The goal of personalised medicine in the intensive care unit (ICU) is to predict which diagnostic tests, monitoring interventions and treatments translate to improved outcomes given the variation between patients. Unfortunately, processes such as gene transcription and drug metabolism are dynamic in the critically ill; that is, information obtained during static non-diseased conditions may have limited applicability. We propose an alternative way of personalising medicine in the ICU on a real-time basis using information derived from the application of artificial intelligence on a high-resolution database. Calculation of maintenance fluid requirement at the height of systemic inflammatory response was selected to investigate the feasibility of this approach.The Multi-parameter Intelligent Monitoring for Intensive Care II (MIMIC II) is a database of patients admitted to the Beth Israel Deaconess Medical Center ICU in Boston. Patients who were on vasopressors for more than six hours during the first 24 hours of admission were identified from the database. Demographic and physiological variables that might affect fluid requirement or reflect the intravascular volume during the first 24 hours in the ICU were extracted from the database. The outcome to be predicted is the total amount of fluid given during the second 24 hours in the ICU, including all the fluid boluses administered.We represented the variables by learning a Bayesian network from the underlying data. Using 10-fold cross-validation repeated 100 times, the accuracy of the model in predicting the outcome is 77.8%. The network generated has a threshold Bayes factor of seven representing the posterior probability of the model given the observed data. This Bayes factor translates into p < 0.05 assuming a Gaussian distribution of the variables.Based on the model, the probability that a patient would require a certain range of fluid on day two can be predicted. In the presence of a larger database, analysis may be limited to patients with identical clinical presentation, demographic factors, co-morbidities, current physiological data and those who did not develop complications as a result of fluid administration. By better predicting maintenance fluid requirements based on the previous day's physiological variables, one might be able to prevent hypotensive episodes requiring fluid boluses during the course of the following day. The gold standard in evidence-based medicine is a well-designed, well-executed multi-centre prospective randomised controlled trial. However, in the intensive care unit (ICU), it would be impossible to perform such a study to determine whether every diagnostic test, monitoring device or treatment intervention leads to improved patient outcomes. Even when such trials are performed and subsequently published, they rarely, if ever, provide clear evidence on which to base the management of an individual patient.Patients enrolled in these studies are heterogeneous, and conclusions are valid for the 'average' patient. Unfortunately, each patient is unique in terms of how he responds to an intervention. He may not benefit or, worse, may be harmed by a medication, device or procedure that has been shown to correlate with a good patient outcome 'on average'. In addition, these studies investigate one treatment at a time. In reality, treatments are given simultaneously to a patient in the ICU and interact with each other. The nature of these interactions is likely to vary from patient to patient, and perhaps even within the same patient at different points in time.Over the years, we have adopted a multitude of diagnostic tests, monitoring devices and treatments in the ICU based on underpowered studies, in most cases non-randomised, which demonstrate modest benefits on soft clinical endpoints or intermediate outcomes. It is unclear which of these interventions contribute to survival benefit. Despite all the medical advances available in the ICU, less than half of patients who experience severe sepsis are alive one year later . AnotherOver the past decade, we have witnessed the electronification of health care delivery and with it, the creation of large ICU databases of tremendous granularity and resolution. At the same time, the concept of personalised medicine emerged. The goal of personalised medicine is to provide the right treatment to the right patient at the right time. It involves the integration of genomics, proteomics, metabolomics, systems biology, bioimaging and other disciplines in order to characterise the uniqueness of a patient and predict his risk of developing a disease or his response to treatment. It is a tool that can potentially optimise care customisation in the ICU where it is needed the most, given how sick the patients are and how some treatments can lead to worse clinical outcomes. Unfortunately, the dynamic cytokine and neurohormonal milieu of the critically ill patient alters such processes as gene transcription and drug metabolism, rendering information derived during static non-diseased conditions of limited use. In this paper, we propose an alternative way of personalising medicine in the ICU using empiric data to build patient-specific and clinical scenario-specific models. We chose the prediction of fluid requirement of the critically-ill patient at the height of inflammatory response to explore the feasibility of this approach.The first 72 hours after admission are critical for ICU patients. Whether the patient is being admitted for sepsis, acute coronary syndrome, multiple traumatic injuries, intracranial haemorrhage, burns or post-operative care after open heart surgery or organ transplantation, this period is characterised by systemic inflammatory responses fueled by a cytokine storm and the patient is most vulnerable to episodes of hypotension and consequently reduced organ perfusion. Suboptimal fluid management during this critical period leads to the release of more inflammatory cytokines and catecholamines that further worsen the haemodynamic status of the patient. As shown in a number of clinical studies, reduced tissue perfusion resulting from fluid under-resuscitation translates into increased illness severity and a longer ICU stay ,5. In prThe Laboratory of Computational Physiology at Massachusetts Institute of Technology developed and maintains the Multi-parameter Intelligent Monitoring for Intensive Care (MIMIC II) database, a high-resolution database of ICU patients admitted to the Beth Israel Deaconess Medical Center in Boston since 2003, who have been de-identified by removal of all protected health information. An Institutional Review Board approval was obtained from both Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center for the development, maintenance and public use of a de-identified ICU database.The MIMIC II database currently consists of data from more than 18,000 patients that have been de-identified and formatted to facilitate data-mining. The three sources of data are waveform data collected from the bedside monitors, hospital information systems and other third-party clinical information systems.Using the MIMIC II database, we identified patients who were on vasopressor agents for more than six hours during the first 24 hours of their ICU admission. For each patient, we obtained demographic data and physiological variables during the first 24-hour period in the ICU. These variables included vital signs, those that affect and/or represent total body water, and those that reflect severity of illness Table . Rather Using R software , linear regression was performed using stepwise forward variable selection and with a 2:1 split sample approach . The total fluid administered during the second 24-hour period in the ICU was selected as the outcome variable. Using Bayesware Discoverer , we also constructed a Bayesian network using the variables identified and extracted from the MIMIC II database. A Bayesian network is generated depicting the relation between variables based on the joint conditional probability distributions of the variables from the data set. The output is a graphical model representing the variables and their probabilistic dependencies. For our model generation, a maximum number of allowable parents was set at 10, and the threshold Bayes factor was set at 7. The variables, including the outcome variable, were divided at quartiles according to frequency.Finally, the search order was arranged so that the outcome variable we are interested in, that is the total fluid intake for the second 24 hours after ICU admission, would have the largest number of nodes considered as potential parents. The accuracy of the model in predicting the outcome is calculated using 10-fold cross validation repeated 100 times.There were a total of 3014 patients who were on at least one vasopressor agent for a minimum period of six hours during their first 24 hours in the ICU and whose total fluid intake and output were recorded.The distribution of the total fluid intake during the second day in the ICU, the outcome variable, was skewed towards the lower values Figure . The valUsing a stepwise forward variable selection on a 2:1 split sample approach, 14 variables were found to be predictive of the total amount of fluid given to the patient on day two in the ICU. The coefficients of the variables in the fitted model, their standard errors and the corresponding p values are shown in Table R-squared was calculated as a measure of the explained variation accounted for by the linear regression model. It is given by the formula:err is the residual sum of squares and SStot is the sum of squares differences from the mean proportional to the variance. The adjusted R-squared value calculated was 0.25, suggesting that very little of the observed variation can actually be explained by the model. The linear regression model suffered from large variation with a high standard residual error, making it suboptimal for clinical application. For this reason, we shifted to a Bayesian network model to represent our variables and outcome.where SSFigure The threshold Bayes factor is the smallest amount of evidence that can be claimed for the null hypothesis (no correlation between variables) or the strongest evidence against it on the basis of the observed data. This is the benchmark to compare it against a p value. The simplest relation between p values and Bayes factors are based on a Gaussian approximation. In that situation, the Bayes factor is calculated with the same numbers used to calculate a p value . The forwhere Z is the number of standard errors from the null effect. This formula allows us to establish an exchange rate between the Bayes factor and p values in a Gaussian case. For a threshold Bayes factor of seven which was used to generate our model, the corresponding maximum p value is 0.05, assuming Gaussian distribution of the variables. Each link between two nodes in the network has a corresponding Bayes factor. These were not shown because prediction of a variable based on the values of the variables it is related to rests solely on the joint conditional probability distribution and not on the individual Bayes factors.Figuring out the fluid requirement to maintain an adequate intravascular volume  is difficult at the time of critical illness. In practice, clinicians fear over-estimating this fluid requirement. This may contribute to the occurrence of hypotensive episodes especially during the period of maximal systemic inflammatory response. These hypotensive episodes may be averted by being able to predict more accurately the fluid requirement of the patient as the disease process evolves in response to treatment or as a result of healing.The goal of this proof-of-concept study is to explore the feasibility of supplementing traditional evidence-based medicine, expert opinion and clinical intuition with information from empiric data. A Bayesian network was generated between physiological variables obtained during the first 24 hours in the ICU and the total amount of fluid given on the second day in the ICU  from a large database. A greedy search algorithm was used with the outcome variable of interest being evaluated first for potential parent nodes, and the demographic variables  being evaluated last. Given the values of the physiological variables from day one, the range of the total fluid given to the patient on day two can be predicted. Cross-validation was used to determine how well a Bayesian network model represents our data. In cross-validation, the model generated from the training set is evaluated against a previously unseen data. The accuracy of the model in predicting the outcome was 77.8%.We suspect the reason why the accuracy of the Bayesian network generated from the data is not better may relate to the limitations of our methodology. The subset of patients included in the analysis is likely to still represent a heterogeneous group given that the reason why the patient was on vasoactive drugs was not considered. The patients likewise probably represent a wide spectrum as regards the degree of inflammatory response, with possible inclusion of patients who have a minimal amount of inflammation but were put on vasopressors nonetheless. What we would like to do in the future, when we have a larger database, is to specify a more homogeneous group of patients in terms of demographic variables, co-morbidities and clinical scenario.Another potential source of model inaccuracy in the ICU is data noise. This includes device-related artifacts , laboratory errors, missing data and erroneous transcription, to name just a few. Filtering during data pre-processing was performed to reduce, but not obliterate, the impact of noise. The choice of the threshold Bayes factor (the likelihood of the model with links between the parent nodes and their children as compared with a model where the variables are independent) is thus crucial in preventing over-fitting when the data is unavoidably noisy.A point of contention is whether to include clinical outcomes  in the generation of the model. We elected to exclude these variables from the model generation because there are other variables that affect these clinical outcomes apart from fluid management (e.g. choice of antibiotics and timeliness of surgery if required). For this proof-of-concept study, we took a simple approach and focused on predicting how much fluid is given to a patient depending on physiological data obtained during the previous 24 hours, regardless of clinical outcome.A number of studies have looked at the application of artificial intelligence tools in the ICU. Barbini and colleagues  and CeveIt is unlikely that we can replace clinician expertise with an intelligent software. We envision three important uses of artificial intelligence tools applied to empiric data. The first is to supplement clinical knowledge to support decisions in specialised, complicated problems where there may not be adequate evidence in the way of prospective randomised controlled trials. Figure We have taken a deductive approach in generating a model from empiric data. Combining such a deductive approach with an inductive knowledge base from domain expertise in pathological physiological processes and available ICU literature may provide a better tool in assisting clinicians in making decisions for individual patients in specific clinical scenarios.There are very few interventions performed in the ICU, whether for diagnostic, monitoring or treatment purposes, that are based on robust evidence. Even when prospective randomised controlled trials are available, they rarely, if ever, provide clear evidence on which to base the management of an individual patient. This project introduces the concept of using empiric data to obtain patient-specific and clinical scenario-specific recommendations in the ICU. Prediction of maintenance fluid is chosen as the problem domain to test the feasibility of the concept. A software application is envisioned that builds a model consisting of patients that are similar to an index patient in terms of age, gender, ethnicity, admitting diagnosis, severity score on admission and co-morbidities. Based on the model, physiological variables that are directly correlated with the outcome variable of interest are identified. The idea is to provide the values of these predictor variables from the index patient to the model, and a predicted range of fluid requirement is obtained from the joint conditional probabilities. We plan to evaluate the effect of the availability of this information in the ICU in an intention-to-treat prospective observational study. An adherence-to-protocol and on-treatment analyses will be incorporated into the design of the study.• Only a handful of ICU interventions, whether for diagnostic, monitoring or treatment purposes, are based on well-designed, well-executed prospective randomised controlled trials.• The project introduces the concept of mining empiric data using artificial intelligence to obtain patient-specific and clinical scenario-specific recommendations in the ICU.• The idea is to build a model using patients that are similar to an index case with regards to age, sex, admitting diagnosis, co-morbidities and severity score.• Prediction of maintenance fluid requirement in the ICU was chosen to explore the feasibility of the approach.• The information obtained from the model may be useful in supplementing a clinician's knowledge base and intuition.ICU: intensive care unit; MIMIC: Multi-parameter Intelligent Monitoring for Intensive Care.The authors declare that they have no competing interests.LC conceived of the study under the guidance of PS. LC and CH performed the data extraction and pre-processing, and with the help of GA, the data analysis. All authors read and approved the final manuscript.


Recent experience has prompted the US FDA to consider whether ethanol ingestion may modify the release characteristics of prolonged-release formulations, where dose dumping may be an issue for patient safety.The influence of ethanol on the in vitro release of opioid drugs from some prolonged-release formulations utilizing different release technologies was examined. Results indicated that the prolonged-release mechanisms remained intact under the testing conditions, although one product showed initial sensitivity to ethanol in its release characteristics. Nevertheless, in this case, extrapolation of the findings to likely outcome in vivo indicated no risk of dose-dumping.It is proposed that prolonged-release medicinal products should be tested during development to ensure robustness to the effects of ethanol on drug release. MST® Continus® tablets were introduced to provide a controlled delivery of morphine over 12 h. This was followed by 12 h release formulations of hydromorphone , oxycodone (OxyContin® tablets), dihydrocodeine (DHC® Continus tablets), and tramadol . Subsequently, preparations providing the delivery of morphine  and tramadol (Zydol XL tablets) over a 24 h period were developed, enabling the management of pain with a convenient once-daily dosing regimen.Since their introduction in the 1980's, oral prolonged-release opioid formulations have been a mainstay in the management of moderate to severe pain, particularly that due to cancer. As these formulations contain a larger unit dose than conventional, immediate release tablets, which are intended for 4–6 hourly administration, it is imperative that their retardation properties are tightly controlled. This is to ensure that a rapid release of the drug (“dose-dumping”) cannot occur. Prolonged-release formulations are subject to stringent limits on in vitro dissolution to ensure a consistent batch-to-batch uniformity of the finished product. In addition, studies are conducted in healthy volunteers to investigate the influence of a high-fat meal, and the associated delayed gastric emptying, on the in vivo release characteristics of each formulation, to ensure that the prolonged delivery of the active moiety is maintained, regardless of dietary status.Some oral prolonged-release dosage forms contain drugs and excipients that exhibit a higher solubility in aqueous solutions containing ethanol. Accordingly, such products may be expected to exhibit more rapid drug dissolution and release in the presence of ingested ethanol. Recently, a once-daily formulation of hydromorphone was withdrawn from the US market following concern over the potential for ethanol-induced dose-dumping. The manufacturers had been prompted to conduct a pharmacokinetic study by the results of an in vitro evaluation of the dissolution of the preparation in different concentrations of ethanol. The results of the latter evaluation are presented in In a subsequent pharmacokinetic study, healthy subjects were protected from the effects of the opioid agonist by naltrexone blockade (HMP1013). Each subject received a single prolonged-release capsule, containing 12 mg of hydromorphone hydrochloride, according to a randomised, crossover design, including a control arm (no ethanol) and 3 arms involving the ingestion of 240 mL of varying concentrations of ethanol immediately before the once-daily hydromorphone prolonged-release capsule. The two higher concentrations of ethanol represented the equivalent of drinking one-third of a bottle of spirit or one-third of a bottle of fortified wine, respectively, over an approximately 5 min period. The results are summarised in max values, and, therefore, the rate of hydromorphone absorption, was increased markedly in some individuals, particularly at the higher concentration of ethanol. After the ingestion of 40% ethanol, the mean increase in Cmax was 5.5-fold, with one individual showing a 16-fold increase.On average, there was a 26% increase in the AUC of hydromorphone when administered following the ingestion of 40% ethanol. The maximum systemic exposure, as indicated by CThese findings were confirmed in a subsequent study (HMP1014), which also showed that the ingestion of ethanol either 3 h before or 4 h after the administration of the once-daily prolonged-release hydromorphone capsule had no effect on the kinetics of the opioid, thereby providing guidance on the time period within which the drug preparation and ethanol should not be taken together.It was recognised that the most extreme test treatment, equating to ingestion of up to the equivalent of one-third of a bottle of spirit taken over only 5 min, represented an extreme challenge to the formulation. Nevertheless, the once-daily prolonged-release hydromorphone capsule was withdrawn voluntarily by the manufacturer, removing any potential risk to patients of inadvertent dose-dumping.This recent experience has prompted the US FDA to consider further the issue of whether ethanol ingestion may modify the release characteristics of new and currently marketed prolonged-release formulations. The main objective of such an approach will be to minimize the risk of ethanol-induced dose dumping, irrespective of any warnings on product labelling and instructions by health care providers . ClearlyHowever, evaluating the consequences of co-ingestion of high doses of ethanol together with prolonged-release formulations in healthy subjects is also not without risk, even in the case of opioids where the co-administration of an opioid antagonist is also feasible. A potential regulatory approach could be to require a standard series of in vitro dissolution tests to establish that the drug-release characteristics of the originator product or generic product are robust in the presence of ethanol.Against this background, the present investigation examined the influence of high concentrations of ethanol on the in vitro release properties of a range of prolonged-release opioid formulations which utilise a variety of different release technologies (matrix control (monolithic and multiparticulate), ion-exchange, coated beads).The effect of ethanol on drug release from the products listed in To offset the effects of chromatographic differences and different rates of evaporation of the modified media, standards used to assay the drugs were maintained at 37°C and prepared with the same media as used in each dissolution test. At least two representative unit doses of each formulation were tested in each case and the mean values of cumulative release were calculated. Drug concentrations were measured by reversed phase HPLC with UV detection at an appropriate wavelength. All of the drug assays were validated to ICH guidelines for specificity, linearity, accuracy and precision.Palladone SR capsules, which utilise a coated bead technology, demonstrate a distinct biphasic effect as a function of ethanol concentration–the initial drug release rate decreased as the ethanol concentration was increased from 5 to 15% v/v then increased to control values at 30% v/v with a further increase compared to control values at 35–40% v/v. To provide confidence in this observation, the experiment was repeated using a different batch of Palladone SR capsules and taking the mean result for 6 separate capsules at alcohol concentrations of 10, 30, and 40% v/v. The effect of ethanol on the pattern of drug release was confirmed, and the maximum coefficient of variation of drug release within unit doses across all sampling points was 3%.Cumulative release profiles for each of the products tested are shown in Experience with the once-daily hydromorphone preparation has highlighted the potential for ethanol to alter the retardation properties of prolonged-release formulations. The exact effect will depend upon gastric emptying time, the absorption and metabolism of ethanol in the stomach, fluid secretion into the stomach and the nature of the formulation.Normally, the gastric emptying of liquids is rapid with a half time of 12 min, such that 95% is emptied in 1 h (Petring & Blake).Basal gastric secretion rates of up to 3 L/day (125 mL/h) have been reported Recognizing the above variables, it was considered that in vitro dissolution studies over 2 h with ethanol concentrations of up to 40%v/v should afford confidence with regard to the likelihood of altered release rate or dose-dumping consistent with the most extreme conditions likely to be encountered in vivo.Palladone SR capsules) indicated a clear increase in dissolution rate in the first hour in the presence of high concentrations of ethanol. Thereafter, hydromorphone was released at a rate consistent with that of the control, as demonstrated by the parallel slopes of the release curves.Of the products tested in this study, only one (Simulation of the in vivo impact of this on the in vivo kinetics of hydromorphone (unpublished) indicated that any increase in peak plasma hydromorphone concentration arising from a 2 h exposure to 40% ethanol would be expected to be of the order of 15–30%. This change is similar in magnitude to that commonly observed when some prolonged-release formulations are compared under fed and fasting conditions. Therefore, such an increase would not be expected to be of clinical significance.The dissolution conditions used routinely for quality control of the release properties of the products that we have investigated differ in terms of pH and dissolution media . HoweverThe products investigated cover a variety of prolonged-release formulation technologies and utilise a broad spectrum of release-controlling excipients. The results have shown that the prolonged-release mechanisms of the products remain intact under the testing conditions. When extrapolated to the in vivo situation, the data indicate that there is no risk of a potentially dangerous dose-dumping. It is believed that the experimental conditions selected, which are expected to be representative of the most extreme conditions likely to be encountered in vivo, were justified by our understanding of gastric conditions and the fate of ethanol in the stomach.Analysis of these data and unpublished confidential material indicates that there is no clear correlation between the ethanol solubility of the ingredients and the ethanol susceptibility of formulations, rather there may be complex interactions between active and inactive ingredients and dosage form design. Therefore, it is proposed that all prolonged-release medicinal products should be subjected to in vitro testing during formulation development to ensure their robustness to the effects on drug release when consumed with alcoholic beverages. This is of particular concern with preparations containing drugs with a narrow therapeutic index or drugs such as strong opioids where careful titration of dosage is necessary. A standardized approach to testing needs to be agreed and adopted internationally by the pharmaceutical industry and regulatory authorities.


CHEST PAIN CHOICE) that communicates the short-term risk of ACS and (2) to evaluate the impact of the decision aid on patient participation in decision-making and resource use.Chest pain is a common presenting complaint in the emergency department (ED). Despite the frequency with which clinicians evaluate patients with chest pain, accurately determining the risk of acute coronary syndrome (ACS) and sharing risk information with patients is challenging. The aims of this study are (1) to develop a decision aid  patient knowledge regarding their short-term risk for ACS and the risks of radiation exposure; (2) quality of the decision making process; (3) patient and clinician acceptability and satisfaction with the decision aid; (4) the proportion of patients who decided to undergo observation unit admission and urgent cardiac stress testing; (5) economic costs and healthcare utilization; and (6) the rate of delayed or missed ACS. To capture these outcomes, we will administer patient and clinician surveys after each visit, obtain video recordings of the clinical encounters, and conduct 30-day phone follow-up.This is a protocol for a parallel, 2-arm randomized trial to compare an intervention group receiving This pilot randomized trial will develop and evaluate a decision aid for use in ED chest pain patients at low risk for ACS and provide a preliminary estimate of its effect on patient participation in decision-making and resource use.Clinical Trials.gov Identifier: NCT01077037 Over 6 million adults present with chest pain in US emergency departments (EDs) each year, making chest pain the second most common presenting complaint . DespiteRisk communication in a busy ED setting is also a challenge. When a patient presents to the ED with chest pain and the initial evaluation for non-cardiac etiologies is unrevealing, the focus of the evaluation shifts to estimating a patient's risk for ACS. Without the assistance of decision support tools, clinicians are challenged to precisely quantify risk and often resort to terms such as "low," "rare," or "uncommon" when communicating risk to patients. One recent study reported that patients often overestimate the level of potential harm when verbal descriptors are used to communicate risk . To incrCHEST PAIN CHOICE, a decision aid to communicate the short-term risk for an ACS and the available management options and (2) test the effect of CHEST PAIN CHOICE, in a randomized clinical trial, on patient knowledge, the quality of the decision making process, patient safety, and resource use.To date, the authors are unaware of any published research investigating the specific role and impact of shared decision making in patients at low risk for ACS. We hypothesize that patients infrequently participate in the decision to undergo prolonged observation and urgent cardiac stress testing and that the use of a decision aid to communicate both the short-term risk of ACS and the risks of ionizing radiation exposure will increase patient involvement in the decision making process, lead to a preference-based decision, and safely decrease resource use. To test our hypothesis, we will accomplish the following specific aims: (1) develop and refine To evaluate the decision aid, we will conduct a patient-level single center pilot randomized trial. The Mayo Clinic Institutional Review Board has approved all study procedures.Patients and emergency physicians will be recruited from the Saint Marys Hospital ED at the Mayo Clinic, a tertiary care academic ED with an annual census of 73,000 patient visits. The trial will be conducted in the flow of routine patient care. This approach will enable us to test how the decision aid performs in the real-world setting.Eligible providers will include clinicians  caring for patients with chest pain. Eligible patients will include adults (>17 years of age) presenting to the ED with a primary complaint of non-traumatic chest pain who are being considered for admission to the ED observation unit for urgent cardiac stress testing.th percentile reference limit  [The trial will exclude patients with an initial cardiac troponin T value above the 995 ng/mL) , known c5 ng/mL) , cocaineWe have previously developed and validated an electronic notification system that is highly sensitive and specific for identifying potentially eligible participants presenting to the ED with chest pain as a primary complaint  [CHEST PAIN CHOICE decision aid prototype has been developed through an iterative process involving collaboration between designers and researchers, field-testing by patients and clinicians, and revision of the decision aid in response to the feedback provided. We have employed this methodology to develop the prior decision aids STATIN CHOICE [OSTEOPOROSIS CHOICE [The N CHOICE   a usual care arm in which the provider will discuss the management options in their usual fashion without the decision aid or pretest probability calculator.We will use a dynamic allocation procedure described by Pocock and Simon  to randoGiven the limited amount of information that is available during the initial ED encounter and the known association of age and sex with cardiovascular risk, we will dynamically stratify by age and sex in the allocation process to ensure that the treatment arms are balanced in regard to these factors. To enroll patients in the trial, the study coordinator will complete the following:• Assess patient eligibility in collaboration with the treating physician and obtain written informed consent from both parties.• Access a secure website, input key patient characteristics, and obtain from the website interface the arm to which the patient is allocated.After randomization, outcome assessors and data analysts will remain blind to allocation. In the event that a patient is suspected of being incorrectly enrolled , the study coordinator will present the case to the principle investigator (E.P.H.) for review. The principle investigator, blinded to both allocation arm and patient outcome, will then consider post-randomization exclusion according to published recommendations .CHEST PAIN CHOICE will increase the quality of the decision-making process, increase patient knowledge, and decrease resource use. However, we anticipate that clinicians will revert to their usual pattern of practice without the calculator -- since access to it is password-protected -- and be reluctant to dismiss patients from the ED. We will also monitor for evidence of contamination by reviewing the video recordings of clinician-patient encounters in the control group.The main disadvantage of randomization at the patient level is reducing the risk of contamination in the control group. Providers may be aware of the hypothesis that use of For patients randomized to the intervention arm, the study coordinator will review the contents of the decision aid in real time with the clinician immediately before the patient encounter. This approach to delivering the decision aid (with just-in-time training by the study coordinator prior to use) has been effectively used in our prior decision aid studies . We haveFor patients randomized to the usual care arm, the clinicians will discuss the results of the diagnostic investigations and management options with the patient in that clinician's usual fashion. We will videotape the patient-clinician discussion for future review. No research-related interventions will be administered.CHEST PAIN CHOICE on the following outcomes: (1) patient knowledge regarding their short-term risk for ACS and the risks of radiation exposure; (2) quality of the decision making process for the patient and clinician; and (3) patient and clinician acceptability and satisfaction with the decision aid. We will also assess (4) the proportion of patients who decide to undergo observation unit admission and urgent cardiac stress testing; (5) economic costs and healthcare utilization; and (6) the rate of delayed or missed ACS (primary safety endpoint). The diagnosis of ACS will be considered delayed or missed if the patient was dismissed from the ED without observation unit admission and urgent stress testing and they meet the definition of ACS within 30 days of the ED visit. ACS will be defined as acute myocardial infarction [Decision-based outcome measures take into account both the Ottawa Framework for Shared Decision Making  and selffarction , ventricA study coordinator will review the electronic medical record and conduct telephone follow-up for all enrolled patients starting at 30 days. The coordinator will verify the patient's telephone number at the time of enrollment to maximize the fidelity of follow-up. For those who are unable to be contacted by phone, we will use the resources of the Rochester Epidemiology Project  to deterWe will survey patients and clinicians after each visit and videotape the decision aid discussion between the clinician and patient in both the intervention and control groups to capture outcomes. The patient surveys • 7 items to assess patient knowledge, 2 of which address the risks of radiation exposure, 2 that address the available management options, 2 about the potential implications of cardiac stress test results (not informed by content on the decision aid), and one question about the patient's personalized risk for ACS within 45 days of the ED visit. These items were fashioned after similar questions, which have demonstrated construct validity and responsiveness to the intervention in previous decision aid trials ,30.• 5 items using a 7-point Likert-type scale to assess the patient's perceptions about the amount, clarity and helpfulness of the information, their desire to receive information about other diagnostic options in the same way this information was delivered, and whether they would recommend the way they received information from their clinician during this encounter to other patients. We have used the same items in our previous trials ,30.• 10 items from the Trust in Physician scale • 17 items from the Decisional Conflict Scale , which a• Additional questions that inquire about the decision made by the patient during the visit and patient satisfaction with the degree of participation in the decision making process.The treating clinician will be asked to complete a survey after each study visit  and explanation of the ON scale  to evaluON scale ,34. VideWe will conduct an economic evaluation of the trial using the Olmsted County Healthcare Expenditure and Utilization Database (OCHEUD). We will limit the analysis to subjects residing in Olmsted County, Minnesota since we have complete data on medical care utilization for this population. OCHEUD is a claims-based database that contains information on medical resource utilization, associated charges, and estimated economic costs for patients receiving care at either the Olmsted Medical Center or the Mayo Clinic and their associated inpatient facilities. Although the services provided represent the clinical practice patterns of Mayo Clinic and Olmsted Medical Center providers, the value of each unit of service has been adjusted to national norms by use of widely accepted valuation techniques. OCHEUD provides an estimated economic cost for each line item in the billing record and allows the aggregation of costs into categories deemed relevant to a particular study. The database serves as a major source of financial information on all patients  and includes line-item detail on date, type, frequency, and billed charge for every good or service provided. We will use data from the OCHEUD database to compare costs and utilization between the intervention and control groups. We will further compare the types of services that were used in each of the groups.We have sufficient funding to enroll and randomize 200 patients. While this number is insufficient to definitively assess the efficacy of the decision aid and its effect on the proportion of patients who decide to undergo observation unit admission and urgent cardiac stress testing, it is sufficient to determine the following:• for knowledge gains, assuming the patients in the control group will, on average, answer 4 of the 7 questions correctly, we will have 90% power to detect a >25.7% increase in mean knowledge (to a mean of 5.8 questions answered correctly) in the intervention group, assuming equal variances between the two arms and alpha = 0.05;• for the proportion of patients who decide to undergo observation unit admission and stress testing, assuming that at least 90% of patients in the control group will be admitted to the ED observation unit (null hypothesis), we will have 95% power to detect a 20% decrease in the proportion of patients who decide to be admitted to the ED observation unit for stress testing  in the decision aid treatment group, with a two-sided test at a 5% significance level.The feasible sample size is also adequate to provide a plausible effect size to plan a definitive multicenter randomized trial.We will report baseline characteristics potentially associated with study outcomes  separately for the intervention and control group. Each factor will be compared using either the Chi-square or Fisher's exact test for categorical variables, depending on which is appropriate for that factor. The continuous factors will be compared using the Wilcoxon rank sum test or t-test as appropriate. Any imbalance found within a risk factor will be explored as a possible factor to adjust for when the outcome measures are being analyzed. Any p-value < 0.10 will be considered a possible imbalance.Study data will be collected and managed using REDCap electronic data capture tools hosted at the Mayo Clinic . REDCap Continuous variables will be reported as mean (± S.D.) or medians with interquartile ranges as appropriate for the distribution of the data. Categorical data will be presented as percent frequency of occurrence. Variables will be compared using relative (relative risk) or absolute (mean differences) measures of association and their 95% confidence intervals. To test hypotheses of association, we will use Wilcoxon rank-sum tests to compare medians, and Chi-square or Fisher's exact tests to compare frequencies. All analyses will be based on two-sided tests at a significance level of 0.05. We will follow the intention to treat principle in our analysis, making every effort to avoid missing data and analyzing patients according to the arm to which they were randomized. All analyses will be conducted using SAS software  version 9.1 TS level 1M3.We have described the design of a clinical trial to determine the effectiveness of a decision aid on patient participation in decision-making and resource use in ED chest pain patients at low risk for ACS. While this is a feasibility trial for a new decision aid, it will provide an estimate of the effect of the decision aid that can be used to inform the design of a larger multicenter trial.An important reason to conduct feasibility trials of decision aids designed for use in the clinical setting is that the tools have potential to impact the nature and content of the patient-physician discussion and the duration of the clinical evaluation. Patients who present to the ED with chest pain may be in a vulnerable emotional state such that they prefer decisions be made on their behalf rather than actively participate in their medical care. The ED is also the safety net for patients of all levels of education and for those without medical insurance, and we anticipate that there may be knowledge transfer challenges that are unique to this practice setting. When clinicians with different practice patterns and level of experience use the decision aid, they may not find it appropriate to use for some patients or may not use the decision aid appropriately. Therefore, video recording the patient-clinician encounter may provide insight into these potential challenges, the effectiveness of the decision aid, and the nature of the patient-physician interaction in a busy ED environment. The results of this study may guide process changes in trial design, changes in inclusion and exclusion criteria, refinement of the decision aid itself, and data to estimate a sample size for design of a larger efficacy study.CHEST PAIN CHOICE will increase patient knowledge and involvement in the decision making process, decrease physician and patient anxiety, and safely decrease resource use in ED patients with chest pain. We will also continue to develop the expertise of our group in the conduct of decision aid trials in complex real-world settings.In conclusion, there is an urgent need to develop and evaluate a shared decision making approach to patients presenting with chest pain to the ED. Chest pain is a common complaint in EDs that challenges emergency clinicians to provide an accurate, safe, and efficient diagnosis. Clinicians seem to have a very low risk tolerance and initiate diagnostic testing in patients with a very low pre-test probability of disease. Overtesting for ACS increases the likelihood of false positive stress testing, exposes patients unnecessarily to ionizing radiation, worsens ED overcrowding, and increases the cost of care. Developing and testing a decision aid that transparently communicates the short-term risk for ACS to both clinicians and patients, the potential risks of radiation exposure, and the available management options is a novel approach to solving a common clinical problem in a patient-centered fashion. Our approach differs from prior risk stratification studies of ED patients with potential ACS in that it seeks to enhance patient involvement in the decision making process rather than relying solely on diagnostic accuracy . We hypothesize that use of ED: emergency department; ACS: acute coronary syndrome; GRACE: Global Registry of Acute Coronary Events; TIMI: Thrombolysis in myocardial infarction; OCHEUD: Olmsted County Healthcare Expenditure and Utilization Database; REDCap: Research Electronic Data Capture;The authors declare that they have no competing interests.MAP contributed to the design of the study, designed study procedures, and wrote the first draft of the manuscript. EPH made substantial contributions to the conception and design of the study and the study protocol, applied for funding, and made critical revisions to the manuscript. JAK made substantial contributions to the conception and design of the study, developed the pretest probability calculator to inform the decision aid, and made critical revisions to the manuscript. NDS contributed to the conception and design of the study, wrote the economic analysis portion of the manuscript, and provided critical revisions to other sections of the manuscript. MB contributed to the conception and design of the study, designed the decision aid, and provided critical revisions to the manuscript. MEB contributed to the statistical analysis of the study, wrote the statistical section of the manuscript, and provided critical revisions to other sections of the manuscript. LJP contributed to the design of the study, designed study procedures, and provided critical revisions to the manuscript. BRA, DMN, ATS, and IGS contributed to the conception and design of the study and made critical revisions to the manuscript. HHT, a cardiologist, provided subspecialty expertise to the conception and design of the study and made critical revisions to the manuscript. VMM made substantial contributions to the conception and design of the study and the study protocol and made critical revisions to the manuscript. All authors approved the final version of this manuscript.General patient survey.Click here for fileWiser choices patient survey (numeracy survey).Click here for fileProvider Survey.Click here for file


Chronic neck pain is a common problem and is often associated with changes in sensorimotor functions, such as reduced proprioceptive acuity of the neck, altered coordination of the cervical muscles, and increased postural sway. In line with these findings there are studies supporting the efficacy of exercises targeting different aspects of sensorimotor function, for example training aimed at improving proprioception and muscle coordination. To further develop this type of exercises we have designed a novel device and method for neck coordination training. The aim of the study was to investigate the clinical applicability of the method and to obtain indications of preliminary effects on sensorimotor functions, symptoms and self-rated characteristics in non-specific chronic neck painThe study was designed as an uncontrolled clinical trial including fourteen subjects with chronic non-specific neck pain. A new device was designed to allow for an open skills task with adjustable difficulty. With visual feedback, subjects had to control the movement of a metal ball on a flat surface with a rim strapped on the subjects' head. Eight training sessions were performed over a four week period. Skill acquisition was measured throughout the intervention period. After intervention subjects were interviewed about their experience of the exercise and pain and sensorimotor functions, including the fast and slow components of postural sway and jerkiness-, range-, position sense-, movement time- and velocity of cervical rotation, were measured. At six-month follow up, self-rated pain, health and functioning was collected.The subjects improved their skill to perform the exercise and were overall positive to the method. No residual negative side-effects due to the exercise were reported. After intervention the fast component of postural sway (p = 0.019) and jerkiness of cervical rotation (p = 0.032) were reduced. The follow up showed decreased disability (one out of three indices) and fear of movement, and increased general health (three out of eight dimensions).The results support the clinical applicability of the method. The improvements in sensorimotor functions may suggest transfer from the exercise to other, non-task specific motor functions and justifies a future randomized controlled trial. Chronic neck pain is a common problem . Since tIn line with the above, studies on neck pain patients evaluating the efficacy of exercise regimes targeting cervical sensorimotor functions have shown promising results. Thus, specific exercises for eye-head-neck coordination were shown to reduce pain -14 as weThe above mentioned exercises focus on slow movements and closed skills tasks . Drawing on the literature on motor learning, an opportunity for further development of exercises targeting sensorimotor function of the neck resides in designing an exercise which entails a more open skills task, for example via an unstable dynamic system. Such an exercise is less predictable and demand on-line adjustments of the neuromuscular control system. The exercise should preferably be performed in a functional position and include active problem solving, feedback of results as well as progression of difficulty in order to promote motor learning . To achiThe present paper describes a novel exercise method aiming at improving sensorimotor functioning of the neck, and a pilot study of its clinical applicability and preliminary indications of its efficacy for persons with chronic non-specific neck pain. The specific aims were to study the skill acquisition and to assess the subjects experiences of the exercise. A further aim was to find out preliminary information about changes in sensorimotor functions, pain and self-reported characteristics after a four week exercise period with the novel method.The study was designed as an uncontrolled clinical trial. Baseline measurements and post intervention measurements were collected within a week before and a week after the intervention, respectively. Follow up measurements were collected six months after the last exercise session. The study was approved by the Regional Ethical Review Board in Uppsala and written informed consent was obtained from all subjects before the start of the trial.Seventeen subjects were recruited from a vocational rehabilitation center  and by advertising in the surrounding area. The inclusion criteria were non-traumatic neck pain, location confirmed with pain drawings , with a ® Classic 100), cotton fabric, copy paper (80 g/m2), all glued on a Plexiglas board, and finally an uncovered Plexiglas board.A newly developed device  was used for the neck-coordination exercise. The device was designed to allow for an exercise involving an open skills task, task variation, continuous feedback and progression of difficulty fig. . The devThe exercise was performed in a functional sitting position in an adjustable office chair. The subject was provided with visual feedback of the device via mirrors. To ensure a good sitting posture during the exercise, the subject was instructed to sit upright with lumbar support and the head balanced in line with the torso, the hips and knees about 90° flexion and the lower arms resting on armrests. In this position the task was to move the metal ball (weight 220 gram) from a starting position, by controlled movements of the head, to the centre of the plate and hold it still for three s , with a mean age of 26. The healthy group performed eight exercise sessions over a four week period. Improvement in exercise performance was measured and the subjects where interviewed after the exercise period. No other measurements where collected. All the healthy subjects showed a rapid improvement in the exercise performance. The interviews revealed an overall positive opinion about the exercise method and no adverse effects were reported other than transient discomfort and tiredness. The most common strategies to succeed with the task were to perform small and slow movements. The supervision of the exercise and the collecting of measurements in the previous and the present pilot studies were executed in a clinical setting by the first author.Measurements collected at baseline were sensorimotor function tests, questionnaires and pain measurements. Post intervention measurements were sensorimotor function tests, pain measurements and subjective experience of the exercise. Six months follow up was accomplished with questionnaires and pain ratings. Throughout the exercise period skill acquisition was measured.The acquisition of the skill to perform the neck coordination task was assessed by recording the trial times as well as monitoring the rate of progression to successively faster surfaces during the intervention period. The outcome variable for the improvement in performing the task, was the slope of the linear regression of the trial times on the fastest surface for each subject. Such calculations were not performed for the slower surfaces due to rapid progression, resulting in insufficient data  for a meaningful regression analysis.To assess the subjective experiences of the method, the subjects were interviewed after the last training session by the test leader asking predetermined questions. Questions included in the interview were: (1) What is your overall opinion about the training method? (2) How comfortable was the plate on the head? (3) Were the instructions easy to understand? (4) Did you experience tiredness, discomfort or pain from the training? (5) Did you use any strategy when trying to succeed with the exercise task? For each question a few categories were formed on the basis of the replies.Tests of postural sway and cervical axial rotation were performed in quiet stance bare footed on a force platform with the feet together, heel-to-heel and toe-to-toe. Instructions were pre-recorded and provided through speakers. The test order was the same for all subjects, starting with postural sway followed by cervical rotation. The selection of tests and the sensorimotor variables calculated from these tests were based on two premises: (1) that they have discriminative value for people with chronic neck pain ,3,5-8 anIn the postural sway test the subject was instructed to stand as still as possible during 30 s with eyes closed and arms crossed over the chest. Prior to the test a 10-s training session was given. A static force platform  was used for measuring the centre of pressure (CoP) migration in the anterior-posterior and medio-lateral directions with a sampling frequency of 30 Hz. It is well established that the CoP signal is composed of two main components, one slow and one fast, reflecting separate mechanisms of the postural control system e.g., ,23). We . We 23])The cervical rotation test was performed in two separate conditions in randomized order; rotation to the right and to the left. In each condition, a block of eight consecutive rotations  was executed with a short resting interval between trials. The subject was instructed to rotate the head with a fast movement as far as possible. Prior to each trial the subject was instructed to memorize the starting position, which was a self-selected neutral position of the head, and to reproduce this position as accurately as possible after each head rotation. The instruction given was "memorize your head position", "make a fast rotation of your head as far as possible" and "return to the starting position as accurately as possible". Prior to each block the subject was given a training session of two trials. Cervical kinematics was measured with an electromagnetic tracking system , with a sampling rate of 60 Hz. Two receivers, one positioned on the forehead and the other above the dorsal spinal process of Th2, were used for recording the axial head rotation relative to the trunk. A quintic spline   was usedROM) was calculated as the maximal angular excursion from the starting  head position. To assess the movement smoothness and speed, the movement time, peak velocity and jerk index were calculated for the rotation from the starting position to maximal excursion angle. The start and stop of the rotation used for these calculations were defined by a threshold of 5% of the peak angular velocity. To estimate the acuity of cervical repositioning we calculated the variable error (VE) of repositioning. First, the difference between the reproduced angle (the angle when the angular velocity had remained below 5% of peak velocity for 0.5 s) and the starting angle (0.5 s before the start of the movement) were calculated for each trial . In order to remove any systematic drift in the errors, which is unrelated to the response variability but will affect VE [jerk index was calculated from the third derivative of the head- trunk angle using the algorithms described in Kitazawa et al. [In total, five outcome variables were calculated from the cervical rotation test: The range of movement , and for the cervical rotation variables: jerk index p = 0.98 and ICC = 0.93, movement time p = 0.37 and ICC = 0.93, peak velocity p = 0.99 and ICC = 0.91, ROM p = 0.039 and ICC = 0.92, repositioning VE p = 0.85 and ICC = 0.73 respectively .Test-retest data from other studies which included the same methods as used in the present study was analysed to get an indication of the reliability of the tests (intra class correlation coefficient (ICC)) and to reveal possible retest effects on mean values (paired t-test). The p-values of the t-test and ICCvisual analogue scale (VAS), on which 0 mm corresponds to "no pain at all" and 100 mm to "worst imaginable pain" [Self-rated pain was assessed as pain at the moment and measured within a week before the day of testing on a blank 100 mm le pain" .The Short Form 36 (SF-36) was used as a measure of subjective functional health and well being [the Neck Disability Index (NDI) [The TAMPA Scale of Kinesiophobia (TSK) was used to measure fear of movement and re-injury due to movement [The Self-Efficacy Scale (SES) was used to measure confidence in performing activities of daily living[The Disability of the Arm, Shoulder and Hand (DASH) questionnaire was used to measure upper extremity disability and symptoms [Self-reported characteristics were assessed by the following questionnaires: ll being . Severitex (NDI) . The TAMmovement . The Selly living. The Dissymptoms . The indOne sample t-test was used to analyse the slopes of the linear regression of the skill acquisition of performing the exercise task. The presumed independence between the sensorimotor variables was tested by calculating Pearson's correlation coefficient between all variables. For independent (non-correlated) variables, paired t-test were used to assess changes between the pre- and post-intervention measurements. For correlated variables repeated measures MANOVA were used, if this MANOVA was significant, paired t-tests were performed to identify the variables that contributed to the effect. Jerk index-, movement time-, and VE of cervical rotation were log transformed before analysis due to skewed distribution. The VAS measurements were analyzed with the Friedman test and the questionnaires scores with Wilcoxon signed ranks test. All analyses were performed using SPSS 13.0 for Windows . In all statistical tests, p < 0.05 was considered significant.All subjects improved their skill to perform the exercise task. This was evident from the fact that all subjects progressed to the most difficult condition during the intervention period and by the fact that all subjects successively decreased their median time per block  on the fastest surface . Five subjects reported post-exercise soreness after the first two-three training sessions. Finally, on the open question about strategies used for the exercise task eight subjects mentioned repositioning VE and ROM from the cervical rotation test and Ra and Tr area from the postural sway test were each uncorrelated to any of the other variables, therefore t-tests were used to assess pre-post intervention changes. Significant decrease was seen for Tr area (p = 0.019) . These variables were therefore analysed with repeated measure MANOVA, which revealed a significant change . Since the MANOVA was significant, the dependent variables were analysed with paired t-tests. This analysis indicated that mainly decreased jerk index contributed to the effect .The correlation analyses of the sensorimotor variables revealed that a p = 0.09 .For the SF-36 significant improvement was seen in three out of eight dimensions Table . These wThe results expose positive findings regarding the clinical applicability of the novel neck coordination exercise. Also, indication on possible positive effects were seen in some of the sensorimotor functions and self-rated characteristics.deep concentration on the task when interviewed about exercise strategies. This indicates that the exercise involved substantial cognitive effort, which is argued to be an important factor for retention and transfer of motor skills [The exercise regime appeared easy to learn, as all subjects improved their skill to perform the exercise task. This was evident by the progression to the most difficult condition and a successively reduced trial time on each condition during the intervention period. These results confirm that the design of the task and the progression of difficulty were well adapted. Most of the subjects expressed a positive opinion about the exercise, and all subjects reported that the task was easy to understand. The adverse effects due to the exercise that were reported were transient tiredness, discomfort, pain and post-exercise soreness. These side-effects were common and occurred predominantly in the early phase of the intervention period, which can be considered normal reactions due to unaccustomed exercise. Only one person experienced discomfort from wearing the device on the head. Together, these facts support the applicability of the method in a clinical practice, as a conjunction to other interventions, e.g., posture correction, manual therapy, strength and endurance exercises, home exercises etc. Also, a majority of the subjects (8 of 13) mentioned r skills .Tr area (the fast component) of postural sway and jerk index  of cervical rotation. This suggests that there may be a transfer effect from the exercise task to other, non-task specific, motor functions, such as increased postural stability and smoothness of cervical movements. Alternatively, these findings may be simple retest effects. However, as presented in the Methods section, former test-retest data on the same variables revealed no retest effects, which speaks against such an interpretation. In accordance with the present finding, improvements in postural sway has been reported in studies on people with neck pain who received physical therapy which included exercises for cervical muscles [jerk index, movement time and peak velocity from the cervical rotation test is somewhat ambiguous to interpret since it is the result of three correlated variables. However, the subsequent paired t-tests indicated that jerk index was the main contributor to the effect. Reduced jerkiness after the exercise indicates that the subjects executed the cervical rotation with smoother movements. Less jerkiness is argued to reflect better movement control [jerk index [Improvements in sensorimotor functions were indicated by the significant decrease in  muscles ,32. A po muscles . Moreove muscles . Since t control . The cli control ,7,8 and rk index  during crk index ,14 no efA relevant question is whether the present sample has impaired sensorimotor functions compared to healthy controls. Comparing the present sample with a group of healthy controls (n = 21) from an unpublished cross-sectional study did not reveal significant reductions in postural control or cervical movement smoothness. Nevertheless, as mentioned above, disturbances in these sensorimotor functions has been documented in previous studies on people with neck pain. Future studies on this novel neck coordination exercise method should therefore preferably include specifically selected samples of people with postural control and movement smoothness disturbances.The improvements seen in some of the questionnaire scores at the six-months follow up could be either an effect of the intervention or an effect of natural recovery over time. The improvements of the TSK score may indicate that individually adjusted exercise have positive effect on fear of re-injury due to movement. This reasoning is supported by the results presented by Bunketorp et al. , showingNo significant improvements were found for pain ratings (VAS). The reason may be that this exercise has no effect on pain, or that the dosage of the exercise was too small. Earlier studies which have reported decreased pain ratings after intervention involved more frequent training regimes ,14,15, sThis study is limited to investigation of the clinical applicability of the novel exercise for subjects with chronic non-traumatic neck pain in a working age population. Other possible applications that may need further exploration is for rehabilitation of acute neck pain, whiplash associated disorders and diseases that involve dysfunction of the postural control, e.g. vestibular and neurological diseases, as well as fall risk in elderly people. The study has some important limitations concerning the implication of the post intervention measurements. Firstly, the lack of a control group and the relatively small sample size imply that no firm conclusions can be drawn regarding the effects on sensorimotor function tests, questionnaires and pain measurements. Secondly, the tests, exercise instructions and interviews were performed by the same experimenter. Blinded test leaders are needed in future studies. Thirdly, eight training sessions of 10–15 minutes is a relatively small dosage, which implies that the exercise may not have reached full effect. Lastly, the sensitivity of the sensorimotor function tests can likely be improved. Longer sampling periods for the postural sway test would probably improve the reliability of the slow component specifically. Testing the postural sway in different conditions could also be valuable, e.g., with open and closed eyes, on firm and soft surface and by using perturbation, such as vibration of calf and neck muscles and galvanic stimulation of the vestibular nerves. The cervical repositioning test may be more sensitive if performed with slow movements in a sitting position.All subjects improved their skill to perform the exercise task. The comprehension of the task was conceived as easy, and a majority expressed a positive opinion about the exercise. Although transient pain and discomfort was common, especially in the early phase of the exercise period, no residual negative side-effects were reported. Taken together, this supports the clinical applicability of the method. The indications on improvements in sensorimotor functions may suggest transfer from the exercise task to other, non-task specific motor functions. The results support a future randomized controlled trial on the exercise effects.The study was supported by funding from Alfta Research Foundation. The patent for the novel device is owned by three of the authors and mr Larson, the engineer.UR participated in the design of the study, carried out the data acquisition, and the statistical analyses and drafted the manuscript. MBJ participated in the design and coordination of the study, the statistical analyses and helped to draft the manuscript. MBE participated in the design and coordination of the study. MD conceived of the study, participated in the design, statistical analyses of the study and helped to draft the manuscript. All authors read and approved the final manuscript.Neck coordination exercise. Movie of neck coordination exercise performed with the novel device on a medium fast surface.Click here for file


The otolith-driven translational vestibulo-ocular reflex (tVOR) generates compensatory eye movements to linear head accelerations. Studies in humans indicate that the cerebellum plays a critical role in the neural control of the tVOR, but little is known about mechanisms of this control or the functions of specific cerebellar structures. Here, we chose to investigate the contribution of the nodulus and uvula, which have been shown by prior studies to be involved in the processing of otolith signals in other contexts.We recorded eye movements in two rhesus monkeys during steps of linear motion along the interaural axis before and after surgical lesions of the cerebellar uvula and nodulus. The lesions strikingly reduced eye velocity during constant-velocity motion but had only a small effect on the response to initial head acceleration. We fit eye velocity to a linear combination of head acceleration and velocity and to a dynamic mathematical model of the tVOR that incorporated a specific integrator of head acceleration. Based on parameter optimization, the lesion decreased the gain of the pathway containing this new integrator by 62%. The component of eye velocity that depended directly on head acceleration changed little (gain decrease of 13%). In a final set of simulations, we compared our data to the predictions of previous models of the tVOR, none of which could account for our experimental findings.Our results provide new and important information regarding the neural control of the tVOR. Specifically, they point to a key role for the cerebellar nodulus and uvula in the mathematical integration of afferent linear head acceleration signals. This function is likely to be critical not only for the tVOR but also for the otolith-mediated reflexes that control posture and balance. The otolith organs sense the head's linear motion and its orientation relative to gravity. Signals proportional to linear head acceleration are carried by otolith afferents from the labyrinth to the brain to drive the translational vestibulo-ocular reflex (tVOR), helping to stabilize vision when the head moves.The central pathways of the tVOR are less well known than those of the rotational VOR (rVOR), although new information has emerged in recent years As part of the vestibulocerebellum, the nodulus and uvula (Nod/Uv) are densely connected to primary and secondary vestibular neurons, and they play a critical role in vestibular reflexes. The Nod/Uv receives a dense collateral projection from ipsilateral semicircular canal and otolith afferents. Saccular afferents project to the uvula Although the role of the Nod/Uv in the tVOR has only recently been considered, a number of studies have examined its contribution to the rVOR, including the interactions between canal and otolith inputs. The Nod/Uv plays a central role in angular velocity storage, the integrator of the central vestibular system that enhances the low-frequency performance of the rVOR Using surgical lesions of the Nod/Uv in rhesus monkeys, we investigated for the first time whether these areas play a direct role in the horizontal tVOR. We measured eye velocity during abrupt steps of interaural translation; Nod/Uv lesions reduced the response to sustained translation but had much less effect on initial eye acceleration. Limited preliminary data from these experiments have been previously presented velocity oscillated about the ideal velocity. These oscillations appeared qualitatively similar to head acceleration, suggesting that eye velocity contains a signal component that is proportional to head acceleration. Thus, in our mathematical modeling (see below), we tested the hypothesis that eye velocity during interaural translation is derived from a combination of head velocity and head acceleration.In both animals, there were two remarkable differences between the dynamics of the movement of the head and the movement of the eye. First, initial eye acceleration exceeded head acceleration. This partially compensated for the response latency, allowing the eyes to “catch up” with the head and reach their ideal velocities more quickly. Such behavior would not be expected if eye velocity were a linear function of head velocity alone. Second, during sustained chair motion, eye Ablation of the Nod/Uv reduced the tVOR, particularly in the dark  and ga (the acceleration parameter) were determined by robust least-squares linear regression. For the series of possible latencies, the fit with the lowest squared residual error was considered to be the best.The disproportionate impairment of steady-state eye velocity after the Nod/Uv lesions suggested that there might be two components of the normal response, one related to head acceleration and the other to head velocity, and that the cerebellar contribution to these two components might differ. To test this hypothesis, we used a least-squares optimization technique to fit recorded eye velocity to a linear combination of head velocity and acceleration:v) but not in the acceleration coefficient (ga). Overall, gv dropped by 55+/−9.7%  and ga did not change .Similar fits were performed for each monkey and for each of the two viewing distances, before and after the Nod/Uv lesions. For each of these eight conditions , data were fit separately for each of the two eyes and the two directions of movement. The ratio of post-lesion to pre-lesion parameters was calculated, and the four values were averaged. For both monkeys, and at both viewing distances, there was a large drop in the velocity coefficient (gacc); and the gain of the integrated pathway (Gi). Optimization was performed using a Levenberg-Marquardt algorithm. The latency parameter was bounded (0–75 ms); the gains were required only to be positive. The error function was the difference between measured and simulated horizontal eye velocity for the whole series of trials. Again, we excluded quick phases and saccades based on criteria for eye acceleration and jerk. The results of the simulations , while the acceleration gain, Gacc, decreased by only 12.6±7.8% (p<0.01). The latencies were not different (p>0.85).Based on this finding, we implemented a more complete model of the tVOR in Simulink® that incorporated a head-acceleration-to-velocity integrator as well as the dynamics of the otoliths and ocular plant . For theulations  were in To assess the robustness of the model fits, we performed a basic sensitivity analysis , in whicOur model included the ‘common’ velocity-to-position neural integrator (NI), since the output of the model is eye position. Without the NI, the final eccentric eye position could not be maintained at the end of the head movement. Models of the saccadic system include a parallel non-integrated pathway to carry the saccadic pulse signal from the burst neurons directly to the ocular motor neurons. Since the burst neurons are not thought to contribute to the VORs, we omitted the direct pathway, similar to models of the rotational VOR. Nonetheless, we did test the effect of including it, which would have given eye velocity a component proportional to head jerk. When the direct pathway was included, the optimization procedure chose a gain that was very low. As Green and Angelaki have suggested In our model, we modeled the tVOR acceleration-to-velocity integrator with a pure integrator, which represented the data well. We also tested the effect on the simulated eye movement of replacing this with a slightly leaky integrator, perhaps more biologically plausible. There was a small effect (<2% decrease) on final eye position (at 500 ms), as long as the time constant of this integrator was at least 5 s.Overall, our model fit the recorded data well, but it did not fit eye velocity at the end of the trials, when head deceleration caused the simulated eye velocity to reverse direction. Such an anti-compensatory eye velocity was seen in the actual data, but the magnitude was much smaller. This suggests that the real tVOR has an additional nonlinearity that treats acceleration and deceleration differently. This might allow the eyes to “catch up” to the target when the head first accelerates but keep the eyes from going too far off target when the head stops moving. Similar properties are reported for smooth pursuit in which the transition dynamics differ between starting and stopping In this study we have shown that the cerebellar nodulus and uvula play an important role in the interaural tVOR: specifically, they contribute to the mathematical integration of head acceleration signals. We will discuss our findings in light of their implications for the role of the cerebellum in the tVOR and with respect to prior studies and models of the tVOR.Most investigations of the interaural tVOR have used sinusoidal translations, although there have been several studies in monkeys and humans of responses to abrupt transient motion The main effect of the Nod/Uv lesions on the interaural tVOR was to reduce sustained eye velocity during steady-state translation. When eye velocity was modeled as a linear combination of head acceleration and velocity, the effect of the lesions was to reduce the velocity but not the acceleration component. This finding suggests that the nodulus and uvula contribute to the integration of linear head acceleration signals derived from utricular afferents.An important role for the nodulus and uvula in the tVOR is not surprising, given the dense projection of primary otolith afferents to this area Here we have considered the contribution of the Nod/Uv in the temporal domain as an integrator of head acceleration. Our post-lesion data are simulated well by a reduction in the scalar gain of this integrator. In the frequency domain, a parallel integrator acts to boost the response gain at low frequencies, and a reduction in integrator gain would therefore disproportionally reduce the low-frequency response of the reflex. Such an enhancement of the low-frequency tVOR is reflected in the frequency response of Nod/Uv neurons facilitate integration for the tVOR, since lesions here impair it. On the other hand, the nodulus and uvula inhibit the integration that underlies angular velocity storage; they are responsible for the reduction in rVOR time constant that occurs during habituation The enhancement of the rVOR at low frequencies has also been attributed to a process of integration, the so-called velocity-storage integrator. Could rotational velocity storage and the tVOR acceleration integrator share a common integration network? In fact, although both depend on the Nod/Uv, key differences in the signal processing requirements and the effect of Nod/Uv lesions suggest that these integrators are, at least to some degree, distinct. In particular, our data suggest that the nodulus and uvula Finally, the tVOR integrator may play an important role in tVOR motor plasticity. In an adaptation study, Zhou, et al. Prior models of the tVOR have largely been based on the experimental data of Paige and colleagues Most pertinent to our current study is the way in which these prior models have approached the “double-integration” question: how is the head acceleration signal carried by utricular afferents converted to eye position? Paige and colleagues The model of Green and Galiana Musallam and Tomlinson In a recent study, Green and Angelaki To compare our experimental results and simulations to the predictions of other tVOR models, we implemented three of these prior models in Simulink: 1) Telford, et al. Schematics of the original models as we implemented them in Simulink are shown in What key features distinguish these models and determine their distinct dynamics? Only our model has two nearly pure integration steps: the tVOR integrator is a pure integrator and the velocity-to-position neural integrator has the usual time constant of 20 seconds, and thus this model best maintains eye velocity during sustained translation. The Angelaki, et al. The Green / Galiana Two other studies have posited a tVOR integrator Our results do not eliminate the possibility of a parallel direct pathway to the common neural integrator  juvenile rhesus monkeys (4–6 kg) before and after surgical lesions of the inferior vermis. All procedures were approved by the Animal Care and Use Committee of the Johns Hopkins Medical Institutions. Eye movements were recorded using binocular dual scleral search coils, in a three-field coil system. During experiments, the animal was seated in a primate chair with the head immobilized, and the chair was secured firmly to a linear sled . The coil frame was attached tightly to the top of the primate chair, such that the head was centered within it, and it remained fixed with respect to the head when the chair moved. Eye coil signals were demodulated by frequency detectors, sampled at 1000 Hz, and stored for later analysis. A belt-driven motor moved the chair along the interaural axis, under computer control. Chair position was measured by a linear transducer  and sampled at 500 Hz.Before these experiments, one of the monkeys underwent intracranial trochlear nerve section , followed by a right inferior oblique recession and a left inferior rectus recession, as part of a different study Cerebellar lesions were performed by one of the authors (R.J.T.) using standard neurosurgical procedures, as previously described Each trial began with the chair still and the monkey fixating a laser target, back-projected on a translucent screen that was either 27 or 70 cm in front of the eyes. Other than the target, the room was dark. The target was either straight ahead or 10° up or down from the center. We did not observe any difference in the dynamics of horizontal eye velocity based on vertical eye position. Thus, for the purpose of this study, we combined trials from all three vertical positions, in order to maximize the amount of data available for each optimization procedure.g) to a speed of 40 cm/s, then moved at constant speed for 320 ms, after which it was decelerated to a stop (0.20 g). The total displacement of each trial was 20 cm. Leftward and rightward trials were alternated . The fixation target either remained on or was extinguished at the onset of chair motion; in the latter case, motion occurred in complete darkness.After the monkey achieved fixation of the target (determined by a fixation window), the chair was accelerated (0.26 www.scipy.org) and matplotlib packages (matplotlib.sourceforge.net). Raw data were converted to three-dimensional rotation vectors, eye position vectors, and angular velocity vectors using methods that have been previously described Data were analyzed using custom programs written in MATLAB™ and in Python, using the numpy, scipy  were combined for analysis. Trials were synchronized on the time that the chair speed crossed a threshold of 1 cm/s.ideal is ideal eye velocity, xh is the linear position of the head, Ideal eye velocity is defined as the eye velocity that would keep the fovea on the target. Because an eye rotation compensates for a head translation, ideal eye velocity for the tVOR depends on the distance from the eye to the target. The exact relationship is:2 and 50,000°/s3, respectively. These segments were excluded when calculating eye velocity , and integrator gain (Gi). The error function was the difference between recorded and simulated eye velocity for the set of trials. Additional details of this model are given in the For the Simulink model , we adde