This study was done to develop a method to inactivate Escherichia coli O157H7 on radish and cabbage seeds using simultaneous treatments with gaseous chlorine dioxide (ClO2) and heat at high relative humidity (RH) without decreasing seeds’ viability. Gaseous ClO2 was spontaneously vaporized from a solution containing hydrochloric acid (HCl, 1 N) and sodium chlorite (NaClO2, 100,000 ppm). Using a sealed container (1.8 L), an equation (y = 5687×, R2 = 0.9948) based on the amount of gaseous ClO2 generated from HCl-NaClO2 solution at 60 °C and 85% RH was developed. When radish or cabbage seeds were exposed to gaseous ClO2 at concentrations up to 3,000 ppm for 120 min, germination rates did not significantly decrease (P > 0.05). When seeds inoculated with E. coli O157H7 were treated with 2,000 or 3,000 ppm of gaseous ClO2 in an atmosphere with 85% RH at 60 °C, populations (6.8-6.9 log CFU/g) on both types of seeds were decreased to below the detection limit for enrichment (-0.5 log CFU/g) within 90 min. This study provides useful information for developing a decontamination method to control E. coli O157H7 and perhaps other foodborne pathogens on plant seeds by simultaneous treatment with gaseous ClO2 and heat at high RH.The effectiveness of three novel „host defence peptides” identified in human Apolipoprotein B (ApoB) as novel antimicrobial and antibiofilm agents to be employed in food industry is reported. ApoB-derived peptides have been found to exert significant antimicrobial effects towards Salmonella typhimurium ATCC® 14028 and Salmonella enteritidis 706 RIVM strains. Furthermore, they have been found to retain antimicrobial activity under experimental conditions selected to simulate those occurring during food storage, transportation and heat treatment, and have been found to be endowed with antibiofilm properties. Based on these findings, to evaluate the applicability of ApoB-derived peptides as food biopreservatives, coating solutions composed by chitosan (CH) and an ApoB-derived peptide have been prepared and found to be able to prevent Salmonella cells attachment to different kinds of surfaces employed in food industry. Finally, obtained coating solution has been demonstrated to hinder microbial proliferation in chicken meat samples. Altogether, obtained findings indicate that ApoB-derived peptides are promising candidates as novel biopreservatives for food packaging.Tibetan kefir grains (TKG) are multi-functional starter cultures used in foods and have been applied in various fermentation systems. This study aimed to investigate the microbial community composition of TKG, the detoxification abilities of TKG and their isolates towards common mycotoxins, and the potential for applying TKG and their associated microbial populations to avoid mycotoxin contamination in dairy products. Cultivation-independent high-throughput sequencing of bacterial and fungal rDNA genes indicated that Lactobacillus kefiranofaciens and Kazachstania turicensis were the most abundant bacterial and fungal taxa, respectively. In addition, 27 total isolates were obtained using cultivation methods. TKG removed more than 90% of the Ochratoxin A (OTA) after 24 h, while the isolate Kazachstania unisporus AC-2 exhibited the highest removal capacity (~46.1%). Further, the isolate exhibited good resistance to acid and bile salts environment. Analysis of the OTA detoxification mechanism revealed that both adsorption and degradation activities were exhibited by TKG, with adsorption playing a major detoxification role. Furthermore, the addition of OTA did not affect the microbial community structure of TKG. These results indicate that TKG-fermented products can naturally remove mycotoxin contamination of milk and could potentially be practically applied as probiotics in fermentation products.The FDA Produce Safety Rule states that water used for irrigation purposes, likely to come into contact with the edible portion of fruit and vegetables, must not exceed a defined limit of Escherichia coli populations. Although aquaponics has not been included in this guideline, it is worth investigating to establish a baseline for facilities to reference in produce production. Two microbial assays were performed, one a decoupled media-based aquaponics system over one year and another on a decoupled nutrient film technique (NFT) aquaponics system over 16 days. Water was sampled from each system over time to analyze changes of E. coli and coliforms. The geometric mean (GM) and statistical threshold variable (STV) were calculated based on E. coli populations from the irrigation source in each system. From the first experiment, it was determined, based on the FDA Produce Safety Rule, that E. coli must be monitored more closely from June to January as they were above the advised limit. The second experiment determined that E. coli and coliforms in the water significantly decreased over 16 days. Water should be held for 8 d and up to 16 d to reduce the likelihood of foodborne pathogens to contaminate produce.A quantitative microbial risk assessment (QMRA) model predicting the listeriosis risk related to the consumption of Ready- To- Eat (RTE) cooked meat products sliced at retail stores in Greece was developed. The probability of illness per serving assessed for 87 products available in the Greek market was found highly related to the nitrite concentration; products having a lower concentration showed a higher risk per serving. The predicted 95th percentiles of the annual listeriosis cases totaled 33 of which 13 cases were less then 65 years old and 20 cases ≥65 years old. The highest number of cases was predicted for mortadella, smoked turkey, boiled turkey and parizer, which were the most frequently consumed product categories. Two scenarios for assessing potential interventions to reduce the risk were tested setting a use-by date of 14 days (these products have no use-by date based on current European Union legislation) and improving the temperature control during domestic storage. The two scenarios resulted in a decrease of the 95th and 99th percentiles of the total annual cases by 97% and 88%, respectively.Toxoplasma gondii infection can result in toxoplasmosis and potential psychological effects. Research commonly focuses on infection through contact with cat fecal matter or consumption of contaminated meat. However, T. gondii oocysts can persist in the environment for years and may be present in soils and on soil-grown produce. Rates of oocyst DNA recovery from produce were high, with 18% of vegetable samples testing positive for T. gondii via PCR test and melt curve analysis. Radishes had significantly higher oocyst counts than arugula, collard greens, kale, lettuce, and spinach. There were no significant differences in oocyst detection rates between samples taken from organic farmer’s markets and conventional grocery stores. This study demonstrates that these oocysts can transfer to produce grown both conventionally and using organic techniques.Postharvest treatments with sanitizers and fungicides are applied to increase the quality, safety and shelf life of fresh produce including cantaloupes (also known as rockmelons). The primary role of sanitizers during cantaloupe washing is to prevent cross contamination of potentially pathogenic bacteria in washwater. Postharvest fungicide sprays or dips are employed to inhibit spoilage-causing fungi. While assessing the compatibility of these antimicrobials based on the measurement of active ingredients levels provides some indication of antimicrobial capacity, there is limited data on whether the interaction between these chemicals in wash water modifies their overall efficacy against relevant microorganisms. The aim of this research was to determine how chlorine- and peroxyacetic acid-based sanitizers interact with commercial guazatine- and imazalil-based fungicide formulations used on cantaloupes, and whether mixing these augments or suppresses anti-microbial activity against relevant human pathogens and spoilage fungi in wash water. The results were unpredictable while most combinations were antimicrobial, the chlorine-based sanitizer when mixed with the guazatine-based fungicide had significantly reduced efficacy against pathogenic Salmonella spp. (~2.7 log) and the fungal spoilage organisms, Trichothecium roseum and Rhizopus stolonifera. Mixing the chlorine-based sanitizer with an imazalil-based fungicide produced a range of outcomes with antagonistic, indifferent and synergistic interactions observed for the fungal species tested. The peroxyacetic acid-based sanitizer led to indifferent interactions with the guazatine-based fungicide, while antagonism and synergy were observed when mixed with the imazalil-based fungicide. This study demonstrates that mixing postharvest agrichemicals used in the cantaloupe industry may increase the risk of microbial contamination and thereby potentially compromise food safety and quality.Genomic diversity of Listeria monocytogenes isolates from the deboning and slicing areas of three dry-cured ham processing plants was analysed. L. monocytogenes was detected in 58 out of 491 samples from the environment and equipment surfaces, all from the deboning area, with differences in prevalence among facilities. The most frequent PCR-serogroup was IIa (74.1%) followed by IIb and IIc, and only one isolate was serogroup IVb. Twenty different pulsotypes and 11 sequence types (STs) grouped into 10 clonal complexes (CCs) were determined. ST121 (CC121) and ST9 (CC9) were the most abundant. Premature stop codons (PMSC6 and PMSC19) associated with attenuated virulence were found in the inlA sequence in 7 out of 12 selected strains. CC121 strains were strong biofilm formers and some harboured the transposon Tn6188, related with increased tolerance to quaternary ammonium compounds. L. monocytogenes clones considered hypovirulent resulted predominant in the deboning areas. The clonal structure and potential virulence of the isolates could help to establish adequate control measures and cleaning protocols for the comprehensive elimination of the pathogen in dry-cured ham processing environment.The use of non-Saccharomyces yeast together with S. cerevisiae in winemaking is a current trend. Apart from the organoleptic modulation of the wine, the composition of the resulting yeast lees is different and may thus impact malolactic fermentation (MLF). Yeasts of Saccharomyces cerevisiae, Torulaspora delbrueckii and Metschnikowia pulcherrima were inactivated and added to a synthetic wine. Three different strains of Oenococcus oeni were inoculated and MLF was monitored. Non-Saccharomyces lees, especially from some strains of T. delbrueckii, showed higher compatibility with some O. oeni strains, with a shorter MLF and a maintained bacterial cell viability. The supplementation of lees increased nitrogen compounds available by O. oeni. A lower mannoprotein consumption was related with longer MLF. Amino acid assimilation by O. oeni was strain specific. There may be many other compounds regulating these yeast lees-O. oeni interactions apart from the well-known mannoproteins and amino acids. This is the first study of MLF with different O. oeni strains in the presence of S. cerevisiae and non-Saccharomyces yeast lees to report a strain-specific interaction between them.Photobacterium spp. occur frequently in marine environments but have been recently also found as common spoilers on chilled meats. The environmental conditions in these ecological niches differ especially regarding salinity and ambient pressure. Linking the occurrence of photobacteria in different niches may elucidate its ecology and bring insights for the food industry. We investigated tolerance of Photobacterium (P.) phosphoreum and P. carnosum strains to high hydrostatic pressure and salinity and aligned our observations with presence of relevant genes. The strains were isolated from packaged meats and salmon (or the sea) to identify adaptations to marine and terrestrial habitats. Growth of all P. carnosum strains was reduced by 40 MPa hydrostatic pressure and >3% sodium chloride, suggesting loss of traits associated with marine habitats. In contrast, P. phosphoreum strains were only slightly affected, suggesting general adaptation to marine habitats. In accordance, these strains had gene clusters associated with marine niches, e.g. flagellar and lux-operons, being incomplete in P. carnosum. Occurrence of P. carnosum strains on packaged salmon and P. phosphoreum strains on meats therefore likely results from cross-contamination in meat and fish processing. Still, these strains showed intermediate traits regarding pressure- and halotolerance, suggesting developing adaptation to their respective environment.

The question of whether additional dimensions should be added to the EQ-5D, so-called bolt-ons, has been researched since the 1990s. Several candidate bolt-ons have been tested. The aim of this systematic review was to provide an overview of EQ-5D bolt-on studies, including the origin of possible suitable bolt-ons, their format, and methods that were used to examine their value.

Studies were identified through database search and reference screening and assessed based on a set of inclusion criteria. All studies that investigated bolt-ons for the EQ-5D were eligible for inclusion. Two reviewers independently extracted information from all included studies on objectives, study design, EQ-5D version used, the investigated bolt-ons, methods used to achieve objectives, and outcomes.

Of 308 initially identified studies, 28 studies met the inclusion criteria. Of these studies, 3 identified potentially suitable bolt-on dimensions, 13 investigated the psychometric performance of EQ-5D+ bolt-on(s), and 6 investig making on whether or not to implement a bolt-on dimension to the EQ-5D.

The main objective of this review was to map how decision analytic models are used in surgical innovation (in which research phase, with what aim) and to understand how challenges related to the assessment of surgical interventions are incorporated.

We systematically searched PubMed, Embase, and the Cochrane Library for studies published in 2018. We included original articles using a decision analytic model to compare surgical strategies. We included modeling studies of surgical innovations. General, innovation, and modeling characteristics were extracted, as were outcomes, recommendations, and handling of challenges related to the assessment of surgical interventions (learning curve, incremental innovation, dynamic pricing, quality variation, organizational impact).

We included 46 studies. The number of studies increased with each research phase, from 4% (n= 2) in the preclinical phase to 40% (n= 20) in phase 3 studies. Eighty-one studies were excluded because they investigated established surgical pros still largely overlooked in surgery; therefore, the opportunity to inform research and development may not be optimally used.

The mapping technique can estimate generic preference-based measure scores through a specific measure that cannot be used in economic evaluations. This study compared 2 response mapping methods to estimate EQ-5D-5L scores using the Western Ontario McMaster Universities Osteoarthritis (WOMAC).

The sample consisted of 758 patients with the hip or knee osteoarthritis recruited in baseline. Bayesian networks (BN) and multinomial logistic regression (ML) were used as response mapping models. Predictions were obtained using the 6-month follow-up as a validation sample. The mean absolute error, mean squared error, deviation from the root mean squared error and intraclass correlation coefficient were calculated as precision measures.

There was 5.5% of missing data, which was removed. The mean age was 69.6 years (standard deviation= 10.5), with 61.6% of women. The BN model presented lower mean absolute error, mean squared error, root mean squared error and higher intraclass correlation coefficient than the ML model. Only the WOMAC items pain and physical function items were related with the EQ-5D-5L dimensions.

BN response mapping models are more robust methods, with better prediction results, than ML models. The BN model also provided a graphic representation of the dependency relationships between the EQ-5D-5L dimensions and the different WOMAC items that could be useful in the clinical investigation of patients with hip or knee osteoarthritis.

BN response mapping models are more robust methods, with better prediction results, than ML models. The BN model also provided a graphic representation of the dependency relationships between the EQ-5D-5L dimensions and the different WOMAC items that could be useful in the clinical investigation of patients with hip or knee osteoarthritis.

To develop a cancer-specific multi-attribute utility instrument derived from the Functional Assessment of Cancer Therapy – General (FACT-G) health-related quality of life (HRQL) questionnaire.

We derived a descriptive system based on a subset of the 27-item FACT-G. Item selection was informed by psychometric analyses of existing FACT-G data (n= 6912) and by patient input (n= 82). We then conducted an online valuation survey, with participants recruited via an Australian general population online panel. A discrete choice experiment (DCE) was used, with attributes being the HRQL dimensions of the descriptive system and survival duration, and 16 choice-pairs per participant. Utility decrements were estimated with conditional logit and mixed logit modeling.

Eight HRQL dimensions were included in the descriptive system pain, fatigue, nausea, sleep, work, social support, sadness, and future health worry; each with 5 levels. Of 1737 panel members who accessed the valuation survey, 1644 (95%) completed 1 or morte cost-utility analyses based on items from the FACT-G and related FACIT questionnaires containing FACT-G items.

To compare the ex ante willingness to pay (WTP) of healthy individuals for generous insurance coverage of novel lung cancer treatments to the WTP for coverage of such treatment among individuals with lung cancer.

A survey was administered to 2 cohorts of US adults (1) healthy individuals without cancer and (2) individuals diagnosed with lung cancer. A multiple random staircase survey design was used to elicit respondent WTP for coverage of novel lung cancer therapy associated with survival gains.

Of the 84 937 healthy individuals invited, 300 completed the survey. Of the 36 249 in the lung cancer cohort invited, 250 completed the survey. Mean age by cohort was 50.0 (SD 14.6) and 48.4 (SD 16.8) years, and 55.2% and 47.2% were female, respectively. Respondents in the healthy and lung cancer cohorts were willing to pay $97.52 (95% confidence interval (CI) $89.89-$105.15) and $22 304 (95% CI $20 194-$24 414) per month, respectively, for coverage of a novel therapy providing 5-year survival of 15% versus standard-of-care therapy with a 5-year survival of 4%. After accounting for the likelihood that healthy individuals are diagnosed with lung cancer in the future, we estimated that 89.8% of the total value of new lung cancer treatments comes from the WTP healthy individuals place on generous insurance coverage.

Total societal willingness to pay for lung cancer is much higher than conventionally thought, as most healthy individuals are risk-averse and highly value having lung cancer treatments available to them in the future.

Total societal willingness to pay for lung cancer is much higher than conventionally thought, as most healthy individuals are risk-averse and highly value having lung cancer treatments available to them in the future.

Health-related quality of life (HRQOL) is a complicated concept that can be measured using multiple health items. Although HRQOL is closely associated with people’s subjective assessment of their own health, a limited number of studies have investigated which health items are considered most important and relevant by the general population. Even fewer empirical studies have investigated how HRQOL is understood in non-Western populations. This study used multidimensional unfolding analysis in a Chinese general population to explore the constructs of HRQOL.

A scoping review of Chinese generic HRQOL measures and a series of qualitative interviews produced a list of 42 potentially important health items in a Chinese cultural setting; 110 Chinese participants in face-to-face interviews ranked the health items from most important to least important. Responses were coded into a rectangular 110× 42 matrix, and multidimensional unfolding was conducted to analyze participants’ preferences for health items.

It was HRQOL in other general populations.

To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies.

We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation (1) capping annual costs in the comparator arm at $150 000 per year; (2) „sharing” the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Hospital-acquired infections (HAIs) place a substantial burden on health systems. Tools are required to quantify the change in this burden as a result of a preventive intervention. We aim to estimate how much a reduction in the rate of hospital-acquired infections translates into a change in hospital mortality and length of stay.

Using multistate modelling and competing risks methodology, we created a tool to estimate the reduction in burden after the introduction of a preventive effect on the infection rate. The tool requires as inputs the patients’ length of hospital stay, patients’ infection information (status, time), patients’ final outcome (discharged alive, dead), and a preventive effect. We demonstrated the methods on both simulated data and 3 published data sets from Germany, France, and Spain.

A hypothetical prevention that cuts the infection rate in half would result in 21 lives and 2212 patient-days saved in French ventilator-associated pneumonia data, 61 lives and 3125 patient-days saved in Spanish nosocomial infection data, and 20 lives and 1585 patient-days saved in German nosocomial pneumonia data.

Our tool provides a quick and easy means of acquiring an impression of the impact a preventive measure would have on the burden of an infection. The tool requires quantities routinely collected and computation can be done with a calculator. R code is provided for researchers to determine the burden in various settings with various effects. Furthermore, cost data can be used to get the financial benefit of the reduction in burden.

Our tool provides a quick and easy means of acquiring an impression of the impact a preventive measure would have on the burden of an infection. The tool requires quantities routinely collected and computation can be done with a calculator. R code is provided for researchers to determine the burden in various settings with various effects. Furthermore, cost data can be used to get the financial benefit of the reduction in burden.

Unblinded trials are common in oncology, but patient knowledge of treatment assignment may bias response to questionnaires. We sought to ascertain the extent of possible bias arising from patient knowledge of treatment assignment.

This is a retrospective analysis of data from 2 randomized trials in multiple myeloma, 1 double-blind and 1 open label. We compared changes in patient reports of symptoms, function, and health status from prerandomization (screening) to baseline (pretreatment but postrandomization) across control and investigational arms in the 2 trials. Changes from prerandomization scores at ~2 and 6 months on treatment were evaluated only across control arms to avoid comparisons between 2 different experimental drugs. All scores were on 0- to 100-point scales. Inverse probability weighting, entropy balancing, and multiple imputation using propensity score splines were used to compare score changes across similar groups of patients.

Minimal changes from screening were seen at baseline in all arms. In the control arm, mean changes of <7 points were seen for all domains at 2 and 6 months. The effect of unblinding at 6 months in social function was a decline of less than 6 points (weighting-3.09; 95% confidence interval-8.41 to 2.23; balancing-4.55; 95% confidence interval-9.86 to 0.76; imputation-5.34; 95% confidence interval-10.64 to-0.04).

In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.

In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.Health technology assessment agencies often prefer that utilities used to calculate quality-adjusted life years in cost-utility analyses (CUAs) are derived using standardized methods, such as generic preference-based measures completed by patients in clinical trials. However, there are situations when no standardized approach is feasible or appropriate for a specific medical condition or treatment that must be represented in a CUA. When this occurs, vignette-based methods are often used to estimate utilities. A vignette (sometimes called a „scenario,” „health state description,” „health state vignette,” or „health state”) is a description of a health state that is valued in a preference elicitation task to obtain a utility estimate. This method is sometimes the only feasible way to estimate utilities representing a concept that is important for a CUA. Consequently, vignette-based studies continue to be conducted and published, with the resulting utilities used in economic models to inform decision making about healthcare resource allocation. Despite the potential impact of vignette-based utilities on medical decision making, there is no published guidance or review of this methodology. This article provides recommendations for researchers, health technology assessment reviewers, and policymakers who may be deciding whether to use vignette-based methods, designing a vignette study, using vignette-based utilities in a CUA, or evaluating a CUA that includes vignette-based utilities. Recommendations are provided on (A) when to use vignette-based utilities, (B) methods for developing vignettes, (C) valuing vignettes, (D) use of vignette-based utilities in models, and (E) limitations of vignette methods.

In the United States, brand-name prescription drugs remain expensive until market exclusivity ends and lower-cost generics become available. Delayed generic drug uptake may increase spending and worsen medication adherence and patient outcomes. We assessed recent trends and factors associated with generic uptake.

Among 227 drugs facing new generic competition from 2012 to 2017, we used a national claims database to measure generic uptake in the first and second year after generic entry, defined as the proportion of claims for a generic version of the drug. Using linear regression, we evaluated associations between generic uptake and key drug characteristics.

Mean generic uptake was 66.1% (standard deviation 22.1%) in the first year and 82.7% (standard deviation 21.6%) in the second year after generic entry. From 2012 to 2017 generic uptake decreased 4.3% per year in the first year (95% confidence interval, 2.8%-5.8%, P < .001) and 3.2%/year in the second year (95% confidence interval, 1.2%-5.1%). Generic uptake was lower for injected than oral drugs in the first year (38.5% vs 70.0%, P < .001) and second year (50.3% vs 86.9%, P < .001). In the second year, generic uptake was higher among drugs with an authorized generic (86.1 vs 80.1%, P= .045) and those with ≥3 generic competitors (87.7% vs 78.6%, P= .055).

Early generic uptake decreased over the past several years. This trend may adversely affect patients and increase prescription drug spending. Policies are needed to encourage generic competition, particularly among injected drugs administered in a hospital or clinic setting.

Early generic uptake decreased over the past several years. This trend may adversely affect patients and increase prescription drug spending. Policies are needed to encourage generic competition, particularly among injected drugs administered in a hospital or clinic setting.

To experiment with new approaches of collaboration in healthcare delivery, local authorities implement new models of care. Regarding the local decision context of these models, multi-criteria decision analysis (MCDA) may be of added value to cost-utility analysis (CUA), because it covers a wider range of outcomes. This study compares the 2 methods using a side-by-side application.

A new Dutch model of care, Primary Care Plus (PC+), was used as a case study to compare the results of CUA and MCDA. Data of patients referred to PC+ or care-as-usual were retrieved by questionnaires and administrative databases with a 3-month follow-up. Propensity score matching together with generalized linear regression models was used to reduce confounding. Univariate and probabilistic sensitivity analyses were performed to explore uncertainty in the results.

Although both methods indicated PC+ as the dominant alternative, complementary differences were observed. MCDA provided additional evidence that PC+ improved access to care (standardized performance score of 0.742 vs 0.670) and that improvement in health-related quality of life was driven by the psychological well-being component (standardized performance score of 0.710 vs 0.704). Furthermore, MCDA estimated the budget required for PC+ to be affordable in addition to preferable (€521.42 per patient). Additionally, MCDA was less sensitive to the utility measures used.

MCDA may facilitate an auditable and transparent evaluation of new models of care by providing additional information on a wider range of outcomes and incorporating affordability. However, more effort is needed to increase the usability of MCDA among local decision makers.

MCDA may facilitate an auditable and transparent evaluation of new models of care by providing additional information on a wider range of outcomes and incorporating affordability. However, more effort is needed to increase the usability of MCDA among local decision makers.

The Institute for Clinical and Economic Review (ICER) is an independent organization that reviews drugs and devices with a focus on emerging agents. As part of their evaluation, ICER estimates value-based prices (VBP) at $50 000 to $150 000 per quality-adjusted life-year (QALY) gained thresholds. We compared actual estimated net prices to ICER-estimated VBPs.

We reviewed ICER final evidence reports from November 2007 to October 2020. List prices were combined with average discounts obtained from SSR Health to estimate net prices. If a drug had been evaluated more than once for the same indication, only the more recent VBP was included.

A total of 34 ICER reports provided unique VBPs for 102 drugs. The net price of 81% of drugs exceeded the $100 000 per QALY VBP and 71% exceeded the $150 000 per QALY VBP. The median change in net price needed to reach the $150 000 per QALY VBP was a 36% reduction. The median decrease in net price needed was highest for drugs targeting rare inherited disorders (n= 15; 62%) and lowest for cardiometabolic disorders (n= 6; 162% price increase). The reduction in net prices needed to reach ICER-estimated VBPs was higher for drugs evaluated for the first approved indication, rare diseases, less competitive markets, and if the drug approval occurred before the ICER report became available.

Net prices are often above VBPs estimated by ICER. Although gaining awareness among decision makers, the long-term impact of ICER evaluations on pricing and access to new drugs continues to evolve.

Net prices are often above VBPs estimated by ICER. Although gaining awareness among decision makers, the long-term impact of ICER evaluations on pricing and access to new drugs continues to evolve.

Smoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom.

An established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self- United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.

Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective.

Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups Age 70, 80, 90× Nodal status FALSE (F), TRUE (T)× Comorbidity score 0, 1, 2, 3+.

For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3).

From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life.

From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life.

Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios.

An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored.

The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000.

Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.Marine macroalgae, the main primary producers in coastal waters, play important roles in the fishery industry and global carbon cycles. With progressive ocean global changes, however, they are increasingly exposed to enhanced levels of multiple environmental drivers, such as ocean acidification, warming, heatwaves, UV radiation and deoxygenation. While most macroalgae have developed physiological strategies against variations of these drivers, their eco-physiological responses to each or combinations of the drivers differ spatiotemporally and species-specifically. Many freshwater macroalgae are tolerant of pH drop and its diel fluctuations and capable of acclimating to changes in carbonate chemistry. However, calcifying species, such as coralline algae, are very sensitive to acidification of seawater, which reduces their calcification, and additionally, temperature rise and UV further decrease their physiological performance. Except for these calcifying species, both economically important and harmful macroaled on the combined effects of elevated CO2, temperature or heatwaves with UV radiation, exposures to heatwaves during midday under high levels of UV radiation can be detrimental to most species, especially to their microscopic stages which are less tolerant of climate change induced stress. In parallel, reduced availability of dissolved O2 in coastal water along with eutrophication might favour the macroalgae’s carboxylation process by suppressing their oxygenation or photorespiration. In this review, we analyse effects of climate change-relevant drivers individually and/or jointly on different macroalgal groups and different life cycle stages based on the literatures surveyed, and provide perspectives for future studies.Skipjack (Katsuwonus pelamis), yellowfin (Thunnus albacares) and bigeye (Thunnus obesus) tuna are the target species of tropical tuna fisheries in the Indian Ocean, with high commercial value in the international market. High fishing pressure over the past three decades has raised concerns about their sustainability. Understanding life history strategies and stock structure is essential to determine species resilience and how they might respond to exploitation. Here we provide a comprehensive review of available knowledge on the biology, ecology, and stock structure of tropical tuna species in the Indian Ocean. We describe the characteristics of Indian Ocean tropical tuna fisheries and synthesize skipjack, yellowfin, and bigeye tuna key life history attributes such as biogeography, trophic ecology, growth, and reproductive biology. In addition, we evaluate the available literature about their stock structure using different approaches such as analysis of fisheries data, genetic markers, otolith microchemistry and tagging, among others. Based on this review, we conclude that there is a clear lack of ocean basin-scale studies on skipjack, yellowfin and bigeye tuna life history, and that regional stock structure studies indicate that the panmictic population assumption of these stocks should be investigated further. Finally, we identify specific knowledge gaps that should be addressed with priority to ensure a sustainable and effective management of these species.Ocean sciences comprise a vast array of disciplines ranging from physics to socio-economics. The various approaches compete with each other for visibility, rather than cooperate and join forces. Communication beyond the science journals tends to focus on charismatic species and habitats (the ohhh tactics, aimed at provoking wonder) that does not result in the full perception (the ahhh strategy) of the role of ocean sciences for our well-being. Furthermore, natural sciences fail to establish the logical primacy of natural laws over social and economic laws, even though society and the economy cannot exist without the rest of the environment. Sustainability is universally recognized as a stringent priority, but it gives prevalence to economic and social values, relegating natural phenomena to a secondary role natural assets are evaluated with measures of economics (in monetary terms) giving primacy to economic laws over ecological laws. The solution to these problems resides in the cultural evolution of that part of the scientific community that recognizes the necessity of evolving from reductionistic tactics to a holistic strategy, with a timely integration of ocean sciences and technologies and of their collaboration with social and economic sciences.The fossil record shows that the two clavagelloid or watering pot families evolved at different times, the Clavagellidae first in the late Mesozoic (100-66mya), the Penicillidae later in the Cenozoic (33-23mya)-the former originally with, thus, a near-global Tethyan distribution, the latter restricted to the Indo-West Pacific. Representatives of the two clavagelloid families, moreover, have wholly different adventitious tube/crypt structures and, thus, methods of formation suggesting that evolutionary experiments have been undertaken to achieve such radical architectural novelties. This has resulted in one of the most surprising examples of convergent evolution in the Bivalvia. But, what were the ancestors of the Clavagelloidea? The shell and internal morphology of representatives of the three recognized genera of the Lyonsiidae, that is, Lyonsia, Entodesma and Mytilimeria, are described. Species of the latter two genera are highly specialized epibenthic, byssate, nestlers and embedded symbionts of ascidian colonies and sponges, respectively. Species of Lyonsia, however, are mostly shallow endobenthic burrowers. On the basis of these studies, it is concluded that species of Lyonsia can be regarded as representative of the ancestral watering pot (Clavagelloidea) condition. Evidence for this conclusion include the mineralogy, characteristics and ligament structure of the shell and features of the anatomy, importantly the modification of the vestigial pedal retractor muscles to form simple (Clavagellidae) and more complex (Penicillidae) proprioreceptors. Such an anatomy-based conclusion is supported to some extent by DNA analyses of representatives of the Lyonsiidae and the two constituent families of the Clavagelloidea. To some extent because all clavagelloids are exceedingly rare hindering such analyses. Such rarity, however, also argues for the strict conservation of all the species of the Clavagelloidea.Familial hypercholesterolaemia is a common, dominantly inherited disease that results in high concentrations of low-density lipoprotein cholesterol and in premature cardiovascular disease. To prevent cardiovascular disease and premature mortality, patients with the condition need to be identified and to start treatment early in life. In this Review, we discuss the treatment of heterozygous and homozygous familial hypercholesterolaemia in children, including lifestyle modifications, current pharmacological treatment options, and promising novel lipid-lowering treatments. In particular, these new therapies are expected to improve outcomes for patients with severe heterozygous familial hypercholesterolaemia or statin intolerance. For patients with homozygous familial hypercholesterolaemia, lipoprotein apheresis is currently the most valuable therapy available, but new approaches might reduce the need for this effective yet invasive, time-consuming, and expensive treatment.

COVID-19 is usually less severe and has lower case fatality in children than in adults. We aimed to characterise the clinical features of children and adolescents hospitalised with laboratory-confirmed SARS-CoV-2 infection and to evaluate the risk factors for COVID-19-related death in this population.

We did an analysis of all patients younger than 20 years who had quantitative RT-PCR-confirmed COVID-19 and were registered in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe, a nationwide surveillance database of patients admitted to hospital with severe acute respiratory disease in Brazil), between Feb 16, 2020, and Jan 9, 2021. The primary outcome was time to recovery (discharge) or in-hospital death, evaluated by competing risks analysis using the cumulative incidence function.

Of the 82 055 patients younger than 20 years reported to SIVEP-Gripe during the study period, 11 613 (14·2%) had available data showing laboratory-confirmed SARS-CoV-2 infection and were included in thSoutheast region; and those with one (2·96 [2·52-3·47]), two (4·96 [3·80-6·48]), or three or more (7·28 [4·56-11·6]) pre-existing medical conditions relative to those with none.

Death from COVID-19 was associated with age, Indigenous ethnicity, poor geopolitical region, and pre-existing medical conditions. Disparities in health care, poverty, and comorbidities can contribute to magnifying the burden of COVID-19 in more vulnerable and socioeconomically disadvantaged children and adolescents in Brazil.

National Council for Scientific and Technological Development, Research Support Foundation of Minas Gerais.

National Council for Scientific and Technological Development, Research Support Foundation of Minas Gerais.In this work, a new gas chromatography-high-resolution mass spectrometry (GC-HRMS) method based on atmospheric pressure photoionisation (APPI) has been developed for the accurate determination of short-chain chlorinated paraffins (SCCPs) as a reliable alternative to the established methods. To the best of our knowledge, this is the first time these compounds has been analysed by GC-MS using atmospheric pressure photoionisation (APPI). Efficient ionisation of SCCPs was achieved using the new GC-APPI source by the formation of [M+Cl]- adduct ions in negative ion mode using dopant-assisted APPI with a mixture of acetone/CCl4 (31, v/v). Operating at a resolution of 70,000 FWHM (full width at half maximum) and monitoring the [M+Cl]- adduct ions for each congener group, a selective determination of the SCCPs was achieved, avoiding isobaric interferences between homologue groups with different carbon chain length and chlorination degree. Moreover, the GC-APPI-HRMS response of each congener group was mainly influenceless then 8%) and can be proposed as a reliable alternative of the established methods for the determination of these pollutants in environmental samples.Measuring enzyme kinetics is of great importance to understand many biological processes and improve biosensing and industrial applications. Conventional methods of measuring enzyme kinetics require to prepare a series of solutions with different substrate concentrations and measure the signal response over time with these solutions, leading to tedious sample preparation steps, high reagents/sample consumption, and difficulties in studying fast enzyme kinetics. Here we report a one-step assay to measure enzyme kinetics using a 3D-printed microfluidic device, which eliminates the steps of preparing and handling multiple solutions thereby simplifying the whole workflow significantly. The assay is enabled by a highly efficient vibrating sharp-tip mixing method that can mix multiple streams of fluids with minimal mixing length (∼300 μm) and time (as low as 3 ms), and a wide range of working flow rates from 1.5 μL/min to 750 μL/min. Owing to the high performance of the mixer, a series of experiments with different substrate concentrations are performed by simply adjusting the flow rates of reagents loaded from three inlets in one experiment run. The Michaelis-Menten kinetics of the horseradish peroxidase (HRP)-catalyzed reaction between H2O2 and amplex red is measured in this system. The calculated Michaelis constant is consistent with the values from literature and conventional analysis methods. Due to the simplicity in fabrication and operation, rapid analysis, low power consumption (1.4-45.0 mW), and high temporal resolution, this method will significantly facilitate enzyme kinetics measurement, and offers great potential for optimizing enzyme based biosensing experiments and probing many biochemical processes.The design of a cheap, simple, and handy sensing system for rapid quantitation of pharmaceuticals becomes mandatory to ease drug development procedures, quality control, health care, etc. This work describes a simple, innovative, and easily manufactured paper-based device using a correction pen as a plotter for hydrophobic/lipophobic barriers and graphene quantum dots for recognition and quantification of the hemostatic drug carbazochrome, via fluorescence turn-off mechanism mediated by the inner filter effect. A smartphone-based all-in-one device fitted with an inexpensive 365 nm flashlight as a UV light source and a free image processing software was developed for rapid and reliable interpretation of the fluorescence change from the paper-based device upon introduction of the drug. The simple and convenient steps permit the analysis of many samples in a very short time. The smartphone-based all-in-one device featured excellent sensitivity for carbazochrome with a limit of detection equals to 12 ng/detection zone and good %recovery (100.