Field Trauma Triage among Older Adults: A Cost-Effectiveness Analysis.

BACKGROUND: National guidelines for prehospital trauma triage aim to identify seriously injured patients who may benefit from transport to trauma centers. These guidelines have poor sensitivity for serious injury among older adults. We evaluated the cost-effectiveness of a high-sensitivity triage strategy for older adults. STUDY DESIGN: We developed a Markov chain Monte Carlo microsimulation model to estimate the cost-effectiveness of high-sensitivity field triage criteria among older adults compared with current practice. The model used a retrospective cohort of 3621 community-dwelling Medicare beneficiaries who were transported by emergency medical services after an acute injury in 7 counties in the northwestern US during January to December 2011. These data informed model estimates of emergency medical services triage assessment, hospital transport patterns, and outcomes from index hospitalization up to 1 year after discharge. Outcomes beyond 1 year were modeled using published literature. Differences in cost and quality-adjusted life years (QALYs) were calculated for both strategies using a lifetime analytical horizon. We calculated the incremental cost-effectiveness ratio (cost per QALY gained) to assess cost-effectiveness, which we defined using a threshold of less than $100,000 per QALY. RESULTS: High-sensitivity trauma field triage for older adults would produce a small incremental benefit in average trauma system effectiveness (0.0003 QALY) per patient at a cost of $1,236,295 per QALY. Sensitivity analysis indicates that the cost of initial hospitalization and emergency medical services adherence to triage status (ie transporting triage-positive patients to a trauma center) had the largest influence on overall cost-effectiveness. CONCLUSIONS: High-sensitivity trauma field triage is not cost-effective among older adults.

The Cost of a Fall Among Older Adults Requiring Emergency Services.

BACKGROUND/OBJECTIVE: The cost of a fall among older adults requiring emergency services is unclear, especially beyond the acute care period. We evaluated medical expenditures (costs) to 1 year among community-dwelling older adults who fell and required ambulance transport, including acute versus post-acute periods, the primary drivers of cost, and comparison to baseline expenditures. DESIGN: Retrospective cohort analysis. SETTING: Forty-four emergency medical services agencies transporting to 51 emergency department in seven northwest counties from January 1, 2011, to December 31, 2011, with follow-up through December 31, 2012. PARTICIPANTS: We included 2,494 community-dwelling adults, 65 years and older, transported by ambulance after a fall with continuous fee-for-service Medicare coverage. MEASUREMENTS: The primary outcome was total Medicare expenditures to 1 year (2019 U.S. dollars), with separation by acute versus post-acute periods and by cost category. We included 48 variables in a standardized risk-adjustment model to generate adjusted cost estimates. RESULTS: The median age was 83 years, with 74% female, and 41.9% requiring admission during the index visit. The median total cost of a fall to 1 year was $26,143 (interquartile range (IQR) = $9,634-$68,086), including acute care median $1,957 (IQR = $1,298-$12,924) and post-acute median $20,560 (IQR = $5,673-$58,074). Baseline costs for the previous year were median $8,642 (IQR = $479-$10,948). Costs increased across all categories except outpatient, with the largest increase for inpatient costs (baseline median $0 vs postfall median $9,477). In multivariable analysis, the following were associated with higher costs: high baseline costs, older age, comorbidities, extremity fractures (lower extremity, pelvis, and humerus), noninjury diagnoses, and surgical interventions. Compared with baseline, costs increased for 74.6% of patients, with a median increase of $12,682 (IQR = -$185 to $51,189). CONCLUSION: Older adults who fall and require emergency services have increased healthcare expenditures compared with baseline, particularly during the post-acute period. Comorbidities, noninjury medical conditions, fracture type, and surgical interventions were independently associated with increased costs.

Comparison of Injured Older Adults Included in vs Excluded From Trauma Registries With 1-Year Follow-up.

Importance: Trauma registries are the primary data mechanism in trauma systems to evaluate and improve the care of injured patients. Research has suggested that trauma registries may miss high-risk older adults, who commonly experience morbidity and mortality after injury. Objective: To compare injured older adults who were included in with those excluded from trauma registries, with a focus on patients with serious injuries, requiring major surgery, or dying after injury. Design, Setting, and Participants: This cohort study included all injured adults 65 years and older transported by 44 emergency medical services agencies to 51 trauma and nontrauma centers in 7 counties in Oregon and Washington from January 1, 2011, to December 31, 2011, with follow-up through December 31, 2012. Record linkage was used to match emergency medical services records with state trauma registries, state discharge databases, state death registries, and Medicare claims. Data were analyzed from August to November 2018. Exposures: Inclusion in vs exclusion from a trauma registry. Main Outcomes and Measures: Mortality up to 12 months, including time to death and causes of death. Results: Of 8161 included patients, 5579 (68.4%) were women, and the mean (SE) age was 82.2 (0.10) years. A total of 1720 older adults (21.1%) were matched to a trauma registry record. Seriously injured patients not captured by trauma registries ranged from 18% (7 of 38 patients with abdominal-pelvic Abbreviated Injury Scale score of 3 or greater) to 80.0% (1792 of 2241 patients with extremity Abbreviated Injury Scale score of 3 or greater), while 68 of 186 patients requiring major nonorthopedic surgery (36.6%) and 1809 of 2325 patients requiring orthopedic surgery (77.8%) were not included in trauma registries. Of patients with serious injuries or undergoing major surgery missed by trauma registries (range by injury and procedure type, 36.0% to 57.1%), 36.4% (39.3% when excluding serious extremity injuries and orthopedic procedures) were treated at trauma centers, particularly level III through V hospitals. When registry and nonregistry groups were tracked over 12 months, 93 of 188 in-hospital deaths (49.5%) and 1531 of 1887 total deaths (81.1%) occurred in the nonregistry cohort. Conclusions and Relevance: In their current form, trauma registries are ineffective in capturing, tracking, and evaluating injured older adults, although mortality following injury is frequently due to noninjury causes. High-risk injured older adults are not included in registries because of care in nontrauma hospitals, restrictive registry inclusion criteria, and being missed by registries in trauma centers.

Long-term outcomes among injured older adults transported by emergency medical services.

INTRODUCTION/OBJECTIVE: Little is known about the long-term outcomes of injured older adults cared for in trauma systems. We sought to describe mortality and causes of death over time, and the independent association of injury severity, comorbidities, and other factors on 12-month mortality among injured older adults transported by emergency medical services (EMS). MATERIALS AND METHODS: This was a population-based cohort study of injured adults ≥ 65 years in the United States transported by 44 EMS agencies to 51 hospitals from January 1, 2011 to December 31, 2011, with 12-month follow-up through December 31, 2012. The primary outcomes were time to death and causes of death. We used descriptive statistics and Cox proportional hazards models to generate adjusted hazard ratios (HR). RESULTS: 15,649 injured older adults were transported by EMS, frequently after a fall (84.5%). Serious injuries (Injury Severity Score [ISS] ≥ 16) occurred in 3.5%, with serious extremity injury (Abbreviated Injury Scale score ≥ 3) being most common (17.8%). Mortality rates were: 1.6% in-hospital, 5.1% at 30 days, 9.4% at 90 days and 20.3% at 1 year. The adjusted HR for patients in the highest comorbidity quartile was 2.20 (versus lowest quartile, 95% CI 1.97-2.46, p < .001), while the HR for ISS ≥ 25 was 2.69 (versus ISS 0-8, 95% CI 1.60-4.51, p = .001). Cardiovascular etiologies (53.3%) and dementia (32.7%) were the most common causes of death, with injury listed in 12.8% of death certificates. CONCLUSIONS: Injury requiring EMS transport is a sentinel event among older adults, with death typically occurring months later, often due to cardiovascular causes and dementia. A heavy comorbidity burden had an adjusted mortality risk comparable to severe injury.

Comorbidities, anticoagulants, and geriatric-specific physiology for the field triage of injured older adults.

BACKGROUND: Comorbid conditions and anticoagulants have been considered as field triage criteria to raise the sensitivity for identifying seriously injured older adults, but research is sparse. We evaluated the utility of comorbidities, anticoagulant use, and geriatric-specific physiologic measures to improve the sensitivity of the field triage guidelines for high-risk older adults in the out-of-hospital setting. METHODS: This was a cohort study of injured adults 65 years or older transported by 44 emergency medical services agencies to 51 trauma and nontrauma hospitals in seven Oregon and Washington counties from January 1, 2011, to December 31, 2011. Out-of-hospital predictors included current field triage criteria, 13 comorbidities, preinjury anticoagulant use, and previously developed geriatric specific physiologic measures. The primary outcome (high-risk patients) was Injury Severity Score of 16 or greater or need for major nonorthopedic surgical intervention. We used binary recursive partitioning to develop a clinical decision rule with a target sensitivity of 95% or greater. RESULTS: There were 5,021 older adults, of which 320 (6.4%) had Injury Severity Score of 16 or greater or required major nonorthopedic surgery. Of the 2,639 patients with preinjury medication history available, 400 (15.2%) were taking an anticoagulant. Current field triage practices were 36.6% sensitive (95% confidence interval [CI], 31.2%-42.0%) and 90.1% specific (95% CI, 89.2%-91.0%) for high-risk patients. Recursive partitioning identified (in order): any current field triage criteria, Glasgow Coma Scale score of 14 or less, geriatric-specific vital signs, and comorbidity count of 2 or more. Anticoagulant use was not identified as a predictor variable. The new criteria were 90.3% sensitive (95% CI, 86.8%-93.7%) and 17.0% specific (95% CI, 15.8%-18.1%). CONCLUSIONS: The current field triage guidelines have poor sensitivity for high-risk older adults. Adding comorbidity information and geriatric-specific physiologic measures improved sensitivity, with a decrement in specificity. LEVEL OF EVIDENCE: Prognostic/Epidemiologic, level II.

Variations in the application of exception from informed consent in a multicenter clinical trial.

BACKGROUND: Exception from infor med consent (EFIC) is allowed using federal regulations 21 CFR 50.24 and facilitates research on patients with critical conditions such as cardiac arrest. Little is known regarding the differences in the application of EFIC requirements such as community consultation (CC), public disclosure (PD) and patient notification. We sought to characterize variations in the fulfillment of EFIC requirements in a national multicenter clinical trial in the United States. METHODS: We determined the strategies for fulfillment of EFIC requirements at five regional coordinating centers of the Pragmatic Airway Resuscitation Trial (PART), a cluster-crossover randomized trial comparing airway devices in out-of-hospital cardiac arrest. We collected information from the including site demographics, how CC and PD were implemented, methods undertaken by the site investigative team to meet the local IRB's interpretation, and patient notification timing (post-enrollment). We analyzed the data using descriptive statistics. RESULTS: Sites had multiple approaches to CC, including social media advertising, random digit dialing surveys, working with city officials, and websites with embedded surveys. All sites used more than one approach for conducting CC. Public Disclosure activities included press releases through various means, website documentation, and letters to community members and local officials. Time from CC to study approval ranged from 42 days to 253 days. CONCLUSION: EFIC implementation varies across sites and highlight community and regional variation. Different EFIC approaches may be needed to effectively accomplish the goals of community consultation, public disclosure, and patient notification.

Out-of-Hospital Research in the Era of Electronic Health Records.

Conducting out-of-hospital research is unique and challenging and requires tracking patients across multiple phases of care, using multiple sources of patient records and multiple hospitals. The logistics and strategies used for out-of-hospital research are distinct from other forms of clinical research. The increasing use of electronic health records (EHRs) by hospitals and emergency medical services (EMS) agencies presents a large opportunity for accelerating out-of-hospital research, as well as particular challenges. In this study, we describe seven key aspects of designing and implementing out-of-hospital research in the era of EHRs: (1) selection of research sites, (2) defining the patient population, (3) patient sampling and sample size calculations, (4) EMS data, (5) hospital selection, (6) handling missing data, and (7) statistical analysis. We use examples from a recent prospective out-of-hospital cohort study to illustrate these topics, including lessons learned.

Post-resuscitation arterial oxygen and carbon dioxide and outcomes after out-of-hospital cardiac arrest.

OBJECTIVE: To determine if arterial oxygen and carbon dioxide abnormalities in the first 24h after return of spontaneous circulation (ROSC) are associated with increased mortality in adult out-of-hospital cardiac arrest (OHCA). METHODS: We used data from the Resuscitation Outcomes Consortium (ROC), including adult OHCA with sustained ROSC ≥1h after Emergency Department arrival and at least one arterial blood gas (ABG) measurement. Among ABGs measured during the first 24h of hospitalization, we identified the presence of hyperoxemia (PaO2≥300mmHg), hypoxemia (PaO2<60mmHg), hypercarbia (PaCO2>50mmHg) and hypocarbia (PaCO2<30mmHg). We evaluated the associations between oxygen and carbon dioxide abnormalities and hospital mortality, adjusting for confounders. RESULTS: Among 9186 OHCA included in the analysis, hospital mortality was 67.3%. Hyperoxemia, hypoxemia, hypercarbia, and hypocarbia occurred in 26.5%, 19.0%, 51.0% and 30.6%, respectively. Initial hyperoxemia only was not associated with hospital mortality (adjusted OR 1.10; 95% CI: 0.97-1.26). However, final and any hyperoxemia (1.25; 1.11-1.41) were associated with increased hospital mortality. Initial (1.58; 1.30-1.92), final (3.06; 2.42-3.86) and any (1.76; 1.54-2.02) hypoxemia (PaO2<60mmHg) were associated with increased hospital mortality. Initial (1.89; 1.70-2.10); final (2.57; 2.18-3.04) and any (1.85; 1.67-2.05) hypercarbia (PaCO2>50mmHg) were associated with increased hospital mortality. Initial (1.13; 0.90-1.41), final (1.19; 1.04-1.37) and any (1.01; 0.91-1.12) hypocarbia (PaCO2<30mmHg) were not associated with hospital mortality. CONCLUSIONS: In the first 24h after ROSC, abnormal post-arrest oxygen and carbon dioxide tensions are associated with increased out of-hospital cardiac arrest mortality.

Prospective Validation of the National Field Triage Guidelines for Identifying Seriously Injured Persons.

BACKGROUND: The national field trauma triage guidelines have been widely implemented in US trauma systems, but never prospectively validated. We sought to prospectively validate the guidelines, as applied by out-of-hospital providers, for identifying high-risk trauma patients. STUDY DESIGN: This was an out-of-hospital prospective cohort study from January 1, 2011 through December 31, 2011 with 44 Emergency Medical Services agencies in 7 counties in 2 states. We enrolled injured patients transported to 28 acute care hospitals, including 7 major trauma centers (Level I and II trauma hospitals) and 21 nontrauma hospitals. The primary exposure term was Emergency Medical Services' use of one or more field triage criteria in the national field triage guidelines. Outcomes included Injured Severity Score ≥16 (primary) and critical resource use within 24 hours of emergency department arrival (secondary). RESULTS: We enrolled 53,487 injured children and adults transported by Emergency Medical Services to an acute care hospital, 17,633 of which were sampled for the primary analysis; 13.9% met field triage guidelines, 3.1% had Injury Severity Score ≥16, and 1.7% required early critical resources. The sensitivity and specificity of the field triage guidelines were 66.2% (95% CI, 60.2-71.7%) and 87.8% (95% CI, 87.7-88.0%) for Injury Severity Score ≥16 and 80.1% (95% CI, 65.8-89.4%) and 87.3% (95% CI 87.1-87.4%) for early critical resource use. Triage guideline sensitivity decreased with age, from 87.4% in children to 51.8% in older adults. CONCLUSIONS: The national field triage guidelines are relatively insensitive for identifying seriously injured patients and patients requiring early critical interventions, particularly among older adults.

Why persons choose to opt out of an exception from informed consent cardiac arrest trial.

BACKGROUND: We sought to characterize persons who requested to opt out of an exception from informed consent (EFIC) cardiac arrest trial and their reasons for opting out. METHODS: At one site of a multi-site, out-of-hospital, cardiac arrest EFIC trial (September 2007 - June 2009), persons who did not want to participate in the study could request an opt-out "NO STUDY" bracelet to prevent trial enrollment. We surveyed all persons who requested a bracelet by phone interview, web or mail. Opt-out bracelets were advertised in all public communication about the study, including community consultation and public disclosure efforts. Survey questions included demographics, Likert scale items about attitudes toward the trial and research in general, plus open-ended questions. We used descriptive statistics for standardized questions and qualitative analysis to identify common themes from open-ended questions. RESULTS: Sixty bracelets were requested by 50 individuals. Surveys were completed by 46 persons (92% response rate). Seventy percent of respondents agreed emergency research is important, but 87% objected to any research without consent. In the qualitative analysis, 5 overlapping themes emerged: questioning the ethics of EFIC research; concerns about how the study would impact end-of-life preferences; subjective emotions including sarcasm, anger, and allusions to past unethical research; negative reference to unrelated public health controversies; and objections to the study protocol based on misinformation. CONCLUSIONS: A primary reason for opting out from this EFIC trial was opposition to all research without informed consent, despite stated support for emergency research. Understanding the demographics and beliefs of persons opting out may aid researchers planning EFIC studies and help provide clarity in future EFIC-related community education efforts.

Optimization of a histopathological biomarker for sphingomyelin accumulation in acid sphingomyelinase deficiency.

Niemann-Pick disease (types A and B), or acid sphingomyelinase deficiency, is an inherited deficiency of acid sphingomyelinase, resulting in intralysosomal accumulation of sphingomyelin in cells throughout the body, particularly within those of the reticuloendothelial system. These cellular changes result in hepatosplenomegaly and pulmonary infiltrates in humans. A knockout mouse model mimics many elements of human ASMD and is useful for studying disease histopathology. However, traditional formalin-fixation and paraffin embedding of ASMD tissues dissolves sphingomyelin, resulting in tissues with a foamy cell appearance, making quantitative analysis of the substrate difficult. To optimize substrate fixation and staining, a modified osmium tetroxide and potassium dichromate postfixation method was developed to preserve sphingomyelin in epon-araldite embedded tissue and pulmonary cytology specimens. After processing, semi-thin sections were incubated with tannic acid solution followed by staining with toluidine blue/borax. This modified method provides excellent preservation and staining contrast of sphingomyelin with other cell structures. The resulting high-resolution light microscopy sections permit digital quantification of sphingomyelin in light microscopic fields. A lysenin affinity stain for sphingomyelin was also developed for use on these semi-thin epon sections. Finally, ultrathin serial sections can be cut from these same tissue blocks and stained for ultrastructural examination by electron microscopy.

Cricket: notching up runs for food and alcohol companies?

OBJECTIVE: To analyse sports sponsorship by food and alcohol companies by quantifying the proportion of time that the main sponsor's logo was seen during each of three cricket telecasts, the extent of paid advertising during the telecast and the contribution by the main sponsor to this, and to describe the associated ground advertising. METHODS: DVD recordings of the three telecasts were analysed for visibility of the main sponsor's logo during actual playing time and for each sponsor's proportion of the advertising time during breaks in telecast. RESULTS: The main sponsor's logo was visible on a range of equipment and clothing that resulted in it being clearly identifiable from 44% to 74% of the game time. The proportion of paid advertising time in these three telecasts varied from 3% to 20%, reflecting the difference in advertising content of paid television versus free-to-air. IMPLICATIONS: While television food advertising to children is under review, sporting telecasts also reach children and, until recently, have avoided scrutiny. This content analysis of three recent cricket telecasts reveals an unacceptable level of exposure to food and alcohol marketing, particularly in the form of the main sponsor's logo. Sponsorship is not covered by the voluntary codes of practice that address some forms of advertising. A new system of regulation is required to reduce this unacceptable level of exposure.

Local media influence on opting out from an exception from informed consent trial.

STUDY OBJECTIVE: News media are used for community education and notification in exception from informed consent clinical trials, yet their effectiveness as an added safeguard in such research remains unknown. We assessed the number of callers requesting opt-out bracelets after each local media report and described the errors and content within each media report. METHODS: We undertook a descriptive analysis of local media trial coverage (newspaper, television, radio, and Web log) and opt-out requests during a 41-month period at a single site participating in an exception from informed consent out-of-hospital trial. Two nontrial investigators independently assessed 41 content-based media variables (including background, trial information, graphics, errors, publication information, and assessment) with a standardized, semiqualitative data collection tool. Major errors were considered serious misrepresentation of the trial purpose or protocol, whereas minor errors included misinformation unlikely to mislead the lay reader about the trial. We plotted the temporal relationship between opt-out bracelet requests and media reports. Descriptive information about the news sources and the trial coverage are presented. RESULTS: We collected 39 trial-related media reports (33 newspaper, 1 television, 1 radio, and 4 blogs). There were 13 errors in 9 (23%) publications, 7 of which were major and 6 minor. Of 384 requests for 710 bracelets, 310 requests (80%) occurred within 4 days after trial media coverage. Graphic timeline representation of the data suggested a close association between media reports about the trial and requests for opt-out bracelets. CONCLUSION: According to results from a single site, local media coverage for an exception from informed consent clinical trial had a substantial portion of errors and appeared closely associated with opt-out requests.

Out-of-hospital cardiac arrest frequency and survival: evidence for temporal variability.

AIM: Some cardiac phenomena demonstrate temporal variability. We evaluated temporal variability in out-of-hospital cardiac arrest (OHCA) frequency and outcome. METHODS: Prospective cohort study (the Resuscitation Outcomes Consortium) of all OHCA of presumed cardiac cause who were treated by emergency medical services within 9 US and Canadian sites between 12/1/2005 and 02/28/2007. In each site, Emergency Medical System records were collected and analyzed. Outcomes were individually verified by trained data abstractors. RESULTS: There were 9667 included patients. Median age was 68 (IQR 24) years, 66.7% were male and 8.3% survived to hospital discharge. The frequency of cardiac arrest varied significantly across time blocks (p<0.001). Compared to the 0001-0600 hourly time block, the odds ratios and 95% CIs for the occurrence of OHCA were 2.02 (1.90, 2.15) in the 0601-1200 block, 2.01 (1.89, 2.15) in the 1201-1800 block, and 1.73 (1.62, 1.85) in the 1801-2400 block. The frequency of all OHCA varied significantly by day of week (p=0.03) and month of year (p<0.001) with the highest frequencies on Saturday and during December. Survival to hospital discharge was lowest when the OHCA occurred during the 0001-0600 time block (7.3%) and highest during the 1201-1800 time block (9.6%). Survival was highest for OHCAs occurring on Mondays (10.0%) and lowest for those on Wednesdays (6.8%) (p=0.02). CONCLUSION: There is temporal variability in OHCA frequency and outcome. Underlying patient, EMS system and environmental factors need to be explored to offer further insight into these observed patterns.

Emergency medical service providers' attitudes and experiences regarding enrolling patients in clinical research trials.

OBJECTIVE: The purpose of this study was to evaluate Emergency Medical Services (EMS) providers' attitudes and experiences about enrolling patients in clinical research trials utilizing the federal rules for exception from informed consent. We hypothesized that Emergency Medical Technicians (EMTs) would have varied attitudes about research using an exception from informed consent which could have an impact on the research. METHODS AND SETTING: Since January 2007, the EMS system has been participating in a randomized, multi-center interventional trial in which out-of-hospital providers enroll critically injured trauma patients using exception from informed consent.A voluntary, anonymous, written survey was administered to EMS providers during an in-service. The survey included demographics and Likert-type questions about their experiences with and attitudes towards research in general, and research using an exception from informed consent for an out-of-hospital clinical trial. RESULTS: The response rate was 79.3% (844/1067). Most respondents, 93.3%, agreed that "research in EMS care is important." However, 38.5% also agreed that individual EMTs/paramedics should maintain the personal right of refusal to enroll patients in EMS trials. Fifty-four percent of respondents agreed with the statement that "the right of research subjects to make their own choices is more important than the interests of the general community." In response to statements about the current study, 11.3% agreed that "the study is unethical because the patient cannot consent" and 69.2% responded that they would personally be willing to be enrolled in the study before they were able to give consent if they were seriously injured. Those who had not enrolled a patient into the study (681 respondents) were asked their reasons: 76.8% had not encountered an eligible patient or did not work for an agency that carried the fluid; 4.3% did not have time; 4.1% forgot and 1.1% stated that they were opposed to enrolling patients in studies without their consent. CONCLUSION: The majority of EMS personnel in one community support EMS research and this specific out-of-hospital clinical trial being conducted under an exception from informed consent. Potential barriers to enrollment were identified. Further study in other systems is warranted to better understand EMS provider perspectives about exception from informed consent research.

The random dialing survey as a tool for community consultation for research involving the emergency medicine exception from informed consent.

STUDY OBJECTIVE: In 1996, the Food and Drug Administration and the Department of Health and Human Services enacted rules allowing a narrow exception from informed consent for critically ill patients enrolled in emergency research. These include requirements for community consultation prior to trial implementation. Previous studies have noted difficulty in engaging the community. We seek to describe the experience with random dialing surveys as a tool for community consultation across 5 metropolitan regions in the United States. METHODS: Random dialing surveys were used as part of the community consultation for an out-of-hospital clinical trial sponsored by the Resuscitation Outcomes Consortium. The survey method was designed to obtain a representative sample of the community according to population demographics and geography. Logistics of survey administration, role of the survey in community consultation, and survey results by population demographics are discussed. RESULTS: Random dialing surveys were conducted in 5 of 8 US Resuscitation Outcomes Consortium sites. Overall, 70% to 79% of respondents indicated they would be willing to be enrolled in this study. Support for the inclusion of children (aged 15 to 18 years) ranged from 52% to 71%. Respondents aged 18 to 34 years were more willing to participate in the trial than older age groups. Women and racial minorities were less likely to favor the inclusion of minors. CONCLUSION: Random dialing surveys provide an additional tool to engage the community and obtain a sample of the opinion of the population about research conducted under the emergency exception from informed consent regulations. Similar results were obtained across 5 diverse communities in the United States.

Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease.

Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we showed that the storage pathology in the ASM knockout (ASMKO) mouse brain could be corrected by intracerebral injections of cell, gene and protein based therapies. However, except for instances where distal areas were targeted with viral vectors, correction of lysosomal storage pathology was typically limited to a region within a few millimeters from the injection site. As NPA is a global neurometabolic disease, the development of delivery strategies that maximize the distribution of the enzyme throughout the CNS is likely necessary to arrest or delay progression of the disease. To address this challenge, we evaluated the effectiveness of intracerebroventricular (ICV) delivery of recombinant human ASM into ASMKO mice. Our findings showed that ICV delivery of the enzyme led to widespread distribution of the hydrolase throughout the CNS. Moreover, a significant reduction in lysosomal accumulation of sphingomyelin was observed throughout the brain and also within the spinal cord and viscera. Importantly, we demonstrated that repeated ICV infusions of ASM were effective at improving the disease phenotype in the ASMKO mouse as indicated by a partial alleviation of the motor abnormalities. These findings support the continued exploration of ICV delivery of recombinant lysosomal enzymes as a therapeutic modality for LSDs such as NPA that manifests substrate accumulation within the CNS.

A geospatial analysis of persons opting out of an exception from informed consent out-of-hospital clinical trial.

STUDY OBJECTIVE: For trials involving exception from informed consent, some IRBs require that community members be allowed to "opt out" prior to enrollment. We tested for geospatial clustering of opt-out requests and the associated census tract characteristics in one study region. METHODS: This was a retrospective study at a single site of a multicenter exception from informed consent resuscitation trial. We collected and geocoded mailing addresses for persons requesting opt-out bracelets over 16 months, then tested for geospatial clustering using geographic information systems (GIS) analysis. Characteristics for tracts with and without bracelet clustering were compared using univariate tests, multivariable regression, and classification and regression tree (CART) analysis. RESULTS: We received 395 phone calls requesting 718 bracelets, of which 673 were analyzable. Of 397 census tracts in the region, 208 (52%) had at least one request and 38 (10%) demonstrated clustering. In multivariable models, an increasing proportion of family households (OR .90, 95%CI .85-.93), veterans (OR .91, 95%CI .81-1.02), and renters (OR .96, 95%CI .92-.99) were associated with lower odds of requesting an opt-out bracelet, while census tracts with higher income had higher odds of opting-out (OR 1.07, 95%CI 1.02-1.11). Using CART, the proportion of family households and graduate education identified the majority of opt-out requests by census tracts (cross-validation sensitivity 92%, specificity 56%). CONCLUSIONS: Opt-out requests for an exception from informed consent trial at one study site were geographically clustered and associated with certain population demographics. These findings may help identify key target groups for community consultation in future trials.

Community consultation methods in a study using exception to informed consent.

OBJECTIVE: The most effective means of community consultation is unknown. We evaluated differences in community opinion elicited by varying means of consultation. METHODS: We compared responses with a cross-sectional, standardized survey administered as part of the community consultation for the Resuscitation Outcomes Consortium (ROC) hypertonic saline trial. Surveys were obtained from four sources: two sets of random-digit dialing phone surveys, paper surveys from community meetings, and web-based surveys. RESULTS: Three hundred sixty-one usable surveys were obtained: 186 from phone survey 1; 86 from phone survey 2 (using slightly modified wording); 54 from community meetings (8 from open forums; 46 from existing meetings); and 35 from a web site. Demographics were similar between the sets except that the surveys obtained from community meetings had the highest minority representation (63.3% nonwhite). Community meeting respondents were more willing than phone or web respondents to receive experimental treatment for themselves (93.6% vs. 77.5% overall) and for a family member (95.2% vs. 74.9% overall). The web-based survey generated the least feedback and had the most higher-income responders. CONCLUSIONS: Responses varied by method of consultation. The open forums were very poorly attended, despite heavy advertising by investigators. Furthermore, attendees at those meetings provided the least objection to proposed research without informed consent. Phone surveys elicited the most objections. We suggest that an efficient method of community consultation is random-digit dialing supplemented with discussion at already scheduled events to target special populations.

Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models of ALS has shown that insulin-like growth factor-1 (IGF-1) slows disease progression when delivered at disease onset. However, IGF-1's mechanism of action along the neuromuscular axis remains unclear. In this study, symptomatic ALS mice received IGF-1 through stereotaxic injection of an IGF-1-expressing viral vector to the deep cerebellar nuclei (DCN), a region of the cerebellum with extensive brain stem and spinal cord connections. We found that delivery of IGF-1 to the central nervous system (CNS) reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice. To explore the mechanism of action of IGF-1, we used a newly developed in vitro model of ALS. We demonstrate that IGF-1 is potently neuroprotective and attenuates glial cell-mediated release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO). Our results show that delivering IGF-1 to the CNS is sufficient to delay disease progression in a mouse model of familial ALS and demonstrate for the first time that IGF-1 attenuates the pathological activity of non-neuronal cells that contribute to disease progression. Our findings highlight an innovative approach for delivering IGF-1 to the CNS.