An Exploratory Study of Physical Therapists From High-Income Countries Practising Outside of Their Scope in Low and Middle-Income Countries.

PURPOSE: To quantify how often physical therapists from high-income countries (HIC) travelling to low- and middle-income countries (LMIC) practise outside their scope of practice, in what circumstances, and their likelihood of doing the same in the future. METHODS: An exploratory descriptive study using a survey. RESULTS: One hundred and twenty-six licensed physical therapists from around the world participated. Physical therapists typically spent less than a month (73.8 per cent) in LMIC; 67.5 per cent believed that physical therapists practise outside of their scope, and 31.7 per cent reported doing so. Reasons were believing that something is better than nothing (47.5 per cent ), a mismatch between the physical therapist's and host's expectations (40.0 per cent ), and preserving their relationship with the host (25.0 per cent ). It was deemed appropriate by 64.5 per cent to practise outside of their scope in some situations and 53.8% considered repeating the activity in the future. Half of the respondent's first experience in LMIC occurred as a student or in their first decade of practice. CONCLUSIONS: Working in LMIC requires a keen understanding of the risks and challenges associated with such experiences. To ensure best practice, a skill set that consists of critical self-reflection, systems thinking, and structural competency combined with clinical competency and accountability is imperative.

Use of CTA Test Dose to Trigger a Low Cardiac Output Protocol Improves Acute Stroke CTP Data Analyzed with RAPID Software.

BACKGROUND AND PURPOSE: Contrast curve truncation in CTP protocols may introduce errors. We sought to identify risk factors and design a protocol to avoid truncation while limiting radiation. MATERIALS AND METHODS: In an initial fixed-timing cohort, patients underwent a 65-second CTP with 2-second delay postcontrast injection. Multivariable analysis identified factors associated with truncation. A later case-specific cohort underwent either the original protocol or a low cardiac output protocol with a 7-second delay and 75-second scanning window, with selection determined by CTA test-dose enhancement upswing delay. Time-density curves were assessed for truncation and compared between the 2 groups, and the radiation dose was evaluated. RESULTS: From September 2017 through May 2018, one hundred fifty-three patients underwent the standard fixed-timing protocol. Age (OR, 1.82/10-year increase; P = .019), reduced left ventricle ejection fraction (OR, 9.23; P = .001), and hypertension (OR, 0.32; P = .06) were independently associated with truncation in an exploratory multivariable model. From May 2018 through April 2019, one hundred fifty-seven patients underwent either the standard (72 patients) or low cardiac output protocol (85 patients). The fixed-timing cohort had 15 truncations (9.8%) versus 4 in the case-specific cohort (2.5%; P = .009). If the low cardiac output protocol were applied to those with >10.6% predicted risk of truncation based on age, left ventricle ejection fraction, and hypertension, the number of truncations would have decreased from 15 to 4 in the fixed-timing cohort. CONCLUSIONS: Older age, left ventricle ejection fraction, and the absence of hypertension increase the risk of time-density curve truncation. However, a CTA test-dose-directed case-specific protocol can reduce truncation to ensure accurate data while mitigating radiation dose increases.

Improved breast cancer histological grading using deep learning.

BACKGROUND: The Nottingham histological grade (NHG) is a well-established prognostic factor for breast cancer that is broadly used in clinical decision making. However, ∼50% of patients are classified as grade 2, an intermediate risk group with low clinical value. To improve risk stratification of NHG 2 breast cancer patients, we developed and validated a novel histological grade model (DeepGrade) based on digital whole-slide histopathology images (WSIs) and deep learning. PATIENTS AND METHODS: In this observational retrospective study, routine WSIs stained with haematoxylin and eosin from 1567 patients were utilised for model optimisation and validation. Model generalisability was further evaluated in an external test set with 1262 patients. NHG 2 cases were stratified into two groups, DG2-high and DG2-low, and the prognostic value was assessed. The main outcome was recurrence-free survival. RESULTS: DeepGrade provides independent prognostic information for stratification of NHG 2 cases in the internal test set, where DG2-high showed an increased risk for recurrence (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.24-6.97, P = 0.015) compared with the DG2-low group after adjusting for established risk factors (independent test data). DG2-low also shared phenotypic similarities with NHG 1, and DG2-high with NHG 3, suggesting that the model identifies morphological patterns in NHG 2 that are associated with more aggressive tumours. The prognostic value of DeepGrade was further assessed in the external test set, confirming an increased risk for recurrence in DG2-high (HR 1.91, 95% CI 1.11-3.29, P = 0.019). CONCLUSIONS: The proposed model-based stratification of patients with NHG 2 tumours is prognostic and adds clinically relevant information over routine histological grading. The methodology offers a cost-effective alternative to molecular profiling to extract information relevant for clinical decisions.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Artificial intelligence as the next step towards precision pathology.

Pathology is the cornerstone of cancer care. The need for accuracy in histopathologic diagnosis of cancer is increasing as personalized cancer therapy requires accurate biomarker assessment. The appearance of digital image analysis holds promise to improve both the volume and precision of histomorphological evaluation. Recently, machine learning, and particularly deep learning, has enabled rapid advances in computational pathology. The integration of machine learning into routine care will be a milestone for the healthcare sector in the next decade, and histopathology is right at the centre of this revolution. Examples of potential high-value machine learning applications include both model-based assessment of routine diagnostic features in pathology, and the ability to extract and identify novel features that provide insights into a disease. Recent groundbreaking results have demonstrated that applications of machine learning methods in pathology significantly improves metastases detection in lymph nodes, Ki67 scoring in breast cancer, Gleason grading in prostate cancer and tumour-infiltrating lymphocyte (TIL) scoring in melanoma. Furthermore, deep learning models have also been demonstrated to be able to predict status of some molecular markers in lung, prostate, gastric and colorectal cancer based on standard HE slides. Moreover, prognostic (survival outcomes) deep neural network models based on digitized HE slides have been demonstrated in several diseases, including lung cancer, melanoma and glioma. In this review, we aim to present and summarize the latest developments in digital image analysis and in the application of artificial intelligence in diagnostic pathology.

Interplay of mitochondrial fission-fusion with cell cycle regulation: Possible impacts on stem cell and organismal aging.

Declining mitochondrial function and homeostasis is a hallmark of aging. It is appreciated that the role of mitochondria is much more complex than generating reactive oxygen species to cause aging-related tissue damage. More recent literature describes that the ability of mitochondria to undergo fission or fusion events with each other impacts aging processes. A dynamic balance of mitochondrial fission and fusion events is required to sustain critical cellular functions including cell cycle. Specifically, cell cycle regulators modulate molecular activities of the mitochondrial fission (and fusion) machinery towards regulating cell cycle progression. In this review, we discus literature leading to our understanding on how shifts in the dynamic balance of mitochondrial fission and fusion can modulate progression through, exit from, and re-entry to the cell cycle or in undergoing senescence. Importantly, core regulators of mitochondrial fission or fusion are emerging as crucial stem cell regulators. We discuss the implication of such regulation in stem cells in the context of aging, given that aberrations in adult stem cells promote aging. We also propose a few hypotheses that may provide direction for further understanding about the roles of mitochondrial fission-fusion dynamics in aging biology.

Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure.

The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time. BMS-986231 significantly decreased LV filling pressures, end-diastolic stiffness, the time-constant of relaxation, end-diastolic wall stress, systemic vascular resistance, and myocardial oxygen consumption. BMS-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects.

CXL-1020, a Novel Nitroxyl (HNO) Prodrug, Is More Effective than Milrinone in Models of Diastolic Dysfunction-A Cardiovascular Therapeutic: An Efficacy and Safety Study in the Rat.

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies. In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca2+ entry via L-type Ca2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.

[A toddler with a red, swollen arm after vaccination]. / Een kleuter met een rode, gezwollen arm na vaccinatie.

An almost 4-year-old girl developed swelling, redness and pruritus of the vaccinated arm 2 days after immunisation with DPTP. The girl had no fever. The reaction spread around the upper arm and the elbow. We made the diagnosis of 'extensive limb swelling'. The symptoms disappeared spontaneously within 1 week.

3D imaging using combined neutron-photon fan-beam tomography: A Monte Carlo study.

The application of combined neutron-photon tomography for 3D imaging is examined using MCNP5 simulations for objects of simple shapes and different materials. Two-dimensional transmission projections were simulated for fan-beam scans using 2.5MeV deuterium-deuterium and 14MeV deuterium-tritium neutron sources, and high-energy X-ray sources, such as 1MeV, 6MeV and 9MeV. Photons enable assessment of electron density and related mass density, neutrons aid in estimating the product of density and material-specific microscopic cross section- the ratio between the two provides the composition, while CT allows shape evaluation. Using a developed imaging technique, objects and their material compositions have been visualized.

Dosimetric feasibility of intensity modulated proton therapy in a transverse magnetic field of 1.5 T.

Proton therapy promises higher dose conformality in comparison with regular radiotherapy techniques. Also, image guidance has an increasing role in radiotherapy and MRI is a prime candidate for this imaging. Therefore, in this paper the dosimetric feasibility of Intensity Modulated Proton Therapy (IMPT) in a magnetic field of 1.5 T and the effect on the generated dose distributions compared to those at 0 T is evaluated, using the Monte Carlo software TOol for PArticle Simulation (TOPAS). For three different anatomic sites IMPT plans are generated. It is shown that the generation of an IMPT plan in a magnetic field is feasible, the impact of the magnetic field is small, and the resulting dose distributions are equivalent for 0 T and 1.5 T. Also, the framework of Monte Carlo simulation combined with an inverse optimization method can be used to generate IMPT plans. These plans can be used in future dosimetric comparisons with e.g. IMRT and conventional IMPT. Finally, this study shows that IMPT in a 1.5 T magnetic field is dosimetrically feasible.

Frequent sputum production is associated with disturbed night's rest and impaired sleep quality in patients with COPD.

PURPOSE: In this study, we measured night's rest parameters measured with an accelerometer and sleep quality in mild to very severe patients with COPD. Furthermore, our aim was to investigate the association between night's rest parameters and clinical variables and the association between sleep quality and quality of life or health status. METHODS: Mild to very severe COPD patients were recruited from general practitioners and outpatient clinics of general hospitals to participate in a cross-sectional study on physical activity in patients with COPD. A total of 103 patients (mean age 65 years, 67 % male) wore the accelerometer during night's rest for at least four nights and were included in the analyses. RESULTS: No significant associations were found between objectively measured body movements during night's rest or subjective sleep quality and lung function, dyspnoea severity, body composition and physical activity during the day. Patients with frequent sputum production during the day had a higher number of sitting transitions during the night (5.3 vs 4.3 sitting transitions) and more frequently got out of bed compared to patients who hardly ever produced sputum during the day (1.0 vs 0.8 times per night). Furthermore, these patients also reported worse sleep quality (Pittsburgh sleep quality index (PSQI) score 4 vs 3). CONCLUSIONS: Our results indicate that objectively measured body movements during night's rest like body postures and transitions are not related to sleep quality in patients with COPD. We did find an association between frequent sputum production and disturbances during night's rest and sleep quality. Future studies should investigate whether the treatment of mucus hypersecretion leads to improved night's rest.

Oestrogen receptors ß1 and ßcx have divergent roles in breast cancer survival and lymph node metastasis.

BACKGROUND: The expression of oestrogen receptor (ER) α characterises a subset of breast cancers associated with good response to endocrine therapy. However, the clinical significance of the second ER, ERß1, and its splice variant ERßcx is still unclear. METHODS: We here report an assessment of ERα, ERß1 and ERßcx by immunohistochemistry using quantitative digital image analysis of 340 primary tumours and corresponding sentinel lymph nodes. RESULTS: No differences were seen in ER levels in primary tumours vs lymph node metastases. ERß1 and ERßcx were equally distributed among age groups and tumour histological grades. Loss of ERß1 in the primary tumour was strongly associated with poor survival. Its prognostic impact was particularly evident in young patients and in high-grade tumours. The worst outcome was seen in the tumours lacking both ERα and ERß1. ERßcx expression in the primary tumour correlated with a higher risk of lymph node metastasis, and with poor survival when expressed in sentinel node lymphocytes. CONCLUSIONS: Our study reveals highly significant although antagonising roles of ERß1 and ERßcx in breast cancer. Consequently, we suggest that the histopathological assessment of ERß1 is of value as a prognostic and potentially predictive biomarker.

Virtual treatment of basilar aneurysms using shape memory polymer foam.

Numerical simulations are performed on patient-specific basilar aneurysms that are treated with shape memory polymer (SMP) foam. In order to assess the post-treatment hemodynamics, two modeling approaches are employed. In the first, the foam geometry is obtained from a micro-CT scan and the pulsatile blood flow within the foam is simulated for both Newtonian and non-Newtonian viscosity models. In the second, the foam is represented as a porous media continuum, which has permeability properties that are determined by computing the pressure gradient through the foam geometry over a range of flow speeds comparable to those of in vivo conditions. Virtual angiography and additional post-processing demonstrate that the SMP foam significantly reduces the blood flow speed within the treated aneurysms, while eliminating the high-frequency velocity fluctuations that are present within the pre-treatment aneurysms. An estimation of the initial locations of thrombus formation throughout the SMP foam is obtained by means of a low fidelity thrombosis model that is based upon the residence time and shear rate of blood. The Newtonian viscosity model and the porous media model capture similar qualitative trends, though both yield a smaller volume of thrombus within the SMP foam.

Evidence for rapid evolution of phenology in an invasive grass.

Evolutionary dynamics of integrative traits such as phenology are predicted to be critically important to range expansion and invasion success, yet there are few empirical examples of such phenomena. In this study, we used multiple common gardens to examine the evolutionary significance of latitudinal variation in phenology of a widespread invasive species, the Asian short-day flowering annual grass Microstegium vimineum. In environmentally controlled growth chambers, we grew plants from seeds collected from multiple latitudes across the species' invasive range. Flowering time and biomass were both strongly correlated with the latitude of population origin such that populations collected from more northern latitudes flowered significantly earlier and at lower biomass than populations from southern locations. We suggest that this pattern may be the result of rapid adaptive evolution of phenology over a period of less than one hundred years and that such changes have likely promoted the northward range expansion of this species. We note that possible barriers to gene flow, including bottlenecks and inbreeding, have apparently not forestalled evolutionary processes for this plant. Furthermore, we hypothesize that evolution of phenology may be a widespread and potentially essential process during range expansion for many invasive plant species.

Spin-lattice relaxation in aluminum-doped semiconducting 4H and 6H polytypes of silicon carbide.

NMR spin-lattice relaxation efficiency is similar at all carbon and silicon sites in aluminum-doped 4H- and 6H-polytype silicon carbide samples, indicating that the valence band edge (the top of the valence band), where the holes are located in p-doped materials, has similar charge densities at all atomic sites. This is in marked contrast to nitrogen-doped samples of the same polytypes where huge site-specific differences in relaxation efficiency indicate that the conduction band edge (the bottom of the conduction band), where the mobile electrons are located in n-doped materials, has very different charge densities at the different sites. An attempt was made to observe (27)Al NMR signals directly, but they are too broad, due to paramagnetic line broadening, to provide useful information about aluminum doping.

Comparison of anesthesia technique on outcomes of endovascular repair of abdominal aortic aneurysms: a five-year review of monitored anesthesia care with local anesthesia vs. general or regional anesthesia.

AIM: This retrospective study compares outcomes according to anesthesia technique of a consecutive series of 48 endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) performed by one vascular surgeon at a single institution over a five-year period. METHODS: Demographic, pre-procedure, procedure-related, recovery room, surgical unit, and hospital outcome variables were extracted and compared between patients receiving general or regional anesthesia and those receiving monitored anesthesia care (MAC) with local anesthesia. RESULTS: Eighteen (37.5%) patients received general or regional anesthesia and 30 (62.5%) patients received MAC with local anesthesia. No statistically significant differences in demographics or pre-procedure variables were calculated between study groups. Conversion to open repair was not required, no intraoperative complications occurred, and conversion from MAC with local anesthesia to general anesthesia was not required. The only significant differences calculated were in length of anesthesia (P=0.001, power 0.962) and time to ambulation (P=0.004, power 0.871), with significantly lower median times in the MAC and local anesthesia groups. Other than one (2.1%) patient in the MAC with local anesthesia group whose death was related to history of severe coronary disease, no other acute medical complications occurred. CONCLUSION: The results of this study suggest that use of MAC with local anesthesia during EVAR of AAAs is comparable to general and regional anesthesia in terms of safety and efficacy. Furthermore, MAC with local anesthesia confers additional outcome benefits versus general and regional anesthesia, as it is less invasive, offers greater hemodynamic stability, and enables better communication with the patient.

Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries.

Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 +/- 0.14 (n = 4 animals; mean +/- SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.

Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes.

To evaluate potential mechanisms of clinical hepatotoxicity, 4 endothelin receptor antagonists (ERAs) were examined for substrate activity and inhibition of hepatic uptake and efflux transporters in sandwich-cultured human hepatocytes. The 4 transporters studied were sodium-dependent taurocholate cotransporter (NTCP), organic anion transporter (OATP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2). ERA transporter inhibition was examined using the substrates taurocholate (for NTCP and BSEP), [(3)H]estradiol-17beta-D-glucuronide (for OATP), and [2-D-penicillamine, 5-D-penicillamine]enkephalin (for MRP2). ERA substrate activity was evaluated using probe inhibitors ritonavir (OATP and BSEP), bromosulfalein (OATP), erythromycin (P-glycoprotein), probenecid (MRP2 and OATP), and cyclosporin (NTCP). ERAs were tested at 2, 20, and 100 micromol*L-1 for inhibition and at 2 micromol*L-1 as substrates. OATP, NTCP, or BSEP transport activity was not reduced by ambrisentan or darusentan. Bosentan and sitaxsentan attenuated NTCP transport at higher concentrations. Only sitaxsentan decreased OATP transport (52%), and only bosentan reduced BSEP transport (78%). MRP2 transport activity was unaltered. OATP inhibitors decreased influx of all ERAs. Darusentan influx was least affected (84%-100% of control), whereas bosentan was most affected (32%-58% of control). NTCP did not contribute to influx of ERAs. Only bosentan and darusentan were shown as substrates for both BSEP and P-glycoprotein efflux. All ERAs tested were substrates for at least one hepatic transporter. Bosentan and sitaxsentan, but not ambrisentan and darusentan, inhibited human hepatic transporters, which provides a potential mechanism for the increased hepatotoxicity observed for these agents in the clinical setting.