Myocardial Infarction with Nonobstructive Coronary Arteries.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is an important subtype of myocardial infarction (MI) that occurs in approximately 6-8% of patients with spontaneous MI who are referred for coronary angiography. MINOCA disproportionately affects women, but men are also affected. Pathogenesis is more variable than in MI with obstructive coronary artery disease (MI-CAD). Dominant mechanisms include atherosclerosis, thrombosis, and coronary artery spasm. Management of MINOCA varies based on the underlying mechanism of infarction. Therefore, systematic approaches to diagnosis are recommended. The combination of invasive coronary angiography, multivessel intracoronary imaging, provocative testing for coronary spasm, and cardiac magnetic resonance imaging provides the greatest diagnostic yield. Current clinical practice guidelines for the secondary prevention of MI are based largely on data from patients with MI-CAD. Thus, optimal medications after MINOCA are uncertain. Clinical trials focused on the treatment of patients with MINOCA are urgently needed to define optimal care.

Using millimeter-sized carbon-deuterium foils for high-precision deuterium-tritium neutron spectrum measurements in direct-drive inertial confinement fusion at the OMEGA laser facility.

Millimeter-sized CD foils fielded close (order mm) to inertial confinement fusion (ICF) implosions have been proposed as a game-changer for improving energy resolution and allowing time-resolution in neutron spectrum measurements using the magnetic recoil technique. This paper presents results from initial experiments testing this concept for direct drive ICF at the OMEGA Laser Facility. While the foils are shown to produce reasonable signals, inferred spectral broadening is seen to be high (∼5 keV) and signal levels are low (by ∼20%) compared to expectation. Before this type of foil is used for precision experiments, the foil mount must be improved, oxygen uptake in the foils must be better characterized, and impact of uncontrolled foil motion prior to detection must be investigated.

Standard versus hypofractionated intensity-modulated radiotherapy for prostate cancer: assessing the impact on dose modulation and normal tissue effects when using patient-specific cancer biology.

Hypofractionation of prostate cancer radiotherapy achieves tumour control at lower total radiation doses, however, increased rectal and bladder toxicities have been observed. To realise the radiobiological advantage of hypofractionation whilst minimising harm, the potential reduction in dose to organs at risk was investigated for biofocused radiotherapy. Patient-specific tumour location and cell density information were derived from multiparametric imaging. Uniform-dose plans and biologically-optimised plans were generated for a standard schedule (78 Gy/39 fractions) and hypofractionated schedules (60 Gy/20 fractions and 36.25 Gy/5 fractions). Results showed that biologically-optimised plans yielded statistically lower doses to the rectum and bladder compared to isoeffective uniform-dose plans for all fractionation schedules. A reduction in the number of fractions increased the target dose modulation required to achieve equal tumour control. On average, biologically-optimised, moderately-hypofractionated plans demonstrated 15.3% (p-value: <0.01) and 23.8% (p-value: 0.02) reduction in rectal and bladder dose compared with standard fractionation. The tissue-sparing effect was more pronounced in extreme hypofractionation with mean reduction in rectal and bladder dose of 43.3% (p-value: < 0.01) and 41.8% (p-value: 0.02), respectively. This study suggests that the ability to utilise patient-specific tumour biology information will provide greater incentive to employ hypofractionation in the treatment of localised prostate cancer with radiotherapy. However, to exploit the radiobiological advantages given by hypofractionation, greater attention to geometric accuracy is required due to increased sensitivity to treatment uncertainties.

Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Voxel-level biological optimisation of prostate IMRT using patient-specific tumour location and clonogen density derived from mpMRI.

AIMS: This study aimed to develop a framework for optimising prostate intensity-modulated radiotherapy (IMRT) based on patient-specific tumour biology, derived from multiparametric MRI (mpMRI). The framework included a probabilistic treatment planning technique in the effort to yield dose distributions with an improved expected treatment outcome compared with uniform-dose planning approaches. METHODS: IMRT plans were generated for five prostate cancer patients using two inverse planning methods: uniform-dose to the planning target volume and probabilistic biological optimisation for clinical target volume tumour control probability (TCP) maximisation. Patient-specific tumour location and clonogen density information were derived from mpMRI and geometric uncertainties were incorporated in the TCP calculation. Potential reduction in dose to sensitive structures was assessed by comparing dose metrics of uniform-dose plans with biologically-optimised plans of an equivalent level of expected tumour control. RESULTS: The planning study demonstrated biological optimisation has the potential to reduce expected normal tissue toxicity without sacrificing local control by shaping the dose distribution to the spatial distribution of tumour characteristics. On average, biologically-optimised plans achieved 38.6% (p-value: < 0.01) and 51.2% (p-value: < 0.01) reduction in expected rectum and bladder equivalent uniform dose, respectively, when compared with uniform-dose planning. CONCLUSIONS: It was concluded that varying the dose distribution within the prostate to take account for each patient's clonogen distribution was feasible. Lower doses to normal structures compared to uniform-dose plans was possible whilst providing robust plans against geometric uncertainties. Further validation in a larger cohort is warranted along with considerations for adaptive therapy and limiting urethral dose.

Loperamide induced cardiac arrhythmia successfully supported with veno-arterial ECMO (VA-ECMO), molecular adsorbent recirculating system (MARS) and continuous renal replacement therapy (CRRT).

Introduction: This case of Loperamide misuse had refractory ventricular arrhythmias and was successfully supported by VA ECMO. Loperamide is currently available without prescription and can be obtained in large quantities over the internet despite Food and Drug Administration (FDA) 2016 black box warning noting cardiac toxicity. This case illustrates the life-threatening toxicity of loperamide and suggests a supportive modality to provide clinical time while the drug is cleared endogenously or exogenously. Case report: A 36-year-old female was found minimally responsive. Vital signs and monitoring revealed wide complex bradycardia, undetectable blood pressure, hypothermia, bradypnea, and hypoglycemia. The rhythm degenerated to polymorphic ventricular tachycardia cardia refractory to multiple ACLS protocols. VA-ECMO was initiated with immediate stabilization. Subsequent history revealed massive consumption of loperamide taking 400-600 mg daily. Highest known loperamide and N-desmethyl-loperamide levels were 32 and 500 ng/ml respectively. Since loperamide and metabolites are known to be protein bound, molecular adsorbent recirculating system (MARS) was initiated for toxin clearance. Additionally, she developed acute renal failure supported by CRRT. She was ultimately weaned from ECMO, MARS, and CRRT and discharged neurologically intact on hospital day 12. Discussion: VA ECMO for hemodynamic support provided the needed time for natural resolution of the cardiac toxicity while providing adequate perfusion. MARS was used in the setting of highly protein bound toxins, but drug clearance could not be demonstrated through serial levels. VA ECMO (or referral to a center with VA ECMO) should be considered with lethal loperamide-induced cardiotoxicity and perhaps other cardio-toxins.

Implementation of the foil-on-hohlraum technique for the magnetic recoil spectrometer for time-resolved neutron measurements at the National Ignition Facility.

The next-generation Magnetic Recoil Spectrometer, called MRSt, will provide time-resolved measurements of the deuterium-tritium-neutron spectrum from inertial confinement fusion implosions at the National Ignition Facility. These measurements will provide critical information about the time evolution of the fuel assembly, hot-spot formation, and nuclear burn. The absolute neutron spectrum in the energy range of 12-16 MeV will be measured with high accuracy (∼5%), unprecedented energy resolution (∼100 keV) and, for the first time ever, time resolution (∼20 ps). Crucial to the design of the system is a CD conversion foil for the production of recoil deuterons positioned as close to the implosion as possible. The foil-on-hohlraum technique has been demonstrated by placing a 1-mm-diameter, 40-µm-thick CD foil on the hohlraum diagnostic band along the line-of-sight of the current time-integrated MRS system, which measured the recoil deuterons. In addition to providing validation of the foil-on-hohlraum technique for the MRSt design, substantial improvement of the MRS energy resolution has been demonstrated.

Radiobiological parameters in a tumour control probability model for prostate cancer LDR brachytherapy.

To provide recommendations for the selection of radiobiological parameters for prostate cancer treatment planning. Recommendations were based on validation of the previously published values, parameter estimation and a consideration of their sensitivity within a tumour control probability (TCP) model using clinical outcomes data from low-dose-rate (LDR) brachytherapy. The proposed TCP model incorporated radiosensitivity (α) heterogeneity and a non-uniform distribution of clonogens. The clinical outcomes data included 849 prostate cancer patients treated with LDR brachytherapy at four Australian centres between 1995 and 2012. Phoenix definition of biochemical failure was used. Validation of the published values from four selected literature and parameter estimation was performed with a maximum likelihood estimation method. Each parameter was varied to evaluate the change in calculated TCP to quantify the sensitivity of the model to its radiobiological parameters. Using a previously published parameter set and a total clonogen number of 196 000 provided TCP estimates that best described the patient cohort. Fitting of all parameters with a maximum likelihood estimation was not possible. Variations in prostate TCP ranged from 0.004% to 0.67% per 1% change in each parameter. The largest variation was caused by the log-normal distribution parameters for α (mean, [Formula: see text], and standard deviation, σ α ). Based on the results using the clinical cohort data, we recommend a previously published dataset is used for future application of the TCP model with inclusion of a patient-specific, non-uniform clonogen density distribution which could be derived from multiparametric imaging. The reduction in uncertainties in these parameters will improve the confidence in using biological models for clinical radiotherapy planning.

Telehealth Support of Managed Care for a Correctional System: The Open Architecture Telehealth Model.

INTRODUCTION: The intent was to evaluate time to match initial investment of a new, statewide correctional system telehealth program based upon cumulative savings by avoidance of transportation and custody-related costs. MATERIALS AND METHODS: The setting was a statewide correctional system where prisoners received medical care through enhanced telemedicine technology supported by newly recruited specialty providers delivered through an open architecture system. The patients were incarcerated persons requiring nonemergent consultations in 10 specialties. A financial model was created to estimate transportation expenses, including vehicular use and custody staff, during the out of prison travel for traditional face-to-face care. Cost savings were then estimated by multiplying transportation expenses by the number of telehealth encounters (avoided cost) and summed cumulatively. Savings were mapped monthly. Private sector specialists were recruited, provided security clearance, trained in the use of the technology, and provided a secure site to provide services. MEASUREMENTS AND MAIN RESULTS: Based on the financial model, 1.2 million dollars in savings, equaling the initial capital investment, were achieved at 32 months. The total number of patient telemedicine encounters increased from 2,365 (±98/month) to 3,748 during the first 32 months of operation (July 2013 through January 2016: ±117/month) with 89% of the established specialties performed by telemedicine technologies. DISCUSSION: It was initially estimated to require 48 months to achieve the investment savings, but savings were achieved in 32 months, demonstrating greater adoption than expected. While finances were quantifiable, enhanced public safety by avoidance of out of prison time is unquantifiable, but judged to be significant.

Impact of Ketamine Use on Adjunctive Analgesic and Sedative Medications in Critically Ill Trauma Patients.

BACKGROUND: Ketamine may be used to manage pain and agitation that is refractory to what are usually considered traditional agents such as fentanyl, propofol, benzodiazepines, and dexmedetomidine; however, literature describing the use of ketamine continuous infusions for this purpose in critically ill trauma patients is limited. OBJECTIVES: The primary objective of this study was to determine the impact of the initiation of a ketamine continuous infusion on sedative and analgesic use in critically ill trauma patients. Secondary objectives were to identify the patient population in which ketamine was initiated, assess the proportion of time patients were at their goal level of sedation, and determine the dosing patterns of adjunctive sedative agents. METHODS: This single-center retrospective chart review over a 19-month period included critically ill mechanically ventilated adult trauma patients in whom a ketamine continuous infusion was initiated for management of sedation and agitation. Patients who received ketamine for other indications or by the acute pain management service were not included in this evaluation. RESULTS: Thirty-six patients were included in the study. Patients in whom ketamine was initiated tended to be white men with blunt trauma. Overall, the initiation of ketamine was associated with a decrease in the amount of opioids and propofol used and an increase in the amount of ziprasidone and dexmedetomidine needed to achieve the goal Richmond Agitation Sedation Score. When compared with the time period before ketamine initiation, the proportion of time that patients achieved goal sedation was not significantly different after the addition of ketamine. CONCLUSIONS: Although the use of ketamine in critically ill mechanically ventilated adult trauma patients was associated with decreased opioid use, it was also associated with increased use of dexmedetomidine and ziprasidone to achieve and maintain sedation. Further examination of clinical outcomes associated with these differences in drug use in a larger population of trauma patients is warranted before routine use of ketamine for analgesia and sedation can be recommended.

Awareness during general anaesthesia in the first 4,000 incidents reported to webAIRS.

The aim of this study was to analyse the incidents related to awareness during general anaesthesia in the first 4,000 cases reported to webAIRS-an anaesthetic incident reporting system established in Australia and New Zealand in 2009. Included incidents were those in which the reporter selected "neurological" as the main category and "awareness/dreaming/nightmares" as a subcategory, those where the narrative report included the word "awareness" and those identified by the authors as possibly relevant to awareness. Sixty-one awareness-related incidents were analysed: 16 were classified as "awareness", 31 were classified as "no awareness but increased risk of awareness" and 14 were classified as "no awareness and no increased risk of awareness". Among 47 incidents in the former two categories, 42 (89%) were associated with low anaesthetic delivery and 24 (51%) were associated with signs of intraoperative wakefulness. Memory of intraoperative events caused significant ongoing distress for five of the 16 awareness patients. Patients continue to be put at risk of awareness by a range of well-described errors (such as syringe swaps) but also by some new errors related to recently introduced anaesthetic equipment, such as electronic anaesthesia workstations.

What's eating you? Cheyletiella mites.

Cheyletiella are nonburrowing mites commonly found on rabbits, dogs, and cats. The mites have been known to cause disease in humans, ranging from mild dermatitis to more severe illness with systemic symptoms. Because these mites do not complete any part of their life cycle in humans, diagnosis can be challenging. Herein, we review various clinical presentations associated with Cheyletiella mites as well as diagnostic techniques and treatment options for both humans and animals.

What's eating you? lone star tick (Amblyomma americanum).

Amblyomma americanum, also known as the lone star tick, is found in much of the eastern United States. Since the mid-20th century, the lone star tick has been implicated in human disease. Today, A americanum remains an important vector for tick-borne illness. In addition to others, species of Rickettsia, Ehrlichia, and Borrelia are all transmitted by the lone star tick. Recently described conditions such as Southern tick-associated rash illness and anaphylaxis to red meat following tick bites have been attributed to the lone star tick. Impressive local reactions also can result after bites from A americanum. Early treatment of tick-borne illness is crucial to ensure good patient outcomes. Tick-control measures also are an important part of disease management in endemic areas. We discuss the tick's biology, human illnesses associated with A americanum, and methods to control tick numbers and eliminate disease in local reservoirs.

High-resolution measurements of the DT neutron spectrum using new CD foils in the Magnetic Recoil neutron Spectrometer (MRS) on the National Ignition Facility.

The Magnetic Recoil neutron Spectrometer (MRS) on the National Ignition Facility measures the DT neutron spectrum from cryogenically layered inertial confinement fusion implosions. Yield, areal density, apparent ion temperature, and directional fluid flow are inferred from the MRS data. This paper describes recent advances in MRS measurements of the primary peak using new, thinner, reduced-area deuterated plastic (CD) conversion foils. The new foils allow operation of MRS at yields 2 orders of magnitude higher than previously possible, at a resolution down to ∼200 keV FWHM.

Development of a registration framework to validate MRI with histology for prostate focal therapy.

PURPOSE: Focal therapy has been proposed as an alternative method to whole-gland treatment for prostate cancer when aiming to reduce treatment side effects. The authors recently validated a radiobiological model which takes into account tumor location and tumor characteristics including tumor cell density, Gleason score, and hypoxia in order to plan optimal dose distributions for focal therapy. The authors propose that this model can be informed using multiparametric MRI (mpMRI) and in this study present a registration framework developed to map prostate mpMRI and histology data, where histology will provide the "ground truth" data regarding tumor location and biology. The authors aim to apply this framework to a growing database to develop a prostate biological atlas which will enable MRI based planning for prostate focal therapy treatment. METHODS: Six patients scheduled for routine radical prostatectomy were used in this proof-of-concept study. Each patient underwent mpMRI scanning prior to surgery, after which the excised prostate specimen was formalin fixed and mounted in agarose gel in a custom designed sectioning box. T2-weighted MRI of the specimen in the sectioning box was acquired, after which 5 mm sections of the prostate were cut and histology sections were microtomed. A number of image processing and registration steps were used to register histology images with ex vivo MRI and deformable image registration (DIR) was applied to 3D T2w images to align the in vivo and ex vivo MRI data. Dice coefficient metrics and corresponding feature points from two independent annotators were selected in order to assess the DIR accuracy. RESULTS: Images from all six patients were registered, providing histology and in vivo MRI in the ex vivo MRI frame of reference for each patient. Results demonstrated that their DIR methodology to register in vivo and ex vivo 3D T2w MRI improved accuracy in comparison with an initial manual alignment for prostates containing features which were readily visible on MRI. The average estimated uncertainty between in vivo MRI and histology was 3.3 mm, which included an average error of 3.1 mm between in vivo and ex vivo MRI after applying DIR. The mean dice coefficient for the prostate contour between in vivo and ex vivo MRI increased from 0.83 before DIR to 0.93 after DIR. CONCLUSIONS: The authors have developed a registration framework for mapping in vivo MRI data of the prostate with histology by implementing a number of processing steps and ex vivo MRI of the prostate specimen. Validation of DIR was challenging, particularly in prostates with few or mostly linear rather than spherical shaped features. Refinement of their MR imaging protocols to improve the data quality is currently underway which may improve registration accuracy. Additional mpMRI sequences will be registered within this framework to quantify prostate tumor location and biology.

Measurement of charged-particle stopping in warm dense plasma.

We measured the stopping of energetic protons in an isochorically heated solid-density Be plasma with an electron temperature of ∼32 eV, corresponding to moderately coupled [(e^{2}/a)/(k_{B}T_{e}+E_{F})∼0.3] and moderately degenerate [k_{B}T_{e}/E_{F}∼2] "warm-dense matter" (WDM) conditions. We present the first high-accuracy measurements of charged-particle energy loss through dense plasma, which shows an increased loss relative to cold matter, consistent with a reduced mean ionization potential. The data agree with stopping models based on an ad hoc treatment of free and bound electrons, as well as the average-atom local-density approximation; this work is the first test of these theories in WDM plasma.

Edema pulmonar agudo por hidroclorotiazida: una reacción adversa poco conocida / Hydrochlorothiazide-induced acute pulmonary edema: a rare adverse reaction

In Chile, hydrochlorothiazide is frequently prescribed as first line antihypertensive therapy. Among it’s well known adverse reactions are: electrolytic disorders, hyperuricemia, dyslipidemia, agranulocytosis and azotemia. Acute pulmonary edema is a rare and potentially lethal adverse effect. Only 50 cases have been reported since 1968. In this article, we discuss a case of a 70 year old woman who, one hour after the ingestion of hydrochlorotiazide, presented acute and progressive dyspnea. Her clinical and radiologic findings are compatible with non-cardiogenic acute pulmonary edema.

En Chile, la hidroclorotiazida se utiliza ampliamente como terapia de primera línea en la hipertensión arterial esencial. Entre los efectos adversos más conocidos destacan: trastornos hidroelectrolíticos, hiperuricemia, dislipidemia, azotemia, entre otros. El edema pulmonar agudo es un efecto adverso infrecuente y potencialmente grave. Desde 1968, se han reportado 50 casos clínicos en la literatura. En este artículo presentamos el caso clínico de una mujer de 70 años atendida en el Hospital Santiago Oriente quien, una hora posterior a la ingesta de hidroclorotiazida, presenta disnea aguda progresiva. El estudio clínico y radiológico es compatible con edema pulmonar agudo no cardiogénico.