Ethical, Legal, and Social Implications of Personalized Genomic Medicine Research: Current Literature and Suggestions for the Future.

PURPOSE: This review identifies the prominent topics in the literature pertaining to the ethical, legal, and social issues (ELSI) raised by research investigating personalized genomic medicine (PGM). METHODS: The abstracts of 953 articles extracted from scholarly databases and published during a 5-year period (2008-2012) were reviewed. A total of 299 articles met our research criteria and were organized thematically to assess the representation of ELSI issues for stakeholders, health specialties, journals, and empirical studies. RESULTS: ELSI analyses were published in both scientific and ethics journals. Investigational research comprised 45% of the literature reviewed (135 articles) and the remaining 55% (164 articles) comprised normative analyses. Traditional ELSI concerns dominated the discourse including discussions about disclosure of research results. In fact, there was a dramatic increase in the number of articles focused on the disclosure of research results and incidental findings to research participants. Few papers focused on particular disorders, the use of racial categories in research, international communities, or special populations (e.g., adolescents, elderly patients, or ethnic groups). CONCLUSION: Considering that strategies in personalized medicine increasingly target individuals' unique health conditions, environments, and ancestries, further analysis is needed on how ELSI scholarship can better serve the increasingly global, interdisciplinary, and diverse PGM research community.

Short-term outcomes of craniotomy for malignant brain tumors in the elderly.

BACKGROUND: Disparity in resection rates for malignant brain tumors in elderly patients is partially attributed to a belief that advanced age is associated with an increased risk of postoperative morbidity and mortality. The objective of this study was to investigate the effect of advanced age (≥75 years) on 30-day outcomes in patients with primary and metastatic brain tumors who underwent craniotomy for definitive resection of a malignant brain tumor. METHODS: The authors conducted prospective analyses of the American College of Surgeons' National Surgical Quality-Improvement Project (NSQIP) database from 2006 to 2010 of 970 patients aged ≥40 years who underwent craniotomy for definitive resection of neoplasm. Preoperative and intraoperative characteristics and 30-day outcomes were stratified by age. By using propensity scores, 134 patients (aged ≥75 years) were matched to 134 patients ages 40 to 74 years. Logistic regression was used to predict adverse postoperative outcomes. RESULTS: The median length of hospital stay was 5 days; the rate of minor and major complications were 5.9% and 13.1%, respectively; 5.7% of patients returned to the operating room; and 4.3% of patients died within 30 days. Advanced age did not increase the odds for poorer short-term outcomes. CONCLUSIONS: Advanced age did not increase the risk of poor outcomes after surgical resection of primary or metastatic intracranial tumors when analyses were controlled for other risk factors. These results suggest that age should not be used, in isolation, as an a priori factor to discourage pursuing craniotomy.

Advancing the science of patient safety.

Despite a decade's worth of effort, patient safety has improved slowly, in part because of the limited evidence base for the development and widespread dissemination of successful patient safety practices. The Agency for Healthcare Research and Quality sponsored an international group of experts in patient safety and evaluation methods to develop criteria to improve the design, evaluation, and reporting of practice research in patient safety. This article reports the findings and recommendations of this group, which include greater use of theory and logic models, more detailed descriptions of interventions and their implementation, enhanced explanation of desired and unintended outcomes, and better description and measurement of context and of how context influences interventions. Using these criteria and measuring and reporting contexts will improve the science of patient safety.

Patient satisfaction, feasibility and reliability of satisfaction questionnaire among patients with pulmonary tuberculosis in urban Uganda: a cross-sectional study.

BACKGROUND: A comprehensive understanding of the barriers to and facilitators of poor tuberculosis (TB) treatment outcome is still lacking; posing a major obstacle to finding effective solutions. Assessment of patient satisfaction in TB programs would contribute to the understanding of gaps in healthcare delivery and the specific needs of individual patients. However, tools for assessing patient satisfaction are lacking. OBJECTIVE: To establish patient satisfaction, the feasibility and reliability of a questionnaire for healthcare service satisfaction and a questionnaire for satisfaction with information received about TB medicines among adult TB patients attending public and private program clinics in Kampala, Uganda. METHODS: In a cross-sectional study, we recruited 133 patients of known HIV status and confirmed pulmonary TB receiving care at the public and private hospitals in Kampala, Uganda. Participants were enrolled based on length of TB treatment as follows: starting therapy, completed two months of therapy, and completed eight months of therapy. A translated and standardized 13-item patient healthcare service satisfaction questionnaire (PS-13) and the Satisfaction with Information about Medicines Scale (SIMS) tool were administered by trained interviewers. Factor analysis was used to systematically group the PS-13 questionnaire into three factors of technical quality of care, responsiveness to patient preference, and management of patient preference satisfaction subscales. The SIMS tool was analyzed with two subscales of information about the action and usage of medication and the potential problems with medication. RESULTS: Of the 133 participants, 35% (46/133) were starting, 33% (44/133) had completed two months, and 32% (43/133) had completed eight months of TB therapy. The male to female and public to private hospital ratios in the study population were 1:1. The PS-13 and the SIMS tools were highly acceptable and easily administered. Both scales and the subscales demonstrated acceptable internal consistency with Cronbach's alpha above 0.70. Patients that were enrolled at the public hospital had relatively lower PS-13 satisfaction scores (0.48 (95% confidence interval (CI), 0.42 - 0.52)), (0.86 (95% CI, 0.81 - 0.90)) for technical quality of care and responsiveness to patient preferences, respectively compared to patients that were enrolled at the private hospital. For potential problems SIMS subscale, male patients that were recruited at the public hospital had relatively lower satisfaction scores (0.58 (95% CI, 0.40 - 0.86)) compared to female patients after adjusting for other factors. Similarly, patients that had completed eight months of TB treatment had relatively higher satisfaction scores (1.23 (95% CI, 1.06 - 1.44)) for action and usage SIMS subscale, and higher satisfaction scores (1.09 (95% CI, 1.03 - 1.16)) for management of patient preference (PS-13 satisfaction subscale) compared to patients that were starting treatment, respectively. CONCLUSION: The study provides preliminary evidence that the PS-13 service satisfaction and the SIMS tools are reliable measures of patient satisfaction in TB programs. Satisfaction score findings suggest differences in patient satisfaction levels between public and private hospitals; between patients starting and those completing TB therapy.

Feasibility, reliability and validity of health-related quality of life questionnaire among adult pulmonary tuberculosis patients in urban Uganda: cross-sectional study.

BACKGROUND: Despite the availability of standard instruments for evaluating health-related quality life (HRQoL), the feasibility, reliability, and validity of such instruments among tuberculosis (TB) patients in different populations of sub-Saharan Africa where TB burden is of concern, is still lacking. OBJECTIVE: We established the feasibility, reliability, and validity of the Medical Outcomes Survey (MOS) in assessing HRQoL among patients with pulmonary tuberculosis in Kampala, Uganda. METHODS: In a cross-sectional study, 133 patients with known HIV status and confirmed pulmonary TB disease were recruited from one public and one private hospital. Participants were enrolled based on duration of TB treatment according to the following categories: starting therapy, two months of therapy, and eight completed months of therapy. A translated and culturally adapted standardized 35-item MOS instrument was administered by trained interviewers. The visual analogue scale (VAS) was used to cross-validate the MOS. RESULTS: The MOS instrument was highly acceptable and easily administered. All subscales of the MOS demonstrated acceptable internal consistency with Cronbach's alpha above 0.70 except for role function that had 0.65. Each dimension of the MOS was highly correlated with the dimension measured concurrently using the VAS providing evidence of validity. Construct validity demonstrated remarkable differences in the functioning status and well-being among TB patients at different stages of treatment, between patients attending public and private hospitals, and between men and women of older age. Patients who were enrolled from public hospital had significantly lower HRQoL scores (0.78 (95% confidence interval (CI); 0.64-0.95)) for perceived health but significantly higher HRQoL scores (1.15 (95% CI; 1.06-1.26)) for health distress relative to patients from private hospital. Patients who completed an 8 months course of TB therapy had significantly higher HRQoL scores for perceived health (1.93 (95% CI; 1.19-3.13)), health distress subscales (1.29 (95% CI; 1.04-1.59)) and mental health summary scores (1.27 (95% CI; 1.09-1.48)) relative to patients that were starting therapy in multivariable analysis. Completion of 8 months TB therapy among patients who were recruited from the public hospital was associated with a significant increase in HRQoL scores for quality of life subscale (1.26 (95% CI; 1.08-1.49)), physical health summary score (1.22 995% CI; 1.04-1.43)), and VAS (1.08 (95% CI; 1.01-1.15)) relative to patients who were recruited from the private hospital. Older men were significantly associated with lower HRQoL scores for physical health summary score (0.68 (95% CI; 0.49-0.95)) and VAS (0.87 (95% CI; 0.75-0.99)) relative to women of the same age group. No differences were seen between HIV positive and HIV negative patients. CONCLUSION: The study provides evidence that the MOS instrument is valid, and reliably measures HRQoL among TB patients, and can be used in a wide variety of study populations. The HRQoL differed by hospital settings, by duration of TB therapy, and by gender in older age groups.

Adherence to surgical care improvement project measures and the association with postoperative infections.

CONTEXT: The Surgical Care Improvement Project (SCIP) aims to reduce surgical infectious complication rates through measurement and reporting of 6 infection-prevention process-of-care measures. However, an association between SCIP performance and clinical outcomes has not been demonstrated. OBJECTIVE: To examine the relationship between SCIP infection-prevention process-of-care measures and postoperative infection rates. DESIGN, SETTING, PARTICIPANTS: A retrospective cohort study, using Premier Inc's Perspective Database for discharges between July 1, 2006 and March 31, 2008, of 405 720 patients (69% white and 11% black; 46% Medicare patients; and 68% elective surgical cases) from 398 hospitals in the United States for whom SCIP performance was recorded and submitted for public report on the Hospital Compare Web site. Three original infection-prevention measures (S-INF-Core) and all 6 infection-prevention measures (S-INF) were aggregated into 2 separate all-or-none composite scores. Hierarchical logistical models were used to assess process-of-care relationships at the patient level while accounting for hospital characteristics. MAIN OUTCOME MEASURE: The ability of reported adherence to SCIP infection-prevention process-of-care measures (using the 2 composite scores of S-INF and S-INF-Core) to predict postoperative infections. RESULTS: There were 3996 documented postoperative infections. The S-INF composite process-of-care measure predicted a decrease in postoperative infection rates from 14.2 to 6.8 per 1000 discharges (adjusted odds ratio, 0.85; 95% confidence interval, 0.76-0.95). The S-INF-Core composite process-of-care measure predicted a decrease in postoperative infection rates from 11.5 to 5.3 per 1000 discharges (adjusted odds ratio, 0.86; 95% confidence interval, 0.74-1.01), which was not a statistically significantly lower probability of infection. None of the individual SCIP measures were significantly associated with a lower probability of infection. CONCLUSIONS: Among hospitals in the Premier Inc Perspective Database reporting SCIP performance, adherence measured through a global all-or-none composite infection-prevention score was associated with a lower probability of developing a postoperative infection. However, adherence reported on individual SCIP measures, which is the only form in which performance is publicly reported, was not associated with a significantly lower probability of infection.

It Is Time to Reconsider Factorial Designs: How Bradford Hill and R. A. Fisher Shaped the Standard of Clinical Evidence.

OBJECTIVES: Could medical research and quality improvement studies be more productive with greater use of multifactor study designs? METHODS: Drawing on new primary sources and the literature, we examine the roles of A. Bradford Hill and Ronald A. Fisher in introducing the design of experiments in medicine. RESULTS: Hill did not create the randomized controlled trial, but he popularized the idea. His choice to set aside Fisher's advanced study designs shaped the development of clinical research and helped the single-treatment trial to become a methodological standard. CONCLUSIONS: Multifactor designs are not widely used in medicine despite their potential to make improvement initiatives and health services research more efficient and effective. Quality managers, health system leaders, and directors of research institutes could increase productivity and gain important insights by promoting a broader use of factorial designs to study multiple interventions simultaneously and to learn from interactions.

Quality and safety education: foreground and background.

Since 1988, Case Western Reserve University (CWRU), through its School of Medicine, Frances Payne Bolton School of Nursing, and Division of Public Health, has committed to the development and implementation of quality improvement and safety education as a formal part of its health professions curriculum. Faculty moved quality and safety education from the "background" of implicit learning to the "foreground" of established curriculum. The transformation has affected not only course content but also many academic careers in the process. This article highlights 3 of the many quality and safety education activities that have evolved at the CWRU: the graduate-level course on quality improvement, medical student education, and doctoral education. Based on these activities, 4 key elements are presented as essential for a successful and sustainable quality and safety education program: quality improvement role models and champions, strong academic-practice partnerships, a variety of educational modalities, and a supportive learning environment.

Tutorial on Data Balancing: Application to Benchmarking Clinicians.

In this tutorial, we show how data balancing, in general, and stratified covariate balancing, in particular, can be used to benchmark clinicians. This tutorial aims to explain the concepts behind data balancing to readers who do not have a strong statistical background. Data balancing enables the analyst to compare the performance of clinicians with their peer groups on the same set of patients. The comparison is done in 3 steps. First, the patients are described in terms of their conditions/comorbidities. Each combination of comorbidities is treated as a separate type of patient. Second, the analyst measures the frequency of observing different types of patients. Third, expected outcomes are calculated for both the clinician and the peer group. The expected outcome for the clinician is calculated as the sum of product of 2 terms: probability of and the average outcome for different types of patients. The expected outcome for the peer group is calculated in the same way, with one difference: the distribution of peer group's patients is switched with the distribution of the clinician's patients. This allows us to simulate the performance of peer group on the clinician's patients. This switch in frequencies accomplishes the same goal as using propensity weights, or covariate balancing weights, but it avoids the cumbersome need to estimate the weights. In switching the distributions, a problem arises when the peer group does not see the same type of patients as the clinician. When the peer group's outcome for some patient types is missing, a synthetic case is organized. These synthetic cases are constructed from the peer group's experience with 2 complementary parts of the missing case. The reliance on synthetic cases allows one to have a match for every type of clinician's patients. Together, the synthetic case and the switch of distribution allow one to simulate the performance of the clinician and the peer group on same set of cases. The tutorial walks the reader through examples. The procedures described here can be applied to data in electronic health records. We present Standard Query Language for doing so.

Platelet count abnormalities and peri-operative outcomes in adults undergoing elective, non-cardiac surgery.

BACKGROUND: Anemia and transfusion of blood in the peri-operative period have been shown to be associated with increased morbidity and mortality across a wide variety of non-cardiac surgeries. While tests of coagulation, including the platelet count, have frequently been used to identify patients with an increased risk of peri-operative bleeding, results have been equivocal. The aim of this study was to assess the effect of platelet level on outcomes in patients undergoing elective surgery. MATERIALS AND METHODS: Retrospective cohort analysis of prospectively-collected clinical data from American College of Surgeons National Surgical Quality Improvement Program (NSQIP) between 2006-2016. RESULTS: We identified 3,884,400 adult patients who underwent elective, non-cardiac surgery from 2006-2016 at hospitals participating in NSQIP, a prospectively-collected, national clinical database with established reproducibility and validity. After controlling for all peri- and intraoperative factors by matching on propensity scores, patients with all levels of thrombocytopenia or thrombocytosis had higher odds for perioperative transfusion. All levels of thrombocytopenia were associated with higher mortality, but there was no association with complications or other morbidity after matching. On the other hand, thrombocytosis was not associated with mortality; but odds for postoperative complications and 30-day return to the operating room remained slightly increased after matching. CONCLUSIONS: These findings may guide surgeons in the appropriate use and appreciation of the utility of pre-operative screening of the platelet count prior to an elective, non-cardiac surgery.

Personal quality improvement and individualized health process control: an update.

Chronic disease management is about personal quality improvement. This involves tracking personal health measures over time to develop the patient's understanding of common and special cause variation. This can be done through the use of run, control, and time between charts. This review gives examples of different methods taken from the literature.

Quality of care by a hypertension expert: a cautionary tale for pay-for-performance approaches.

CONTEXT: Pay-for-performance programs may be widely implemented, but gaps remain in our understanding of the implementation of performance measurement approaches. OBJECTIVES: To compare 3 approaches to hypertension quality measurement as applied to high-quality care delivered by a hypertension expert. METHODS: Care of 23 patients treated by a single hypertension expert was assessed by 3 measurement approaches: (1) outcome, (2) a multicomponent process, and (3) "outcome-linked" process. Exemplary case studies were identified to illustrate additional challenges to applying the approaches. RESULTS: Forty-four percent of patients (n = 10) had complete concordance between the outcome and outcome-linked process approaches, 22% of patients (n = 5) had complete concordance between the outcome and multicomponent process approaches, 52% of patients (n = 12) had complete concordance between outcome-linked process and multicomponent process approaches, and 22% of patients (n = 5) had uniform agreement among all 3 approaches. Case studies revealed numerous opportunities for misinterpretation or gaming by providers. CONCLUSIONS: Currently available measurement approaches resulted in a varied assessment of provider performance under optimal hypertension care conditions suggesting that caution is required before their use for provider compensation.

Rethinking satisfaction surveys: minute survey.

The Minute Survey uses 2 questions to assess patient's satisfaction. The first question asks the patient to rate overall satisfaction with the care. The second question asks the patient to explain what worked well and what needed improvement. The Minute Survey reduces cost of conducting satisfaction surveys by (1) reducing cost of printing, (2) reducing cost of handling and mailing, (3) increasing response rate and thus reducing the need for follow-up reminder, and (4) by relying on time to dissatisfied patient as opposed to percent of dissatisfied patients. We report response rate of 34% to 77% to minute surveys. The combination of Minute Survey and analysis of time to dissatisfied patient may reduce the cost of conducting satisfaction surveys by 89% compared with Consumer Assessment of Healthcare Providers and Systems survey suggested for use by Centers for Medicare and Medicaid.

Surgeon specialty and patient outcomes in carotid endarterectomy.

OBJECTIVE: The goal of this study was to compare outcomes of carotid endarterectomy performed by neurological, general, and vascular surgeons. METHODS: The authors identified 80,475 patients who underwent carotid endarterectomy between 2006 and 2015 in the National Surgical Quality Improvement Program, a prospectively collected, national clinical database with established reproducibility and validity. Nine hundred forty-three patients were operated on by a neurosurgeon; 75,649 by a vascular surgeon; and 3734 by a general surgeon. Preoperative and intraoperative characteristics and 30-day outcomes were stratified by the surgeon's primary specialty. Using propensity scores, comprising pre- and intraoperative characteristics as well as procedure and diagnostic codes, the authors matched 203 neurosurgery (NS) patients to 203 vascular surgery (VS) patients and 203 NS patients to 203 general surgery (GS) patients. No pre- or intraoperative factors were significantly different between specialties in the matched sample. Regular logistic regression and conditional logistic regression were used to predict postoperative complications in the full sample and in the matched sample. RESULTS: In the complete population sample, NS patients, when compared to patients of general and vascular surgeons, were less likely to be admitted from home and more likely to have carotid artery occlusion or stenosis with cerebral infarction, to be a current smoker, to have had recent chemo- or radiotherapy, to have surgery under general anesthesia, to undergo multiple procedures, and to have longer surgery times. In unadjusted analyses, NS patients were more likely to experience major complications (NS vs VS: odds ratio 1.3, 95% CI 1.1-1.6; NS vs GS: odds ratio 1.3, 95% CI 1.0-1.7); minor complications (NS vs VS: odds ratio 2.9, 95% CI 2.0-4.1; NS vs GS: odds ratio 2.7, 95% CI 1.7-4.2); intra- or postoperative transfusions (NS vs VS: odds ratio 1.6, 95% CI 1.4-1.9; NS vs GS: odds ratio 1.9, 95% CI 1.6-2.3); prolonged hospitalization (NS vs VS: odds ratio 3.0, 95% CI 2.6-3.5; NS vs GS: odds ratio 2.6, 95% CI 2.2-3.0); and discharge to skilled care facilities (NS vs VS: odds ratio 2.8, 95% CI 2.3-3.4; NS vs GS: odds ratio 3.1, 95% CI 2.4-4.1). In adjusted, propensity-matched analyses, however, patients' outcome with carotid endarterectomy performed by NS was comparable with those completed by GS and VS. CONCLUSIONS: Patients who undergo carotid endarterectomy performed by a neurosurgeon tend to have a greater preoperative disease burden than do those treated by a general or vascular surgeon, which contributes significantly to more morbid postoperative courses. In patients matched carefully on the basis of health status at the time of surgery and intraoperative variables that affect results, patients' outcomes after carotid endarterectomy do not appear to depend on the attending surgeon's primary specialty.

Impact of Resident Involvement in Neurosurgery: An American College of Surgeons' National Surgical Quality Improvement Program Database Analysis of 33,977 Patients.

OBJECTIVE: There is conflicting and limited literature on the effect of intraoperative resident involvement on surgical outcomes. Our study assessed effects of resident involvement on outcomes in patients undergoing neurosurgery. METHODS: We identified 33,977 adult neurosurgical cases from 374 hospitals in the 2006-2012 National Surgical Quality Improvement Program, a prospectively collected national database with established reproducibility and validity. Outcomes were compared according to resident involvement before and after 1:1 matching on procedure and perioperative risk factors. RESULTS: Resident involvement was documented in 13,654 cases. We matched 10,170 resident-involved cases with 10,170 attending-alone. In the matched sample, resident involvement was associated with increased surgery duration (average, 34 minutes) and slight increases in odds for prolonged hospital stay (odds ratio, 1.2; 95% confidence interval [CI], 1.2-1.3) and complications (odds ratio, 1.2; 95% CI, 1.1-1.3) including infections (odds ratio, 1.4; 95% CI, 1.2-1.7). Increased risk for infections persisted after controlling for surgery duration (odds ratio, 1.3; 95% CI, 1.1-1.5). The majority of cases were spine surgeries, and resident involvement was not associated with morbidity or mortality for malignant tumor and aneurysm patients. Training level of residents was not associated with differences in outcomes. CONCLUSION: Resident involvement was more common in sicker patients undergoing complex procedures, consistent with academic centers undertaking more complex cases. After controlling for patient and intraoperative characteristics, resident involvement in neurosurgical cases continued to be associated with longer surgical duration and slightly higher infection rates. Longer surgery duration did not account for differences in infection rates.

The health care quality journey of Jönköping County Council, Sweden.

For a decade Jönköping County Council in Sweden has undertaken a countywide effort to improve health and health care with measured success. This issue describes this quality improvement journey.

Does this treatment work for me? The patient's role in assessing medical care.

Randomised clinical trials are designed to determine whether a particular treatment is appropriate to make a significant difference to the health of a defined population and to aid its approval for use. For an accurate, cheap and simple assessment to see if a treatment benefits an individual person, all that is needed is a pen, paper, simple pocket calculator and daily recording of a few variables. It requires the ability to read and write and to understand addition and division. Factorial design of experiments is used to show the impact of several variables and their interaction on the person's health status. An example of a 75-year-old man with an enlarged prostate is used here to illustrate this approach. This person was able to understand and reduce side effects, lower the costs of medication by 83% and improve measured health status by 28%. A multivariate model for this person was then created with about 450 person-days of data.

Autonomic components of Complex Regional Pain Syndrome (CRPS) are favourably affected by Electrical Twitch-Obtaining Intramuscular Stimulation (ETOIMS): effects on blood pressure and heart rate.

INTRODUCTION: Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS). AIM: To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS. METHODS AND MATERIALS: A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or ≥150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1-5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test. RESULTS: The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index. CONCLUSIONS: Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (≥26) and pulse/heart rate (≥8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.