Factors associated with use of opioid rescue medication after surgery.

BACKGROUND: Opioid exposure after surgery increases risk of persistent opioid use. Here, we characterize at-home use of opioid rescue medication during 1-2 days after outpatient surgery (N=270) in a postoperative opioid-sparing context at a Norwegian hospital. METHODS: The postsurgical pain management plan included non-steroidal anti-inflammatory drugs and up to six pills of 5 mg oxycodone as rescue analgesics. In this observational study we assessed risk factors for taking rescue opioids after surgery, by comparing patients who did, with those who did not. RESULTS: Only 35% (N=228) of patients reported taking rescue opioids 1-2 days after discharge. Patients taking rescue opioids after surgery (opioid-takers) differed from non-takers by prevalence of preoperative chronic pain (>3 months; 74% vs 48%), higher pain severity and interference before and after surgery, reporting lower ability to cope with postsurgical pain, higher nervousness about the surgery, being younger, and having received more opioid analgesics in the recovery room. Exploratory predictive modeling identified opioid administration in the recovery room as the most important predictor of at-home rescue medication use. Follow-up after >4 months indicated low acute pain levels (mean±SD = 1.1±1.8), with only four patients (2%, N=217) reporting opioid analgesic use. CONCLUSION: Factors related to at-home rescue medication use closely mirrored known risk factors for persistent opioid use after surgery, such as prior chronic pain, prior substance use, affective disturbances, and pain severity before surgery. These findings are potential targets in patient-centered care. Nevertheless, and reassuringly, findings are consistent with the idea that opioid-sparing postsurgical care can prevent large-scale chronic opioid use.

An olfactory self-test effectively screens for COVID-19.

Background: Key to curtailing the COVID-19 pandemic are wide-scale screening strategies. An ideal screen is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-19, we developed a perceptual measure of olfaction that relies on smelling household odorants and rating them online. Methods: Each participant was instructed to select 5 household items, and rate their perceived odor pleasantness and intensity using an online visual analogue scale. We used this data to assign an olfactory perceptual fingerprint, a value that reflects the perceived difference between odorants. We tested the performance of this real-time tool in a total of 13,484 participants (462 COVID-19 positive) from 134 countries who provided 178,820 perceptual ratings of 60 different household odorants. Results: We observe that olfactory ratings are indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observe indicative power at the individual level (79% sensitivity and 87% specificity). Critically, this olfactory screen remains effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. Conclusions: The current odorant-based olfactory screen adds a component to online symptom-checkers, to potentially provide an added first line of defense that can help fight disease progression at the population level. The data derived from this tool may allow better understanding of the link between COVID-19 and olfaction.

Comparability of Heart Rate Turbulence Methodology: 15 Intervals Suffice to Calculate Turbulence Slope - A Methodological Analysis Using PhysioNet Data of 1074 Patients.

Heart rate turbulence (HRT) is a characteristic heart rate pattern triggered by a ventricular premature contraction (VPC). It can be used to assess autonomic function and health risk for various conditions, e.g., coronary artery disease or cardiomyopathy. While comparability is essential for scientific analysis, especially for research focusing on clinical application, the methodology of HRT still varies widely in the literature. Particularly, the ECG measurement and parameter calculation of HRT differs, including the calculation of turbulence slope (TS). In this article, we focus on common variations in the number of intervals after the VPC that are used to calculate TS (#TSRR) posing two questions: 1) Does a change in #TSRR introduce noticeable changes in HRT parameter values and classification? and 2) Do larger values of turbulence timing (TT) enabled by a larger #TSRR still represent distinct HRT? We compiled a free-access data set of 1,080 annotated long-term ECGs provided by Physionet. HRT parameter values and risk classes were determined both with #TSRR 15 and 20. A standard local tachogram was created by averaging the tachograms of only the files with the best heart rate variability values. The shape of this standard VPC sequence was compared to all VPC sequences grouped by their TT value using dynamic time warping (DTW) in order to identify HRT shapes. When calculated with different #TSRR, our results show only a little difference between the number of files with enough valid VPC sequences to calculate HRT (<1%) and files with different risk classes (5 and 6% for HRT0-2 and HRTA-C, respectively). In the DTW analysis, the difference between averaged sequences with a specific TT and the standard sequence increased with increasing TT. Our analysis suggests that HRT occurs in the early intervals after the VPC and TS calculated from late intervals reflects common heart rate variability rather than a distinct response to the VPC. Even though the differences in classification are marginal, this can lead to problems in clinical application and scientific research. Therefore, we recommend uniformly using #TSRR 15 in HRT analysis.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Countering reproducibility issues in mathematical models with software engineering techniques: A case study using a one-dimensional mathematical model of the atrioventricular node.

One should assume that in silico experiments in systems biology are less susceptible to reproducibility issues than their wet-lab counterparts, because they are free from natural biological variations and their environment can be fully controlled. However, recent studies show that only half of the published mathematical models of biological systems can be reproduced without substantial effort. In this article we examine the potential causes for failed or cumbersome reproductions in a case study of a one-dimensional mathematical model of the atrioventricular node, which took us four months to reproduce. The model demonstrates that even otherwise rigorous studies can be hard to reproduce due to missing information, errors in equations and parameters, a lack in available data files, non-executable code, missing or incomplete experiment protocols, and missing rationales behind equations. Many of these issues seem similar to problems that have been solved in software engineering using techniques such as unit testing, regression tests, continuous integration, version control, archival services, and a thorough modular design with extensive documentation. Applying these techniques, we reimplement the examined model using the modeling language Modelica. The resulting workflow is independent of the model and can be translated to SBML, CellML, and other languages. It guarantees methods reproducibility by executing automated tests in a virtual machine on a server that is physically separated from the development environment. Additionally, it facilitates results reproducibility, because the model is more understandable and because the complete model code, experiment protocols, and simulation data are published and can be accessed in the exact version that was used in this article. We found the additional design and documentation effort well justified, even just considering the immediate benefits during development such as easier and faster debugging, increased understandability of equations, and a reduced requirement for looking up details from the literature.

Characteristics of mathematical modeling languages that facilitate model reuse in systems biology: a software engineering perspective.

Reuse of mathematical models becomes increasingly important in systems biology as research moves toward large, multi-scale models composed of heterogeneous subcomponents. Currently, many models are not easily reusable due to inflexible or confusing code, inappropriate languages, or insufficient documentation. Best practice suggestions rarely cover such low-level design aspects. This gap could be filled by software engineering, which addresses those same issues for software reuse. We show that languages can facilitate reusability by being modular, human-readable, hybrid (i.e., supporting multiple formalisms), open, declarative, and by supporting the graphical representation of models. Modelers should not only use such a language, but be aware of the features that make it desirable and know how to apply them effectively. For this reason, we compare existing suitable languages in detail and demonstrate their benefits for a modular model of the human cardiac conduction system written in Modelica.

Low Heart Rate Variability Predicts Stroke and Other Complications in the First Six Postoperative Months After a Hip Fracture Operation.

Background: One-year mortality after hip fractures is underestimated and is reported as 25%. An improved risk stratifying could contribute to a better follow up of these patients. Heart Rate Variability (HRV) is an easy point-of-care investigation and is been used in cardiology, endocrinology, and perioperative care. This observational study intended to explore relevant associations between HRV parameters and 6-months mortality and morbidity after a hip fracture. Methods: One hundred and sixty-five patients admitted to two hospitals were included, and short-time HRV measurements (5 min, and 10 min at the two hospitals, respectively) were obtained. Mortality data were gathered by means of the Norwegian central address register. Patients, close relatives of patients, and in some cases their general physicians or nursery home physicians were interviewed 6 months postoperatively regarding the incidence of pneumonia, cardiac events, or stroke. Results: One and hundred fifty-seven (95.2%) patients were followed up after 6 months post-surgery. Twenty-one (13%) died during this period. Twenty patients (13%) developed pneumonia, eight (5 %) stroke, and four (2%) myocardial infarction. No HRV parameter was associated with 6-month general mortality. However, patients who developed stroke had significantly lower High Frequency Power (HF, p < 0.001) and lower Very Low Frequency Power (VLF, p = 0.003) at inclusion compared to patients without complications. Patients who developed pneumonia had at the inclusion lower root mean square of successive differences (RMSSD, p = 0.044). Patients with a history of coronary heart disease (n = 41) showed a mortality of 7%. Mortality in this group was associated with standard deviation of beat-to-beat intervals (SDNN, p = 0.006), Total Power (TP, p = 0.009), HF (p = 0.026), and Low Frequency Power (LF, p = 0.012). Beta-blocker intake was associated with lower heart rate, but not with differences in HRV parameters. Conclusion: In this exploratory study, we present for the first-time significant associations between different preoperative HRV parameters and stroke, myocardial infarction, and pneumonia during a 6-month period after hip fracture. HRV might be a simple and effective tool to identify patients at risk that would warrant better follow-up.

'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure.

The endogenous opioid system has been implicated during experiences of pleasure (i.e., from food or sex). Music can elicit intense emotional and bodily sensations of pleasure, called 'Chills'. We investigated the effects of an opioid antagonist (50 mg naltrexone) or placebo (40 µg d3-vitamin) while listening to self-selected music or other 'control' music selected by another participant. We used a novel technique of continuous measurement of pleasantness with an eye tracker system, where participants shifted their eyes along a visual analogue scale, in the semblance of a thermometer so that, as the music unfolded, gaze positions indicated the self-reported hedonic experience. Simultaneously, we obtained pupil diameters. Self-reported pleasure remained unchanged by naltrexone, which - however - selectively decreased pupillary diameters during 'Chills'. Hence, the endogenous µ-opioid signaling is not necessary for subjective enjoyment of music but an opioid blockade dampens pupil responses to peak pleasure, consistent with decreased arousal to the music.

An Understandable, Extensible, and Reusable Implementation of the Hodgkin-Huxley Equations Using Modelica.

The Hodgkin-Huxley model of the squid giant axon has been used for decades as the basis of many action potential models. These models are usually communicated using just a list of equations or a circuit diagram, which makes them unnecessarily complicated both for novices and for experts. We present a modular version of the Hodgkin-Huxley model that is more understandable than the usual monolithic implementations and that can be easily reused and extended. Our model is written in Modelica using software engineering concepts, such as object orientation and inheritance. It retains the electrical analogy, but names and explains individual components in biological terms. We use cognitive load theory to measure understandability as the amount of items that have to be kept in working memory simultaneously. The model is broken down into small self-contained components in human-readable code with extensive documentation. Additionally, it features a hybrid diagram that uses biological symbols in an electrical circuit and that is directly tied to the model code. The new model design avoids many redundancies and reduces the cognitive load associated with understanding the model by a factor of 6. Extensions can be easily applied due to an unifying interface and inheritance from shared base classes. The model can be used in an educational context as a more approachable introduction to mathematical modeling in electrophysiology. Additionally the modeling approach and the base components can be used to make complex Hodgkin-Huxley-type models more understandable and reusable.

HRT assessment reviewed: a systematic review of heart rate turbulence methodology.

Heart rate turbulence (HRT) is a biphasic reaction to a ventricular premature contraction (VPC) mainly mediated by the baroreflex. It can be used for risk stratification in different disease patterns. Despite existing standards there is a lot of variation in terms of measuring and calculating HRT, which complicates research and application. OBJECTIVE: This systematic review outlines and evaluates the methodological spectrum of HRT research, especially filtering criteria, parameter calculation and thresholds. APPROACH: The analysis includes all research papers written in English that have been published before 12.10.2018, are listed on PubMed and involve calculation of HRT parameter values. MAIN RESULTS: HRT assessment is still being performed in various ways and important specifications of the methodology are not given in many articles. Nevertheless, some suggestions regarding HRT methodology can be made: a normalised turbulence slope should be used to uncouple the parameter from heart rate and frequency of extrasystoles. Filtering criteria as formerly reviewed in the guidelines should be met and mentioned. The minimal number of VPC snippets (VPCSs) as well as new cut-off values for different risks need to be further evaluated. Most importantly, the exact and complete methodology must be described to ensure reproducibility and comparability. SIGNIFICANCE: Methodical variation hinders comparability of research and medical application. Our continuing questions help to further standardise the measurement and calculation of HRT and increase its value for medical risk stratification.

Relationship between odor intensity estimates and COVID-19 prevalence prediction in a Swedish population.

In response to the COVID-19 pandemic, countries have implemented various strategies to reduce and slow the spread of the disease in the general population. For countries that have implemented restrictions on its population in a step-wise manner, monitoring of COVID-19 prevalence is of importance to guide decision on when to impose new, or when to abolish old, restrictions. We are here determining whether measures of odor intensity in a large sample can serve as one such measure. Online measures of how intense common household odors are perceived and symptoms of COVID-19 were collected from 2440 Swedes. Average odor intensity ratings were then compared to predicted COVID-19 population prevalence over time in the Swedish population and were found to closely track each other (r=-0.83). Moreover, we found that there was a large difference in rated intensity between individuals with and without COVID-19 symptoms and number of symptoms was related to odor intensity ratings. Finally, we found that individuals progressing from reporting no symptoms to subsequently reporting COVID-19 symptoms demonstrated a large drop in olfactory performance. These data suggest that measures of odor intensity, if obtained in a large and representative sample, can be used as an indicator of COVID-19 disease in the general population. Importantly, this simple measure could easily be implemented in countries without widespread access to COVID-19 testing or implemented as a fast early response before wide-spread testing can be facilitated.

Delirium in patients with hip fracture is associated with increased heart rate variability.

BACKGROUND: Heart rate variability (HRV) is a method to assess the autonomic nervous system and reflects possibly central brain states. HRV has previously not been examined in patients with hip fracture and delirium. AIMS: To explore HRV parameters in hip fracture patients with and without delirium. METHODS: Patients admitted to Oslo University Hospital with hip fracture and sinus rhythm in electrocardiogram (ECG) were included. Delirium was diagnosed using the confusion assessment method. HRV was assessed preoperatively after a relaxing period of five minutes, by measuring an ECG signal over 5 min. Parameters in time domain (the standard deviation of the QRS distances-SDNN) and frequency domain (total power (TP), low frequency (LF), high frequency (HF) and LF/HF ratio) were calculated. RESULTS: Seventy-five patients were included in the study, and 21 of them had subsyndromal delirium and were excluded from the analysis. Fifty-four patients with a mean age of 83.5 years (SD 8.6, 78% females) were included. Twenty-six patients (48%) had preoperative delirium, 11 (20%) developed delirium postoperatively, whereas 17 (31%) never developed delirium. SDNN, TP and HF values were significantly higher in patients with delirium compared to patients without delirium, and LF and LF/HF were lower. Patients developing postoperative delirium had decreased LF and increased HF before symptom onset. DISCUSSION: Increased SDNN, TP and HF and decreased LF values might reflect an abnormal stress response in delirium. CONCLUSION: HRV measurements in patients with hip fractures provide additional information beyond heart rate and might be used to identify relevant pathophysiological factors in delirium.

Anhedonia in chronic pain and prescription opioid misuse.

BACKGROUND: Both acute and chronic pain can disrupt reward processing. Moreover, prolonged prescription opioid use and depressed mood are common in chronic pain samples. Despite the prevalence of these risk factors for anhedonia, little is known about anhedonia in chronic pain populations. METHODS: We conducted a large-scale, systematic study of anhedonia in chronic pain, focusing on its relationship with opioid use/misuse, pain severity, and depression. Chronic pain patients across four distinct samples (N = 488) completed the Snaith-Hamilton Pleasure Scale (SHAPS), measures of opioid use, pain severity and depression, as well as the Current Opioid Misuse Measure (COMM). We used a meta-analytic approach to determine reference levels of anhedonia in healthy samples spanning a variety of countries and diverse age groups, extracting SHAPS scores from 58 published studies totaling 2664 psychiatrically healthy participants. RESULTS: Compared to healthy samples, chronic pain patients showed higher levels of anhedonia, with ~25% of patients scoring above the standard anhedonia cut-off. This difference was not primarily driven by depression levels, which explained less than 25% of variance in anhedonia scores. Neither opioid use duration, dose, nor pain severity alone was significantly associated with anhedonia. Yet, there was a clear effect of opioid misuse, with opioid misusers (COMM ⩾13) reporting greater anhedonia than non-misusers. Opioid misuse remained a significant predictor of anhedonia even after controlling for pain severity, depression and opioid dose. CONCLUSIONS: Study results suggest that both chronic pain and opioid misuse contribute to anhedonia, which may, in turn, drive further pain and misuse.

Hidden Signals-The History and Methods of Heart Rate Variability.

The understanding of heart rate variability (HRV) has increased parallel with the development of modern physiology. Discovered probably first in 1847 by Ludwig, clinical applications evolved in the second part of the twentieth century. Today HRV is mostly used in cardiology and research settings. In general, HRV can be measured over shorter (e.g., 5-10 min) or longer (12 or 24 h) periods. Since 1996, most measurements and calculations are made according to the standard of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. As the first step, the series of times between successive R-peaks in the ECG are in milliseconds. It is crucial, however, to identify and remove extrasystoles and artifacts according to standard protocols. The series of QRS distances between successive heartbeats can be analyzed with simple or more sophisticated algorithms, beginning with standard deviation (SDNN) or by the square root of the mean of the sum of squares of differences between adjacent normal RR (rMSSD). Short-term HRV is frequently analyzed with the help of a non-parametric fast Fourier transformation quantifying the different frequency bands during the measurement period. In the last decades, various non-linear algorithms have been presented, such as different entropy and fractal measures or wavelet analysis. Although most of them have a strong theoretical foundation, their clinical relevance is still debated.

Heart-Rate Variability-More than Heart Beats?

Heart-rate variability (HRV) is frequently introduced as mirroring imbalances within the autonomous nerve system. Many investigations are based on the paradigm that increased sympathetic tone is associated with decreased parasympathetic tone and vice versa. But HRV is probably more than an indicator for probable disturbances in the autonomous system. Some perturbations trigger not reciprocal, but parallel changes of vagal and sympathetic nerve activity. HRV has also been considered as a surrogate parameter of the complex interaction between brain and cardiovascular system. Systems biology is an inter-disciplinary field of study focusing on complex interactions within biological systems like the cardiovascular system, with the help of computational models and time series analysis, beyond others. Time series are considered surrogates of the particular system, reflecting robustness or fragility. Increased variability is usually seen as associated with a good health condition, whereas lowered variability might signify pathological changes. This might explain why lower HRV parameters were related to decreased life expectancy in several studies. Newer integrating theories have been proposed. According to them, HRV reflects as much the state of the heart as the state of the brain. The polyvagal theory suggests that the physiological state dictates the range of behavior and psychological experience. Stressful events perpetuate the rhythms of autonomic states, and subsequently, behaviors. Reduced variability will according to this theory not only be a surrogate but represent a fundamental homeostasis mechanism in a pathological state. The neurovisceral integration model proposes that cardiac vagal tone, described in HRV beyond others as HF-index, can mirror the functional balance of the neural networks implicated in emotion-cognition interactions. Both recent models represent a more holistic approach to understanding the significance of HRV.

Decreases in heart rate variability are associated with postoperative complications in hip fracture patients.

BACKGROUND: To explore relevant associations between deviations in linear and nonlinear heart rate variability (HRV) scores, and short-term morbidity and mortality in patients undergoing hip-surgery after a fracture. METHODS: 165 patients with hip fractures being admitted for surgery at two hospitals were included in a prospective cohort study. A short-term ECG was recorded within 24 hours of arrival. 15 patients had to be excluded due to insufficient quality of the ECG recordings. 150 patients were included in the final analysis. Linear parameters were calculated in time domain: standard deviation of NN intervals (SDNN), root mean square of successive differences (rMSSD); and frequency domain: Total Power (TP), High Frequency Power (HF), Low Frequency Power (LF), Very Low Frequency Power (VLF), and the ratio of LF/HF. Postoperative outcome was evaluated at the time of discharge. This included occurrence of pneumonia, overall infection rate, stroke, myocardial infarction, and all-cause mortality. RESULTS: Patients experiencing complications had significantly lower rMSSD (p = 0.04), and TP (p = 0.03) preoperatively. Postoperative infections were predicted by decreased VLF preoperatively (p = 0.04). There was a significant association between pneumonia and LF/HF<1 (p = 0.03). The likelihood ratio to develop pneumonia when LF/HF < 1 was 6,1. CONCLUSION: HRV seems to reflect the general frailty of the patient with hip fracture and might be used to identify patients in need of increased surveillance or prophylactic treatment.

[Use of cannabinoids in palliative medicine]. / Bruk av cannabinoider i palliativ medisin.

BACKGROUND: Several countries use drugs containing cannabinoids for symptom management in patients that need palliative treatment. MATERIAL AND METHOD: Articles were retrieved through a literature search for randomized controlled studies of cannabinoids used to treat cancer-related symptoms such as pain, nausea and appetite. RESULTS: Evidence for clinical effect is limited. Some randomized studies have shown a treatment effect of cannabinoids in neuropathic pain. Cannabinoid-containing drugs can have a moderate anti-emetic effect and can stimulate appetite in some subgroups of patients. INTERPRETATION: Many questions about clinical efficacy and side effects have still not been answered for cannabinoid-containing drugs and there is not sufficient evidence available from relevant randomised controlled trials to base a decision on whether or not to permit such drugs in palliative care in Norway. It is however likely that drugs containing cannabinoids can help to control certain symptoms in some patients.