Characterising Penetrometer Tip Contact during Concrete Condition Assessment.

Concrete condition-assessing penetrometers need to be able to distinguish between making contact with a hard (concrete) surface as opposed to a semi-solid (corroded concrete) surface. We investigated whether different shaped tips of a cylindrical penetrometer were better than others at maintaining contact with concrete and not slipping. We designed a range of simple symmetric tip shapes, controlled by a single superellipse parameter. We performed a finite element analysis of these parametric models in SolidWorks before machining in stainless steel. We tested our penetrometer tips on a concrete paver cut to four angles at 20∘ increments. The results indicate that the squircle-shaped tip had the least slippage when used for concrete condition assessment.

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis (NASH) in the United Kingdom (UK) in 2018.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) - a progressive subset of non-alcoholic fatty liver disease (NAFLD) - is a chronic liver disease that can progress to advanced fibrosis, cirrhosis, and end-stage liver disease (ESLD) if left untreated. Early-stage NASH is usually asymptomatic, meaning a large proportion of the prevalent population are undiagnosed. Receiving a NASH diagnosis increases the probability that a patient will receive interventions for the purpose of managing their condition. The purpose of this study was to estimate the disease burden and economic impact of diagnosed NASH in the United Kingdom (UK) adult population in 2018. METHODS: The socioeconomic burden of diagnosed NASH from a societal perspective was estimated using cost-of-illness methodology applying a prevalence approach. This involved estimating the number of adults with diagnosed NASH in the UK in a base period (2018) and the economic and wellbeing costs attributable to diagnosed NASH in that period. The analysis was based on a targeted review of the scientific literature, existing databases and consultation with clinical experts, health economists and patient groups. RESULTS: Of the prevalent NASH population in the UK in 2018, an estimated 79.8% were not diagnosed. In particular, of the prevalent population in disease stages F0 to F2, only 2.0% (F0), 2.0% (F1) and 16.5% (F2), respectively, were diagnosed. Total economic costs of diagnosed NASH in the UK ranged from £2.3 billion (lower prevalence scenario, base probability of diagnosis scenario) to £4.2 billion (higher prevalence scenario, base probability of diagnosis scenario). In 2018, people with NASH in the UK were estimated to experience 94,094 to 174,564 disability-adjusted life years (DALYs) overall. Total wellbeing costs associated with NASH in 2018 were estimated to range between £5.6 to £10.5 billion. CONCLUSION: The prevention and appropriate management of adult NASH patients could result in reduced economic costs and improvements in wellbeing.

Examining Whether The Health-In-All-Policies Approach Promotes Health Equity.

Scholars and public health advocates have expressed optimism about the potential for the health-in-all-policies approach to address social disparities in health, but little research has been done on whether it promotes health equity in practice. Based on sixty-five in-depth interviews with US officials in the public and private sectors conducted in five states in 2016-17, we found a relationship between the use of the approach and the prominence of health equity as a policy concern. In emphasizing the social determinants of health, the approach gives public officials and policy entrepreneurs a framework for promoting this goal. In some areas, we found a gradual transition in focus from health generally to health equity. Overall, we found that practitioners of the approach introduce equity selectively and strategically.

Development of a Canadian deceased donation education program for health professionals: a needs assessment survey.

PURPOSE: The purpose of this survey was to determine how Canadian healthcare professionals perceive their deficiencies and educational requirements related to organ and tissue donation. METHODS: We surveyed 641 intensive care unit (ICU) physicians, 1,349 ICU nurses, 1,561 emergency room (ER) physicians, and 1,873 ER nurses. The survey was distributed by the national organization for each profession (the Canadian Association of Emergency Physicians, the Canadian Association of Critical Care Nurses, and the National Emergency Nurses Association). Canadian Blood Services developed the critical care physician list in collaboration with the Canadian Critical Care Society. Survey development included questions related to comfort with, and knowledge of, key competencies in organ and tissue donation. RESULTS: Eight hundred thirty-one (15.3%) of a possible 5,424 respondents participated in the survey. Over 50% of respondents rated the following topics as highly important: knowledge of general organ and tissue donation, neurological determination of death, donation after cardiac death, and medical-legal donation issues. High competency comfort levels ranged from 14.7-50.9% for ICU nurses and 8.0-34.6% for ER nurses. Competency comfort levels were higher for ICU physicians (67.5-85.6%) than for ER physicians who rated all competencies lower. Respondents identified a need for a curriculum on national organ donation and preferred e-learning as the method of education. CONCLUSIONS: Both ICU nurses and ER practitioners expressed low comfort levels with their competencies regarding organ donation. Intensive care unit physicians had a much higher level of comfort; however, the majority of these respondents were specialty trained and working in academic centres with active donation and transplant programs. A national organ donation curriculum is needed.

Influenza A (H1N1pdm09)-Related Critical Illness and Mortality in Mexico and Canada, 2014.

OBJECTIVES: The 2009-2010 influenza A (H1N1pdm09) pandemic caused substantial morbidity and mortality among young patients; however, mortality estimates have been confounded by regional differences in eligibility criteria and inclusion of selected populations. In 2013-2014, H1N1pdm09 became North America's dominant seasonal influenza strain. Our objective was to compare the baseline characteristics, resources, and treatments with outcomes among critically ill patients with influenza A (H1N1pdm09) in Mexican and Canadian hospitals in 2014 using consistent eligibility criteria. DESIGN: Observational study and a survey of available healthcare setting resources. SETTING: Twenty-one hospitals, 13 in Mexico and eight in Canada. PATIENTS: Critically ill patients with confirmed H1N1pdm09 during 2013-2014 influenza season. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main outcome measures were 90-day mortality and independent predictors of mortality. Among 165 adult patients with H1N1pdm09-related critical illness between September 2013 and March 2014, mean age was 48.3 years, 64% were males, and nearly all influenza was community acquired. Patients were severely hypoxic (median PaO2-to-FIO2 ratio, 83 mm Hg), 97% received mechanical ventilation, with mean positive end-expiratory pressure of 14 cm H2O at the onset of critical illness and 26.7% received rescue oxygenation therapy with prone ventilation, extracorporeal life support, high-frequency oscillatory ventilation, or inhaled nitric oxide. At 90 days, mortality was 34.6% (13.9% in Canada vs 50.5% in Mexico, p < 0.0001). Independent predictors of mortality included lower presenting PaO2-to-FIO2 ratio (odds ratio, 0.89 per 10-point increase [95% CI, 0.80-0.99]), age (odds ratio, 1.49 per 10 yr increment [95% CI, 1.10-2.02]), and requiring critical care in Mexico (odds ratio, 7.76 [95% CI, 2.02-27.35]). ICUs in Canada generally had more beds, ventilators, healthcare personnel, and rescue oxygenation therapies. CONCLUSIONS: Influenza A (H1N1pdm09)-related critical illness still predominantly affects relatively young to middle-aged patients and is associated with severe hypoxemic respiratory failure. The local critical care system and available resources may be influential determinants of patient outcome.

Successful partnerships with third sector organisations to enhance the healthcare student experience: a partnership evaluation.

There is limited research surrounding academic partnerships and more research is needed to educate universities, and the private, public and third sectors about the benefits and limitations of such partnerships. The aim of this study was to outline the unique partnership between Macmillan Cancer Support and De Montfort University and to evaluate the progress of this partnership. A qualitative approach was employed which involved interviews with nine members of the partnership's steering group. Interviews were transcribed and analysed using thematic analysis. The results showed that a partnership between a university and a third sector charity can have mutual benefits for all those involved, particularly for students and those affected by cancer. Furthermore, the module to develop volunteering among families affected cancer, created through this partnership is now being considered by other universities as a way of providing holistic and non-traditional lecture based learning experiences. Recommendations are made for future partnerships between third sector charities and universities.

Fluoroscopic assessment of lumbar total disc replacement kinematics during walking.

STUDY DESIGN: Descriptive. OBJECTIVE: The purpose of this study was to determine the in vivo kinematics of functional spinal units, during gait, in individuals with a single-level lumbar total disc replacement (TDR). SUMMARY OF BACKGROUND DATA: TDR is a motion preservation technology that offers an alternative to spinal fusion for treatment of degenerative disc disease. The aim of TDRs is to replicate motion of the functional spinal units, which may protect adjacent intervertebral discs against accelerated degeneration. At present, there is limited understanding of the in vivo motion of TDRs, particularly during dynamic activities such as gait. Such information is important for understanding the wear characteristics of TDRs and furthering design rationale of future implants. METHODS: TDR motions were obtained from 24 participants who underwent implantation with single-level L4-L5 or L5-S1 CHARITÉ or In Motion TDRs. Video fluoroscopy was used to obtain measurements in the frontal and sagittal planes during fixed speed treadmill walking. RESULTS: The mean range of motion between the upper and lower lumbar TDR endplates during walking was 1.6° and 2.4° in the frontal and sagittal planes, respectively. These values were significantly different from zero and corresponded to 19% of the maximum static range of motion in each plane. CONCLUSION: Lumbar TDRs provide a degree of motion preservation at the operative level during moderate speed walking. The distribution of lumbar TDR motions during walking presented here will inform relevant standards for conducting standardized tests of lumbar TDRs, particularly wear assessments, and, hence, enable more realistic mechanical and computer-based wear simulations to be performed. LEVEL OF EVIDENCE: N/A.

Time trends and payer differences in lengths of initial hospitalization for preterm infants, Arkansas, 2004 to 2010.

OBJECTIVE: The objective of this study was to examine the time trend in length of stay (LOS) and explore potential differences in neonatal LOS by insurance type for preterm infants in Arkansas between 2004 and 2010. STUDY DESIGN: There were 18,712 preterm infants included in our analyses. Accelerated failure time models were used to model neonatal LOS as a function of insurance type and discharge year while adjusting for key maternal and infant characteristics, and complication/anomaly indicators. RESULTS: Before adjusting for the complication/anomaly indicators, the LOS for preterm infants delivered to mothers in the Medicaid group was 3.2% shorter than those in the private payer group. Furthermore, each subsequent year was associated with a 1.6% increase in the expected LOS. However, after accounting for complications and anomalies, insurance coverage differences in neonatal LOS were not statistically significant while the trend in LOS persisted at a 0.59% increase for each succeeding year. CONCLUSION: All of the apparent differences in LOS by insurance type and more than half of the apparent increase in LOS over time are accounted for by higher rates of complications among privately insured preterm infants and increasing rates of complications for all surviving preterm infants between 2004 and 2010.

Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial. METHODS/DESIGN: The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping. DISCUSSION: This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00182143 . Date of registration: 10 September 2005.

Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients.

IMPORTANCE: Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin. OBJECTIVE: To evaluate the comparative cost-effectiveness of LMWH vs UFH for prophylaxis against VTE in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Prospective economic evaluation concurrent with the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (May 2006 to June 2010). The economic evaluation adopted a health care payer perspective and in-hospital time horizon; derived baseline characteristics and probabilities of intensive care unit and in-hospital events; and measured costs among 2344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients. MAIN OUTCOMES AND MEASURES: Costs, effects, incremental cost-effectiveness of LMWH vs UFH during the period of hospitalization, and sensitivity analyses across cost ranges. RESULTS: Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1862 patients who received UFH (incremental cost, -$1297 [IQR, -$4398 to $1404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH. CONCLUSIONS AND RELEVANCE: From a health care payer perspective, the use of the LMWH dalteparin for VTE prophylaxis among critically ill medical-surgical patients was more effective and had similar or lower costs than the use of UFH. These findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.

The impact of past introductions on an iconic and economically important species, the red deer of Scotland.

The red deer (Cervus elaphus) is an iconic species in Scotland and, due to its value as a game species, an important element of the Scottish rural economy. The native status of this species is sometimes questioned because of many recorded introductions of nonnative deer in the past that were an attempt to improve trophy size. In this study, we assessed the impact of past introductions on the genetic makeup of Scottish red deer by genotyping at 15 microsatellite loci a large number of samples (n = 1152), including mainland and island Scottish red deer and individuals from several putative external source populations used in introductions to improve trophy size. Population structure and introgression assessment analyses revealed that the impact of introductions was weak in Highland red deer populations but more prominent on the islands, especially on those where current red deer populations are mostly or entirely derived from introductions (Harris & Lewis, Arran, and Rum). Frequent imports of Central-Eastern European red deer into English deer parks were reflected in the higher genetic introgression values found in some of the individuals collected in parks.

Sedation for critically ill or injured adults in the intensive care unit: a shifting paradigm.

As most critically ill or injured patients will require some degree of sedation, the goal of this paper was to comprehensively review the literature associated with use of sedative agents in the intensive care unit (ICU). The first and selected latter portions of this article present a narrative overview of the shifting paradigm in ICU sedation practices, indications for uninterrupted or prolonged ICU sedation, and the pharmacology of sedative agents. In the second portion, we conducted a structured, although not entirely systematic, review of the available evidence associated with use of alternative sedative agents in critically ill or injured adults. Data sources for this review were derived by searching OVID MEDLINE and PubMed from their first available date until May 2012 for relevant randomized controlled trials (RCTs), systematic reviews and/or meta-analyses and economic evaluations. Advances in the technology of mechanical ventilation have permitted clinicians to limit the use of sedation among the critically ill through daily sedative interruptions or other means. These practices have been reported to result in improved mortality, a decreased length of ICU and hospital stay and a lower risk of drug-associated delirium. However, in some cases, prolonged or uninterrupted sedation may still be indicated, such as when patients develop intracranial hypertension following traumatic brain injury. The pharmacokinetics of sedative agents have clinical importance and may be altered by critical illness or injury, co-morbid conditions and/or drug-drug interactions. Although use of validated sedation scales to monitor depth of sedation is likely to reduce adverse events, they have no utility for patients receiving neuromuscular receptor blocking agents. Depth of sedation monitoring devices such as the Bispectral Index (BIS©) also have limitations. Among existing RCTs, no sedative agent has been reported to improve the risk of mortality among the critically ill or injured. Moreover, although propofol may be associated with a shorter time to tracheal extubation and recovery from sedation than midazolam, the risk of hypertriglyceridaemia and hypotension is higher with propofol. Despite dexmedetomidine being linked with a lower risk of drug-associated delirium than alternative sedative agents, this drug increases risk of bradycardia and hypotension. Among adults with severe traumatic brain injury, there are insufficient data to suggest that any single sedative agent decreases the risk of subsequent poor neurological outcomes or mortality. The lack of examination of confounders, including the type of healthcare system in which the investigation was conducted, is a major limitation of existing pharmacoeconomic analyses, which likely limits generalizability of their results.

Compensation neurosis: a too quickly forgotten concept?

There has been great debate concerning the existence and meaning of compensation neurosis. It is included in the International Classification of Diseases (ICD)-9 and -10 but not listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). On the eve of publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), we re-examine the history and concept of compensation neurosis and conceptually update the condition to reflect current psychiatric thought. We consider its utility as a diagnostic entity for forensic evaluations and its components as they relate to exaggeration in injury claims. We also discuss how compensation neurosis differs from malingering and factitious disorder.

Evaluating the effect of hospital and insurance type on the risk of 1-year mortality of very low birth weight infants: controlling for selection bias.

OBJECTIVES: We examined the effect of hospital type and medical coverage on the risk of 1-year mortality of very low birth weight (VLBW) infants while adjusting for possible selection bias. METHODS: The study population was limited to singleton live birth infants having birth weight between 500 and 1500 g with no congenital anomalies who were born in Arkansas hospitals between 2001 and 2007. Propensity score (PS) matching and PS covariate adjustment were used to mitigate selection bias. In addition, a conventional multivariable logistic regression model was used for comparison purposes. RESULTS: Generally, all 3 analytical approaches provided consistent results in terms of the estimated relative risk, absolute risk reduction, and the number needed to treat. Using the PS matching method, VLBW infants delivered at a hospital with a neonatal intensive care unit (NICU) were associated with a 35% relative decrease (95% bootstrap confidence interval, 18.5%-48.9%) in the risk of 1-year mortality as compared with those infants delivered at non-NICU hospitals. Furthermore, our results showed that on average, 16 VLBW infants (95% bootstrap confidence interval, 11-32), would need to be delivered at a hospital with an NICU to prevent 1 additional death at 1 year. However, there was not a difference in the risk of 1-year mortality between VLBW infants born to Medicaid-insured versus non-Medicaid-insured women. CONCLUSIONS: Estimated relative risk of infant mortality was significantly lower for births that occurred in hospitals with an NICU; therefore, greater efforts should be made to deliver VLBW neonates in an NICU hospital.

Improving perinatal regionalization for preterm deliveries in a Medicaid covered population: initial impact of the Arkansas ANGELS intervention.

OBJECTIVE: To examine the factors associated with delivery of preterm infants at neonatal intensive care unit (NICU) hospitals in Arkansas during the period 2001-2006, with a focus on the impact of a Medicaid supported intervention, Antenatal and Neonatal Guidelines, Education, and Learning System (ANGELS), that expanded the consulting capacity of the academic medical center's maternal fetal medicine practice. DATA SOURCES: A dataset of linked Medicaid claims and birth certificates for the time period by clustering Medicaid claims by pregnancy episode. Pregnancy episodes were linked to residential county-level demographic and medical resource characteristics. Deliveries occurring before 35 weeks gestation (n=5,150) were used for analysis. STUDY DESIGN: Logistic regression analysis was used to examine time trends and individual, county, and intervention characteristics associated with delivery at hospitals with NICU, and delivery at the academic medical center. PRINCIPAL FINDINGS: Perceived risk, age, education, and prenatal care characteristics of women affected the likelihood of use of the NICU. The perceived availability of local expertise was associated with a lower likelihood that preterm infants would deliver at the NICU. ANGELS did not increase the overall use of NICU, but it did shift some deliveries to the academic setting. CONCLUSION: Perinatal regionalization is the consequence of a complex set of provider and patient decisions, and it is difficult to alter with a voluntary program.

Late preterm infants: birth outcomes and health care utilization in the first year.

OBJECTIVE: To distinguish the effects of late preterm birth from the complications associated with the causes of delivery timing, this study used propensity score-matching methods on a statewide database that contains information on both mothers and infants. METHODS: Data for this study came from Arkansas Medicaid claims data linked to state birth certificate data for the years 2001 through 2005. We excluded all multiple births, infants with birth defects, and infants at <33 weeks of gestation. Late preterm infants (LPIs) (34 to 36 weeks of gestation) were matched with term infants (37-42 weeks of gestation) according to propensity scores, on the basis of infant, maternal, and clinical characteristics. RESULTS: A total of 5188 LPIs were matched successfully with 15303 term infants. LPIs had increased odds of poor outcomes during their birth hospitalization, including a need for mechanical ventilation (adjusted odds ratio [aOR]: 1.31 [95% confidence interval [CI]: 1.01-1.68]), respiratory distress syndrome (aOR: 2.84 [95% CI: 2.33-3.45]), and hypoglycemia (aOR: 1.60 [95% CI: 1.26-2.03]). Outpatient and inpatient Medicaid expenditures in the first year were both modestly higher (outpatient, adjusted marginal effect: $108 [95% CI: $58-$158]; inpatient, $597 [95% CI: $528-$666]) for LPIs. CONCLUSIONS: LPIs are at increased risk of poor health-related outcomes during their birth hospitalization and of increased health care utilization during their first year.

Early drotrecogin alpha (activated) administration in severe sepsis is associated with lower mortality: a retrospective analysis of the Canadian ENHANCE cohort.

INTRODUCTION: Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy. METHODS: Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored. RESULTS: Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day. CONCLUSIONS: These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age. TRIAL REGISTRATION: Previous trial registration number: NCT00568893.

Under the conditions of intended use - New developments in the FEMA GRAS program and the safety assessment of flavor ingredients.

In 1995 we published a review describing the scientific and legal bases for the GRAS assessment program for flavor ingredients sponsored by the Flavor and Extract Manufacturers Association of the United States (FEMA) [Hallagan, J.B., Hall, R.L., 1995. FEMA GRAS - A GRAS assessment program for flavor ingredients. Regulatory Toxicology and Pharmacology 21, 422]. This review provides new information related to flavor safety assessment and regulation and is intended to complement our previous report. The FEMA GRAS assessment program is the most extensive and longest running industry-sponsored GRAS program and has established a sound record of scientific rigor and transparency. In this review, in addition to providing general information on the topics of flavor safety assessment and regulation, we explore the effects of recent developments on the four pillars of the FEMA GRAS assessment program: (1) general recognition; (2) among experts qualified by scientific training and experience to evaluate safety; (3) through scientific procedures; (4) under the conditions of intended use in food. We conclude that developments since our last review in 1995 have further strengthened the FEMA GRAS assessment program allowing it to maintain its global leadership role in the safety assessment of flavor ingredients.