An Economic Evaluation of a Streamlined Day-Case Atrial Fibrillation Ablation Protocol and Conventional Cryoballoon Ablation versus Antiarrhythmic Drugs in a UK Paroxysmal Atrial Fibrillation Population.

BACKGROUND AND AIMS: Symptom control for atrial fibrillation can be achieved by catheter ablation or drug therapy. We assessed the cost effectiveness of a novel streamlined atrial fibrillation cryoballoon ablation protocol (AVATAR) compared with optimised antiarrhythmic drug (AAD) therapy and a conventional catheter ablation protocol, from a UK National Health Service (NHS) perspective. METHODS: Data from the AVATAR study were assessed to determine the cost effectiveness of the three protocols in a two-step process. In the first stage, statistical analysis of clinical efficacy outcomes was conducted considering either a three-way comparison (AVATAR vs. conventional ablation vs. optimised AAD therapies) or a two-way comparison (pooled ablation protocol data vs. optimised AAD therapies). In the second stage, models assessed the cost effectiveness of the protocols. Costs and some of the clinical inputs in the models were derived from within-trial cost analysis and published literature. The remaining inputs were derived from clinical experts. RESULTS: No significant differences between the ablation protocols were found for any of the clinical outcomes used in the model. Results of a within-trial cost analysis show that AVATAR is cost-saving (£1279 per patient) compared with the conventional ablation protocol. When compared with optimised AAD therapies, AVATAR (pooled conventional and AVATAR ablation protocols efficacy) was found to be more costly while offering improved clinical benefits. Over a lifetime time horizon, the incremental cost-effectiveness ratio of AVATAR was estimated as £21,046 per quality-adjusted life-year gained (95% credible interval £7086-£71,718). CONCLUSIONS: The AVATAR streamlined protocol is likely to be a cost-effective option versus both conventional ablation and optimised AAD therapy in the UK NHS healthcare setting.

ROptimus: a parallel general-purpose adaptive optimization engine.

MOTIVATION: Various computational biology calculations require a probabilistic optimization protocol to determine the parameters that capture the system at a desired state in the configurational space. Many existing methods excel at certain scenarios, but fail in others due, in part, to an inefficient exploration of the parameter space and easy trapping into local minima. Here, we developed a general-purpose optimization engine in R that can be plugged to any, simple or complex, modelling initiative through a few lucid interfacing functions, to perform a seamless optimization with rigorous parameter sampling. RESULTS: ROptimus features simulated annealing and replica exchange implementations equipped with adaptive thermoregulation to drive Monte Carlo optimization process in a flexible manner, through constrained acceptance frequency but unconstrained adaptive pseudo temperature regimens. We exemplify the applicability of our R optimizer to a diverse set of problems spanning data analyses and computational biology tasks. AVAILABILITY AND IMPLEMENTATION: ROptimus is written and implemented in R, and is freely available from CRAN (http://cran.r-project.org/web/packages/ROptimus/index.html) and GitHub (http://github.com/SahakyanLab/ROptimus).

The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial.

BACKGROUND: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. METHODS: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. DISCUSSION: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. TRIAL REGISTRATION: The protocol is registered on Clinical. TRIALS: gov and EudraCT and has approval from UK Ethics and MHRA.

High throughput screening for expanded CTG repeats in myotonic dystrophy type 1 using melt curve analysis.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often nonspecific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and cost prohibitive for population surveys. METHODS: Here, we present a high throughput, low-cost screening tool for CTG repeat expansions using TP-PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye. RESULTS: We determined that multimodal melt profiles from the TP-PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri-modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles. CONCLUSION: We demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large-scale testing programs such as population studies and newborn screening programs.

Monitoring, assessment, and prediction of microbial shifts in coupled catalysis and biodegradation of 1,4-dioxane and co-contaminants.

Microbial community dynamics were characterized following combined catalysis and biodegradation treatment trains for mixtures of 1,4-dioxane and chlorinated volatile organic compounds (CVOCs) in laboratory microcosms. Although a few specific bacterial taxa are capable of removing 1,4-dioxane and individual CVOCs, many microorganisms are inhibited when these contaminants are present in mixtures. Chemical catalysis by tungstated zirconia (WOx/ZrO2) and hydrogen peroxide (H2O2) as a non-selective treatment was designed to achieve nearly 20% 1,4-dioxane and over 60% trichloroethene and 50% dichloroethene removals. Post-catalysis, bioaugmentation with 1,4-dioxane metabolizing bacterial strain,Pseudonocardia dioxanivorans CB1190, removed the remaining 1,4-dioxane. The evolution of the microbial community under different conditions was time-dependent but relatively independent of the concentrations of contaminants. The compositions of microbiomes tended to be similar regardless of complex contaminant mixtures during the biodegradation phase, indicating a r-K strategy transition attributed to the shock experienced during catalysis and the subsequent incubation. The originally dominant genera Pseudomonas and Ralstonia were sensitive to catalytic oxidation, and were overwhelmed by Sphingomonas, Rhodococcus, and other catalyst-tolerant microbes, but microbes capable of biodegradation of organics thrived during the incubation. Methane metabolism, chloroalkane-, and chloroalkene degradation pathways appeared to be responsible for CVOC degradation, based on the identifications of haloacetate dehalogenases, 2-haloacid dehalogenases, and cytochrome P450 family. Network analysis highlighted the potential interspecies competition or commensalism, and dynamics of microbiomes during the biodegradation phase that were in line with shifting predominant genera, confirming the deterministic processes guiding the microbial assembly. Collectively, this study demonstrated that catalysis followed by bioaugmentation is an effective treatment for 1,4-dioxane in the presence of high CVOC concentrations, and it enhanced our understanding of microbial ecological impacts resulting from abiotic-biological treatment trains. These results will be valuable for predicting treatment synergies that lead to cost savings and improve remedial outcomes in short-term active remediation as well as long-term changes to the environmental microbial communities.

Comparing Mortality Prediction by Quick Sequential Organ Failure Assessment with Emergency Physician Judgment.

STUDY OBJECTIVE: The quick sequential organ failure assessment (qSOFA) was proposed to identify infected patients at risk for mortality, an indication of sepsis, in nonintensive care unit settings. This study tests whether qSOFA improves physician prediction of mortality among infected Emergency Department (ED) patients. METHODS: We performed a secondary analysis of a prospective, observational study of potentially septic ED patients, conducted between two urban, academic medical centers, from July 2016 to December 2017. We enrolled ED patients with two or more systemic inflammatory response syndrome criteria and severe sepsis qualifying organ dysfunction, systolic blood pressure <90 mm Hg, or lactate ≥ 4.0 mmol/L. Infectious etiology was adjudicated retrospectively by paired physician review. We excluded noninfected patients. Treating ED physicians submitted judgment for in-hospital mortality (0%-100%) at hospital admission, and qSOFA was calculated retrospectively using ED data. The primary outcome was in-hospital mortality within 28 days. We used logistic regression to predict mortality using physician judgment, qSOFA, and combined physician judgment and qSOFA. To assess differences between models, 95% confidence intervals for area under the curve (AUC) were derived by bootstrapping with 1,000 iterations. RESULTS: Of 405 patients meeting inclusion criteria, 195 (48.1%) were determined to have infection and analyzed. Of analyzed patients, 16 (8.2%) suffered in-hospital mortality within 28 days. Analyzed patients had a mean age of 58.3 (SD 16.5) years and 78 (40%) were female. qSOFA alone (AUC 0.63; 95% CI: 0.53-0.73) was not superior to unstructured physician judgment (AUC 0.80; 0.70-0.89) when predicting 28-day in-hospital mortality with mean AUC difference 0.17 (0.07-0.28) across bootstrapped datasets. Combining qSOFA with physician judgment (AUC 0.79; 0.69-0.89) did not improve performance compared with physician judgment alone. CONCLUSION: When predicting 28-day in-hospital mortality among infected ED patients, qSOFA did not outperform or improve physician judgment.

Patient-reported study of the impact of pediatric-onset myotonic dystrophy.

INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.

ICU Emergencies Simulation Curriculum for Critical Care Fellows: Neurologic Emergencies.

Introduction: The management of neurologic emergencies is an important component of critical care fellowship training. Additional training in neurocritical care has been demonstrated to improve clinical outcomes, though exposure to these emergencies during training can be limited. Methods: Three simulation cases are presented as part of a comprehensive neurologic emergencies curriculum for critical care trainees. The cases represent neurologic catastrophes encountered in the intensive care unit consisting of symptomatic hyponatremia, severe alcohol withdrawal syndrome, and brain herniation syndrome. The case descriptions are complete with learning objectives, critical actions checklists, and debriefing material for facilitators, as well as all necessary personnel briefs and required equipment. Results: The scenarios were completed over the course of the 2016-2017 academic year by first-year critical care fellows. Following curriculum implementation, there was an improvement in self-perceived confidence of fellows in neurologic emergency management skills. Discussion: The cases were felt to be realistic and beneficial and led to perceived improvement in management of neurologic emergencies and leadership during clinical crises.

Gender difference in clinical conditions among hospitalized adults with myotonic dystrophy.

INTRODUCTION: In this study we examined gender differences in adult hospitalizations with myotonic dystrophy (DM). METHODS: From the Nationwide Inpatient Sample (NIS) 2010-2014, we identified 1,891 adult hospitalizations with a DM diagnosis and constructed a comparison group of hospitalizations without DM using propensity score matching. We calculated relative risk by gender for 44 clinical diagnoses that each accounted for at least 5% of DM hospitalizations. RESULTS: Hospitalizations with DM were longer (4.8 vs. 4.1 days, P < 0.0001) and more costly ($13,241 vs. $11,458, P < 0.0001) than those without DM. More than half (25 of 44) of the conditions co-occurring with DM hospitalizations did not differ in their relative risks by gender. For those that differed by gender, only 5 were specific to DM, compared with hospitalizations without DM. DISCUSSION: Our findings highlight the importance of comprehensive and coordinated care for DM rather than gender-oriented care in the inpatient setting. Muscle Nerve 59:348-353, 2019.

An underwater observation dataset for fish classification and fishery assessment.

Using Dual-Frequency Identification Sonar (DIDSON), fishery acoustic observation data was collected from the Ocqueoc River, a tributary of Lake Huron in northern Michigan, USA. Data were collected March through July 2013 and 2016 and included the identification, via technology or expert analysis, of eight fish species as they passed through the DIDSON's field of view. A set of short DIDSON clips containing identified fish was curated. Additionally, two other datasets were created that include visualizations of the acoustic data and longer DIDSON clips. These datasets could complement future research characterizing the abundance and behavior of valued fishes such as walleye (Sander vitreus) or white sucker (Catostomus commersonii) or invasive fishes such as sea lamprey (Petromyzon marinus) or European carp (Cyprinus carpio). Given the abundance of DIDSON data and the fact that a portion of it is labeled, these data could aid in the creation of machine learning tools from DIDSON data, particularly for invasive sea lamprey which are amply represented and a destructive invader of the Laurentian Great Lakes.

A simple, cost-effective emitter for controlled release of fish pheromones: Development, testing, and application to management of the invasive sea lamprey.

Semiochemicals that elicit species-specific attraction or repulsion have proven useful in the management of terrestrial pests and hold considerable promise for control of nuisance aquatic species, particularly invasive fishes. Because aquatic ecosystems are typically large and open, use of a semiochemical to control a spatially dispersed invader will require the development of a cost-effective emitter that is easy to produce, environmentally benign, inexpensive, and controls the release of the semiochemical without altering its structure. We examined the release properties of five polymers, and chose polyethylene glycol (PEG) as the best alternative. In a series of laboratory and field experiments, we examined the response of the invasive sea lamprey to PEG, and to a partial sex pheromone emitted from PEG that has proven effective as a trap bait to capture migrating sea lamprey prior to spawning. Our findings confirm that the sea lamprey does not behaviorally respond to PEG, and that the attractant response to the pheromone component was conserved when emitted from PEG. Further, we deployed the pheromone-PEG emitters as trap bait during typical control operations in three Great Lakes tributaries, observing similar improvements in trap performance when compared to a previous study using mechanically pumped liquid pheromone. Finally, the polymer emitters tended to dissolve unevenly in high flow conditions. We demonstrate that housing the emitter stabilizes the dissolution rate at high water velocity. We conclude the performance characteristics of PEG emitters to achieve controlled-release of a semiochemical are sufficient to recommend its use in conservation and management activities related to native and invasive aquatic organisms.

A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus.

INTRODUCTION: The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight. METHODS AND ANALYSIS: In this multicentre, randomised, controlled, non-blinded trial, male and female patients aged 18-65 years with a body mass index 30-50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58-97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression. TRIAL REGISTRATION NUMBER: ISRCTN30845205, ClinicalTrials.gov Identifier NCT02459561.

Inclusion Body Myositis: What Most Impacts Patients' Lives.

OBJECTIVE: Inclusion body myositis (IBM) is the most common form of idiopathic inflammatory myopathy in adults older than 50 years. Few studies have focused on the functional, physical, and social limitations of this disease. This study identifies pertinent symptoms that impact the health and daily function of patients with IBM. METHODS: We used semistructured interviews with 10 biopsy-confirmed adults with IBM to identify the psychological, physical, and functional limitations that have the greatest impact on the lives of patients with IBM. RESULTS: Participants with IBM provided 644 direct quotes identifying issues that have the greatest effect on their lives. Two hundred nine individual symptoms and 17 symptomatic themes were identified by patients as having a significant impact on their lives. The symptomatic themes mentioned most frequently involved mobility and ambulation, emotional distress, and activity impairment. CONCLUSIONS: Identifying critical issues to patients with IBM is potentially useful for clinicians whose aim is to provide optimal care to patients with IBM.

Disease burden and functional outcomes in congenital myotonic dystrophy: A cross-sectional study.

OBJECTIVE: Herein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood. METHODS: Children with CDM and age-matched controls aged 0 to 13 years were enrolled. Participants were divided into cohorts based on the following age groups: 0-2, 3-6, and 7-13 years. Each cohort received age-appropriate evaluations including functional testing, oral facial strength testing, neuropsychological testing, quality-of-life measurements, and ECG. Independent-samples t test or Wilcoxon 2-sample test was used to compare the differences between children with CDM and controls. Probability values less than 0.05 are reported as significant. RESULTS: Forty-one participants with CDM and 29 healthy controls were enrolled. The 6-minute walk was significantly different between CDM (258.3 m [SD 176.0]) and control participants (568.2 m [SD 73.2]). The mean lip force strength was significantly different in CDM (2.1 N [SD 2.8)] compared to control participants (17.8 N [SD 7.6]). In participants with CDM, the mean IQ (65.8; SD 18.4) was 3 SDs below the mean compared to standardized norms. Measurements of grip strength, sleep quality, and quality of life were also significantly different. Strength measures (oral facial strength, grip strength, and 6-minute walk) correlated with each other but not with participant IQ. CONCLUSIONS: This work identifies important phenotypes associated with CDM during childhood. Several measures of strength and function were significantly different between participants with CDM and controls and may be useful during future therapeutic trials.

Sustainability of school-located influenza vaccination programs in Florida.

BACKGROUND: School-located influenza vaccination (SLIV) programs are a promising strategy for increasing vaccination coverage among schoolchildren. However, questions of economic sustainability have dampened enthusiasm for this approach in the United States. We evaluated SLIV sustainability of a health department led, county-wide SLIV program in Alachua County, Florida. Based on Alachua's outcome data, we modeled the sustainability of SLIV programs statewide using two different implementation costs and at different vaccination rates, reimbursement amount, and Vaccines for Children (VFC) coverage. METHODS: Mass vaccination clinics were conducted at 69 Alachua County schools in 2013 using VFC (for Medicaid and uninsured children) and non-VFC vaccines. Claims were processed after each clinic and submitted to insurance providers for reimbursement ($5 Medicaid and $47.04 from private insurers). We collected programmatic expenditures and volunteer hours to calculate fixed and variable costs for two different implementation costs (with or without in-kind costs included). We project program sustainability for Florida using publicly available county-specific student populations and health insurance enrollment data. RESULTS: Approximately 42% (n=12,853) of pre-kindergarten - 12th grade students participated in the SLIV program in Alachua. Of the 13,815 doses provided, 58% (8042) were non-VFC vaccine. Total implementation cost was $14.95/dose or $7.93/dose if "in-kind" costs were not included. The program generated a net surplus of $24,221, despite losing $4.68 on every VFC dose provided to Medicaid and uninsured children. With volunteers, 99% of Florida counties would be sustainable at a 50% vaccination rate and average reimbursement amount of $3.25 VFC and $37 non-VFC. Without volunteers, 69% of counties would be sustainable at 50% vaccination rate if all VFC recipients were on Medicaid and its reimbursement increased from $5 to $10 (amount private practices receive). CONCLUSIONS AND RELEVANCE: Key factors that contributed to the sustainability and success of an SLIV program are: targeting privately insured children and reducing administration cost through volunteers. Counties with a high proportion of VFC eligible children may not be sustainable without subsidies at $5 Medicaid reimbursement.

Added value of experts' knowledge to improve a quantitative microbial exposure assessment model--Application to aseptic-UHT food products.

In a previous study, a quantitative microbial exposure assessment (QMEA) model applied to an aseptic-UHT food process was developed [Pujol, L., Albert, I., Magras, C., Johnson, N. B., Membré, J. M. Probabilistic exposure assessment model to estimate aseptic UHT product failure rate. 2015 International Journal of Food Microbiology. 192, 124-141]. It quantified Sterility Failure Rate (SFR) associated with Bacillus cereus and Geobacillus stearothermophilus per process module (nine modules in total from raw material reception to end-product storage). Previously, the probabilistic model inputs were set by experts (using knowledge and in-house data). However, only the variability dimension was taken into account. The model was then improved using expert elicitation knowledge in two ways. First, the model was refined by adding the uncertainty dimension to the probabilistic inputs, enabling to set a second order Monte Carlo analysis. The eight following inputs, and their impact on SFR, are presented in detail in this present study: D-value for each bacteria of interest (B. cereus and G. stearothermophilus) associated with the inactivation model for the UHT treatment step, i.e., two inputs; log reduction (decimal reduction) number associated with the inactivation model for the packaging sterilization step for each bacterium and each part of the packaging (product container and sealing component), i.e., four inputs; and bacterial spore air load of the aseptic tank and the filler cabinet rooms, i.e., two inputs. Second, the model was improved by leveraging expert knowledge to develop further the existing model. The proportion of bacteria in the product which settled on surface of pipes (between the UHT treatment and the aseptic tank on one hand, and between the aseptic tank and the filler cabinet on the other hand) leading to a possible biofilm formation for each bacterium, was better characterized. It was modeled as a function of the hygienic design level of the aseptic-UHT line: the experts provided the model structure and most of the model parameters values. Mean of SFR was estimated to 10×10(-8) (95% Confidence Interval=[0×10(-8); 350×10(-8)]) and 570×10(-8) (95% CI=[380×10(-8); 820×10(-8)]) for B. cereus and G. stearothermophilus, respectively. These estimations were more accurate (since the confidence interval was provided) than those given by the model with only variability (for which the estimates were 15×10(-8) and 580×10(-8) for B. cereus and G. stearothermophilus, respectively). The updated model outputs were also compared with those obtained when inputs were described by a generic distribution, without specific information related to the case-study. Results showed that using a generic distribution can lead to unrealistic estimations (e.g., 3,181,000 product units contaminated by G. stearothermophilus among 10(8) product units produced) and emphasized the added value of eliciting information from experts from the relevant specialist field knowledge.

Estimation and evaluation of management options to control and/or reduce the risk of not complying with commercial sterility.

In a previous study, a modular process risk model, from the raw material reception to the final product storage, was built to estimate the risk of a UHT-aseptic line of not complying with commercial sterility (Pujol et al., 2015). This present study was focused on demonstrating how the model (updated version with uncertainty and variability separated and 2(nd) order Monte Carlo procedure run) could be used to assess quantitatively the influence of management options. This assessment was done in three steps: pinpoint which process step had the highest influence on the risk, identify which management option(s) could be the most effective to control and/or reduce the risk, and finally evaluate quantitatively the influence of changing process setting(s) on the risk. For Bacillus cereus, it was identified that during post-process storage in an aseptic tank, there was potentially an air re-contamination due to filter efficiency loss (efficiency loss due to successive in-place sterilizations after cleaning operations), followed by B. cereus growth. Two options were then evaluated: i) reducing by one fifth of the number of filter sterilizations before renewing the filters, ii) designing new UHT-aseptic lines without an aseptic tank, i.e. without a storage period after the thermal process and before filling. Considering the uncertainty in the model, it was not possible to confirm whether these options had a significant influence on the risk associated with B. cereus. On the other hand, for Geobacillus stearothermophilus, combinations of heat-treatment time and temperature enabling the control or reduction in risk by a factor of ca. 100 were determined; for ease of operational implementation, they were presented graphically in the form of iso-risk curves. For instance, it was established that a heat treatment of 138°C for 31s (instead of 138°C for 25s) enabled a reduction in risk to 18×10(-8) (95% CI=[10; 34]×10(-8)), instead of 578×10(-8) (95% CI=[429; 754]×10(-8)) initially. In conclusion, a modular risk model, as the one exemplified here with a UHT-aseptic line, is a valuable tool in process design and operation, bringing definitive quantitative elements into the decision making process.