Impact, regulation and health policy implications of physician migration in OECD countries

BACKGROUND: In the face of rising demand for medical services due to ageing populations, physician migration flows are increasingly affecting the supply of physicians in Organisation for Economic Co-operation and development (OECD) countries. This paper offers an integrated perspective on the impact of physician migration on home and host countries and discusses international regulation and policy approaches governing physician migration. METHODS: Information about migration flows, international regulation and policies governing physician migration were derived from two questionnaires sent to OECD countries, a secondary analysis of EUROSTAT Labour Force Surveys, a literature review and official policy documents of OECD countries. RESULTS: OECD countries increasingly perceive immigration of foreign physicians as a way of sustaining their physician workforce. As a result, countries have entered into international agreements regulating physician migration, although their success has been limited due to the imposition of licensing requirements and the protection of vested interests by domestic physicians. OECD countries have therefore adopted specific policies designed to stimulate the immigration of foreign physicians, whilst minimising its negative impact on the home country. Measures promoting immigration have included international recruitment campaigns, less strict immigration requirements and arrangements that foster shared learning between health care systems. Policies restricting the societal costs of physician emigration from developing countries such as good practice guidelines and taxes on host countries have not yet produced their expected effect or in some cases have not been established at all. CONCLUSIONS: Although OECD countries generally favour long-term policies of national self-sufficiency to sustain their physician workforce, such policies usually co-exist with short-term or medium-term policies to attract foreign physicians. As this is likely to continue, there is a need to create a global framework that enforces physician migration policies that confer benefits on home and host countries. In the long term, OECD countries need to put in place appropriate education and training policies rather than rely on physician migration to address their future needs

Recapitulating thyroid cancer histotypes through engineering embryonic stem cells

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAFV600E or NRASQ61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs

A neural tracking and motor control approach to improve rehabilitation of upper limb movements

<p>Abstract</p> <p>Background</p> <p>Restoration of upper limb movements in subjects recovering from stroke is an essential keystone in rehabilitative practices. Rehabilitation of arm movements, in fact, is usually a far more difficult one as compared to that of lower extremities. For these reasons, researchers are developing new methods and technologies so that the rehabilitative process could be more accurate, rapid and easily accepted by the patient. This paper introduces the proof of concept for a new non-invasive FES-assisted rehabilitation system for the upper limb, called smartFES (sFES), where the electrical stimulation is controlled by a biologically inspired neural inverse dynamics model, fed by the kinematic information associated with the execution of a planar goal-oriented movement. More specifically, this work details two steps of the proposed system: an <it>ad hoc </it>markerless motion analysis algorithm for the estimation of kinematics, and a neural controller that drives a synthetic arm. The vision of the entire system is to acquire kinematics from the analysis of video sequences during planar arm movements and to use it together with a neural inverse dynamics model able to provide the patient with the electrical stimulation patterns needed to perform the movement with the assisted limb.</p> <p>Methods</p> <p>The markerless motion tracking system aims at localizing and monitoring the arm movement by tracking its silhouette. It uses a specifically designed motion estimation method, that we named Neural Snakes, which predicts the arm contour deformation as a first step for a silhouette extraction algorithm. The starting and ending points of the arm movement feed an Artificial Neural Controller, enclosing the muscular Hill's model, which solves the inverse dynamics to obtain the FES patterns needed to move a simulated arm from the starting point to the desired point. Both position error with respect to the requested arm trajectory and comparison between curvature factors have been calculated in order to determine the accuracy of the system.</p> <p>Results</p> <p>The proposed method has been tested on real data acquired during the execution of planar goal-oriented arm movements. Main results concern the capability of the system to accurately recreate the movement task by providing a synthetic arm model with the stimulation patterns estimated by the inverse dynamics model. In the simulation of movements with a length of ± 20 cm, the model has shown an unbiased angular error, and a mean (absolute) position error of about 1.5 cm, thus confirming the ability of the system to reliably drive the model to the desired targets. Moreover, the curvature factors of the factual human movements and of the reconstructed ones are similar, thus encouraging future developments of the system in terms of reproducibility of the desired movements.</p> <p>Conclusion</p> <p>A novel FES-assisted rehabilitation system for the upper limb is presented and two parts of it have been designed and tested. The system includes a markerless motion estimation algorithm, and a biologically inspired neural controller that drives a biomechanical arm model and provides the stimulation patterns that, in a future development, could be used to drive a smart Functional Electrical Stimulation system (sFES). The system is envisioned to help in the rehabilitation of post stroke hemiparetic patients, by assisting the movement of the paretic upper limb, once trained with a set of movements performed by the therapist or in virtual reality. Future work will include the application and testing of the stimulation patterns in real conditions.</p

Self-assembly and anti-amyloid cytotoxicity activity of amyloid beta peptide derivatives

The self-assembly of two derivatives of KLVFF, a fragment Abeta(16-20) of the amyloid beta (Abeta) peptide, is investigated and recovery of viability of neuroblastoma cells exposed to Abeta is observed at sub-stoichiometric peptide concentrations. Fluorescence assays show that NH2-KLVFF-CONH2 undergoes hydrophobic collapse and amyloid formation at the same critical aggregation concentration (cac). In contrast, NH2-K(Boc)LVFF-CONH2 undergoes hydrophobic collapse at a low concentration, followed by amyloid formation at a higher cac. These findings are supported by the beta-sheet features observed by FTIR. Electrospray ionization mass spectrometry indicates that NH2-K(Boc)LVFF-CONH2 forms a significant population of oligomeric species above the cac. Cryo-TEM, used together with SAXS to determine fibril dimensions, shows that the length and degree of twisting of peptide fibrils seem to be influenced by the net peptide charge. Grazing incidence X-ray scattering from thin peptide films shows features of beta-sheet ordering for both peptides, along with evidence for lamellar ordering of NH2-KLVFF-CONH2. This work provides a comprehensive picture of the aggregation properties of these two KLVFF derivatives and show their utility, in unaggregated form, in restoring the viability of neuroblastoma cells against Abeta-induced toxicity

Financial Incentive Increases CPAP Acceptance in Patients from Low Socioeconomic Background

OBJECTIVE: We explored whether financial incentives have a role in patients' decisions to accept (purchase) a continuous positive airway pressure (CPAP) device in a healthcare system that requires cost sharing. DESIGN: Longitudinal interventional study. PATIENTS: The group receiving financial incentive (n = 137, 50.8±10.6 years, apnea/hypopnea index (AHI) 38.7±19.9 events/hr) and the control group (n = 121, 50.9±10.3 years, AHI 39.9±22) underwent attendant titration and a two-week adaptation to CPAP. Patients in the control group had a co-payment of $330-660; the financial incentive group paid a subsidized price of$55. RESULTS: CPAP acceptance was 43% greater (p = 0.02) in the financial incentive group. CPAP acceptance among the low socioeconomic strata (n = 113) (adjusting for age, gender, BMI, tobacco smoking) was enhanced by financial incentive (OR, 95% CI) (3.43, 1.09-10.85), age (1.1, 1.03-1.17), AHI (>30 vs. <30) (4.87, 1.56-15.2), and by family/friends who had positive experience with CPAP (4.29, 1.05-17.51). Among average/high-income patients (n = 145) CPAP acceptance was affected by AHI (>30 vs. <30) (3.16, 1.14-8.75), living with a partner (8.82, 1.03-75.8) but not by the financial incentive. At one-year follow-up CPAP adherence was similar in the financial incentive and control groups, 35% and 39%, respectively (p = 0.82). Adherence rate was sensitive to education (+yr) (1.28, 1.06-1.55) and AHI (>30 vs. <30) (5.25, 1.34-18.5). CONCLUSIONS: Minimizing cost sharing reduces a barrier for CPAP acceptance among low socioeconomic status patients. Thus, financial incentive should be applied as a policy to encourage CPAP treatment, especially among low socioeconomic strata patients

Immunomodulation Targeting Abnormal Protein Conformation Reduces Pathology in a Mouse Model of Alzheimer's Disease

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high β-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid β (sAβ) peptide is converted into highly toxic oligomeric Aβ and fibrillar Aβ that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAβ and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Aβ or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Aβ in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Aβ40/42 levels, as well as reduced Aβ oligomer levels. This type of immunomodulation has the potential to be a universal β-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases

Amitriptyline-Mediated Cognitive Enhancement in Aged 3×Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity

Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD

Robust Biomarkers: Methodologically Tracking Causal Processes in Alzheimer’s Measurement

In biomedical measurement, biomarkers are used to achieve reliable prediction of, and useful causal information about patient outcomes while minimizing complexity of measurement, resources, and invasiveness. A biomarker is an assayable metric that discloses the status of a biological process of interest, be it normative, pathophysiological, or in response to intervention. The greatest utility from biomarkers comes from their ability to help clinicians (and researchers) make and evaluate clinical decisions. In this paper we discuss a specific methodological use of clinical biomarkers in pharmacological measurement: Some biomarkers, called ‘surrogate markers’, are used to substitute for a clinically meaningful endpoint corresponding to events and their penultimate risk factors. We confront the reliability of clinical biomarkers that are used to gather information about clinically meaningful endpoints. Our aim is to present a systematic methodology for assessing the reliability of multiple surrogate markers (and biomarkers in general). To do this we draw upon the robustness analysis literature in the philosophy of science and the empirical use of clinical biomarkers. After introducing robustness analysis we present two problems with biomarkers in relation to reliability. Next, we propose an intervention-based robustness methodology for organizing the reliability of biomarkers in general. We propose three relevant conditions for a robust methodology for biomarkers: (R1) Intervention-based demonstration of partial independence of modes: In biomarkers partial independence can be demonstrated through exogenous interventions that modify a process some number of “steps” removed from each of the markers. (R2) Comparison of diverging and converging results across biomarkers: By systematically comparing partially-independent biomarkers we can track under what conditions markers fail to converge in results, and under which conditions they successfully converge. (R3) Information within the context of theory: Through a systematic cross-comparison of the markers we can make causal conclusions as well as eliminate competing theories. We apply our robust methodology to currently developing Alzheimer’s research to show its usefulness for making causal conclusions