrate. Immunoblotting supported this finding.Although there were no significant relationships with butyrate on the non-tumour tissues, there was a consistent trend in all measures of extent or intensity of staining towards a reduction in expression with elevated butyrate, consistent with the inverse association in tumours.</p> <p>Conclusions</p> <p>The data suggest that butyrate may associate with down-regulation of the expression of K8 in the cancerized colon. If further validated these findings may suggest the chemopreventive value of butyrate is limited to early stage carcinogenesis as low K8 expression is associated with a poor prognosis.</p