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.