Cost-utility analysis of prenatal diagnosis of congenital cardiac diseases using deep learning.

BACKGROUND: Deep learning (DL) is a new technology that can assist prenatal ultrasound (US) in the detection of congenital heart disease (CHD) at the prenatal stage. Hence, an economic-epidemiologic evaluation (aka Cost-Utility Analysis) is required to assist policymakers in deciding whether to adopt the new technology. METHODS: The incremental cost-utility ratios (CUR), of adding DL assisted ultrasound (DL-US) to the current provision of US plus pulse oximetry (POX), was calculated by building a spreadsheet model that integrated demographic, economic epidemiological, health service utilization, screening performance, survival and lifetime quality of life data based on the standard formula: CUR = Increase in Intervention Costs - Decrease in Treatment costs Averted QALY losses of adding DL to US & POX US screening data were based on real-world operational routine reports (as opposed to research studies). The DL screening cost of 145 USD was based on Israeli US costs plus 20.54 USD for reading and recording screens. RESULTS: The addition of DL assisted US, which is associated with increased sensitivity (95% vs 58.1%), resulted in far fewer undiagnosed infants (16 vs 102 [or 2.9% vs 15.4%] of the 560 and 659 births, respectively). Adoption of DL-US will add 1,204 QALYs. with increased screening costs 22.5 million USD largely offset by decreased treatment costs (20.4 million USD). Therefore, the new DL-US technology is considered "very cost-effective", costing only 1,720 USD per QALY. For most performance combinations (sensitivity > 80%, specificity > 90%), the adoption of DL-US is either cost effective or very cost effective. For specificities greater than 98% (with sensitivities above 94%), DL-US (& POX) is said to "dominate" US (& POX) by providing more QALYs at a lower cost. CONCLUSION: Our exploratory CUA calculations indicate the feasibility of DL-US as being at least cost-effective.

Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors.

Importance: New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing. Objective: To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing. Design, Setting, and Participants: This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022. Exposures: The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks. Main Outcomes and Measures: The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries. Results: In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient. Conclusions and Relevance: This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.

Application of probabilistic methods to address variability and uncertainty in estimating risks for non-cancer health effects.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

Mechanistic Considerations in 1,4-Dioxane Cancer Risk Assessment.

The risk assessment of many carcinogens involves extrapolation across large exposure differences between the dose levels used in animal studies and the much lower human exposures. This is true for 1,4-dioxane which has a consistent liver carcinogenic effect in both genders of rats and mice. These data have been applied to risk assessment assuming a linear low dose extrapolation in some cases but non-linear or threshold models have been used in others. This choice hinges on our understanding of the 1,4-dioxane cancer mechanism. While 1,4-dioxane is not genotoxic in standard test batteries and has non-linear toxicokinetics, the mechanism for its carcinogenic effect remains unknown and is an active area of research. This review summarizes the possible modes of action for this chemical, data gaps and application to risk assessment. We find that the cytotoxicity/hyperplasia and metabolic saturation hypotheses do not explain the carcinogenic response and do not take into account 1,4-dioxane's induction of its own metabolism, leading to less likelihood for saturation during chronic exposure. There is evidence for other mechanisms, especially oxidative stress associated with the induction of CYP2E1 and in vivo genotoxicity that is not seen in vitro. The dose response for these effects needs further exploration compared to the time course and dose response for 1,4-dioxane-induced carcinogenesis. An additional consideration is the manner in which these 1,4-dioxane effects may augment naturally occurring and disease-related processes that contribute to the increasing rate of human liver cancer. These factors add to the rationale for using a non-threshold linear approach for extrapolating to low dose for this carcinogen, which is consistent with the default for carcinogens which do not have a clearly defined mode of action.

Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency.

1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or three months (5000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.

Kratom Adulterated with Phenylethylamine and Associated Intracerebral Hemorrhage: Linking Toxicologists and Public Health Officials to Identify Dangerous Adulterants.

INTRODUCTION: Kratom is derived from the plant Mitragyna speciosa which is indigenous to Southeast Asia. Active compounds, mitragynine and 7-hydroxymitragynine, cause mild stimulant and opioid agonist effects. Although reported to have potential benefits in the treatment of opioid use disorder, efficacy remains uncertain while adverse health effects have been reported. A compounding concern is the presence of adulterants given that this is an unregulated product. CASE DETAILS: A 54-year-old fitness instructor who used an online purchased kratom product regularly for one year developed stimulatory effects and suffered a large hemorrhagic stroke with a close temporal relationship to ingestion of a different kratom product from the one he regularly used. A collaborative investigation by medical toxicologists, a regional poison center, the state public health laboratory, and public health officials determined that his new kratom product was adulterated with phenylethylamine (PEA). DISCUSSION: We report a case of PEA adulterated kratom purchased and used with resultant adverse effects. PEA is structurally similar to amphetamine and is known to produce sympathomimetic effects. It is possible the stimulatory effect of PEA resulted in a marked and transient increase in blood pressure resulting in hemorrhagic stroke. CONCLUSION: Medical toxicologists should form working relationships with laboratories and public health officials to aid in early identification of adulterated products that carry risk to the general population.

New Toxicology Tools and the Emerging Paradigm Shift in Environmental Health Decision-Making.

BACKGROUND: Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge. OBJECTIVES: Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied. METHODS: We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment. DISCUSSION: Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro, in silico, and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745.

E-cigarette, or vaping, product use associated lung injury (EVALI): case series and diagnostic approach.

BACKGROUND: Since June, 2019, more than 1000 new cases of e-cigarette, or vaping, product use associated lung injury (EVALI) have been reported in the USA. Patients presented with dyspnoea, cough, and were found to be hypoxaemic with bilateral airspace opacities on chest imaging. Most patients required management in the intensive care unit and steroid therapy. All patients recovered with cessation of vaping, supportive care, and steroid therapy and remained symptom free at follow up. E-cigarette use continues to rapidly escalate in the USA, particularly among youth. METHODS: Cases were defined as patients admitted to the University of Rochester Medical Center (Rochester, NY, USA) who had used e-cigarettes or another vaping device in the 30 days before presentation, and who had bilateral airspace opacification on chest imaging (CT or x-ray). Case details were obtained via medical record review and patient interviews over the past 3 months including symptomatology, physical exam data, imaging studies, laboratory data, vaping history, and subsequent outpatient follow-up data. In collaboration with the New York State Department of Health, our hospital developed a novel clinical practice algorithm based on statewide physician feedback along with input from experts in environmental health, medical toxicology, infectious disease, epidemiology, and chronic disease prevention. FINDINGS: We report 12 cases treated for suspected EVALI at our medical centre between June 6, 2019, and Sept 15, 2019. Ten (83%) patients had dyspnoea, fever, and emesis and nine (75%) had cough. 11 (92%) patients reported the use of e-cigarette cartridges containing tetrahydrocannabinol oil. Although eight (67%) patients required admission to the intensive care unit for hypoxaemic respiratory failure, no deaths occurred. The median hospitalisation duration was 7 days (IQR 7-8). All patients completing follow up (6 [50%]) had resolution of previous chest CT findings and normal spirometry. The clinical algorithm focuses on the key signs and symptoms of EVALI and the importance of ruling out infection and other cardiopulmonary conditions before making a presumptive diagnosis of EVALI. INTERPRETATION: Patients with suspected EVALI in our cohort had life-threatening hypoxaemia, with 67% requiring management in the intensive care unit. Despite the severity of presentation, similar to previous reports of patients with EVALI, most patients improved within 1-2 weeks of initial presentation after vaping cessation and administration of systemic corticosteroids when needed. Almost all (92%) patients with suspected EVALI reported vaping a THC product, making THC containing e-liquids or oils a key focus on the ongoing nationwide investigations into the cause of EVALI. Additional research is required to understand the potential toxins, underlying pathophysiological mechanisms, and identification of susceptible individuals at higher risk for hospitalisation due to EVALI. To our knowledge we present the first clinical practice algorithm for the evaluation and management of EVALI, which will be useful for both acute management and improved accurate reporting of this life-threatening respiratory illness. FUNDING: None.

Burden of Underweight in Israel.

BACKGROUND: This study measures the burden of chronic diseases associated with being underweight. METHODS: Underweight prevalence in the community was obtained from national survey data, together with hospital use rates for malnourished and non-malnourished persons for diagnoses associated with underweight. Meta-analyses of published literature calculated the following disease-specific relative risks: incidence of underweight-associated disease (UAD), mortality from UAD, and all-cause and disease-specific mortality after hospitalization in underweight persons. This enabled the calculation of hospital days, deaths, and disability-adjusted life years (DALYs) attributable to underweight deconstructed into UAD and disease-associated underweight (DAU). Cost estimates were based on general hospitalization costs adjusted by estimates of pharmaceutical and other direct care costs. RESULTS: We found 60,401 (95% confidence interval [CI]: 58,257-63,095) general hospital days, 558 (95% CI: 219-879) deaths, 5258 (95% CI: 2174-8382) potential years of life lost, and 3390 lost DALYs (95% CI: 1511-5333) were attributable to underweight annually in Israeli adults aged ≥18 years. Annually, direct health costs amounted to $145.6 million (95% CI: $141.9-$150.5 million), with general hospital days accounting for $53.4 million, pharmaceuticals $18.2 million, and other direct healthcare costs $73.9 million. Musculoskeletal disorders accounted for nearly half of these costs with coronary heart disease, chronic obstructive pulmonary disease, and stroke accounting for 15.4%, 10.3%, and 9.3%, respectively. CONCLUSIONS: Underweight imposes a considerable health burden in terms of deaths, health service use, and resource costs in Israel. Identification of cost-effective interventions to reduce this burden, not only among hospitalized patients, but also among persons living in the community, is essential.

Should we use Palivizumab immunoprophylaxis for infants against respiratory syncytial virus? - a cost-utility analysis.

BACKGROUND: Passive immunization against RSV (Respiratory Syncytial Virus) is given in most western countries (including Israel) to infants of high risk groups such as premature babies, and infants with Congenital Heart Disease or Congenital Lung Disease. However, immunoprophylaxis costs are extremely high ($2800-$4200 per infant). Using cost-utility analysis criteria, we evaluate whether it is justified to expand, continue or restrict nationwide immunoprophylaxis using palivizumab of high risk infants against RSV. METHODS: Epidemiological, demographic, health service utilisation and economic data were integrated from primary (National Hospitalization Data, etc.) and secondary data sources (ie: from published articles) into a spread-sheet to calculate the cost per averted disability-adjusted life year (DALY) of vaccinating various infant risk groups. Costs of intervention included antibody plus administration costs. Treatment savings and DALYs averted were estimated from applying vaccine efficacy data to relative risks of being hospitalised and treated for RSV, including possible long-term sequelae like asthma and wheezing. RESULTS: For all the groups RSV immunoprophylaxis is clearly not cost effective as its cost per averted DALY exceeds the $105,986 guideline representing thrice the per capita Gross Domestic Product. Vaccine price would have to fall by 48.1% in order to justify vaccinating Congenital Heart Disease or Congenital Lung Disease risk groups respectively on pure cost-effectiveness grounds. For premature babies of < 29 weeks, 29-32 and 33-36 weeks gestation, decreases of 36.8%, 54.5% and 83.3% respectively in vaccine price are required. CONCLUSIONS: Based solely on cost-utility analysis, at current price levels it is difficult to justify the current indications for passive vaccination with Palivizumab against RSV. However, if the manufacturers would reduce the price by 54.5% then it would be cost-effective to vaccinate the Congenital Heart Disease or Congenital Lung Disease risk groups as well as premature babies born before the 33rd week of gestation.

Auditory stimulation improves motor function and caretaker burden in children with cerebral palsy- A randomized double blind study.

AIM: To investigate the impact of auditory stimulation on motor function in children with cerebral palsy (CP) and disabling hypertonia. METHOD: 9 matched pairs (age: 7y5m, SD 4y1m; 13 boys; gross-motor-functional-classification-scale: median 4; manual-ability-classification-system: median 4) were randomized to receive either auditory stimulation embedded in music (study, n = 9) or music alone (sham, control, n = 9) for at least 10 minutes 4 times a week for 4 weeks. Goal-Attainment-Scale, Care-and-Comfort-Hypertonicity-Questionnaire, Gross-Motor-Function-Measure and Quality-of-Upper-Extremity-Skills-Test (QUEST) were assessed before and 5 months following intervention. RESULT: Children receiving auditory stimulation attained more goals than children who listened to music alone (p = 0.002). Parents reported improved care and comfort in children in the study group compared to a slight deterioration in controls (p = 0.002). Upper extremity skills improved in the study group compared to controls (p = 0.006). Similar gross motor function changes were documented in both groups (p = 0.41). One participant reported increased seizure frequency; no other participants with epilepsy reported increased seizure frequency (n = 6/18) and no other adverse events were reported. INTERPRETATION: Auditory stimulation alleviated hypertonia and improved fine and gross motor functions.

Opportunities and Challenges for Dietary Arsenic Intervention.

The diet is emerging as the dominant source of arsenic exposure for most of the U.S. population. Despite this, limited regulatory efforts have been aimed at mitigating exposure, and the role of diet in arsenic exposure and disease processes remains understudied. In this brief, we discuss the evidence linking dietary arsenic intake to human disease and discuss challenges associated with exposure characterization and efforts to quantify risks. In light of these challenges, and in recognition of the potential longer-term process of establishing regulation, we introduce a framework for shorter-term interventions that employs a field-to-plate food supply chain model to identify monitoring, intervention, and communication opportunities as part of a multisector, multiagency, science-informed, public health systems approach to mitigation of dietary arsenic exposure. Such an approach is dependent on coordination across commodity producers, the food industry, nongovernmental organizations, health professionals, researchers, and the regulatory community. https://doi.org/10.1289/EHP3997.

Did two booster doses for schoolchildren change the epidemiology of pertussis in Israel?

Pertussis is the only vaccine-preventable disease that has re-emerged in Israel. In the last two decades, despite high primary immunization coverage, crude incidence increased over tenfold, with especially high morbidity among infants and adolescents and with 19 infant deaths. Two pertussis vaccine boosters were added, in 2005 for 7-year-olds and in 2011 for 13-year-olds. We reviewed age group incidence from 1999 to 2016, before and after the booster program introduction. We compared three groups of 13-15 year-olds with identical primary immunization but different booster immunization histories. Vaccine effectiveness was calculated before and after adjustment for specific incidence in those aged 65 and over. Two years after one booster, adjusted vaccine effectiveness was 74.5%. Two years after two boosters, adjusted vaccine effectiveness was 91.8%. However, crude morbidity rates were not reduced. The booster program has been effective only among recipient groups. The program will be continued. Israel is now encouraging pregnant women to be vaccinated against pertussis to improve protection of infants.

A framework and case studies for evaluation of enzyme ontogeny in children's health risk evaluation.

Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals.

Use of Monte Carlo analysis in a risk-based prioritization of toxic constituents in house dust.

Many chemicals have been detected in house dust with exposures to the general public and particularly young children of potential health concern. House dust is also an indicator of chemicals present in consumer products and the built environment that may constitute a health risk. The current analysis compiles a database of recent house dust concentrations from the United States and Canada, focusing upon semi-volatile constituents. Seven constituents from the phthalate and flame retardant categories were selected for risk-based screening and prioritization: diethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBzP), diisononyl phthalate (DINP), a pentabrominated diphenyl ether congener (BDE-99), hexabromocyclododecane (HBCDD), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroethyl) phosphate (TCEP). Monte Carlo analysis was used to represent the variability in house dust concentration as well as the uncertainty in the toxicology database in the estimation of children's exposure and risk. Constituents were prioritized based upon the percentage of the distribution of risk results for cancer and non-cancer endpoints that exceeded a hazard quotient (HQ) of 1. The greatest percent HQ exceedances were for DEHP (cancer and non-cancer), BDE-99 (non-cancer) and TDCIPP (cancer). Current uses and the potential for reducing levels of these constituents in house dust are discussed. Exposure and risk for other phthalates and flame retardants in house dust may increase if they are used to substitute for these prioritized constituents. Therefore, alternative assessment and green chemistry solutions are important elements in decreasing children's exposure to chemicals of concern in the indoor environment.

Mortality, hospital days and treatment costs of current and reduced sugar consumption in Israel.

BACKGROUND: Consumption of sugar causes tooth decay, overweight and obesity related morbidities. This paper in response to the Minister of Health's request, provides estimates of the mortality, morbidity and health care costs attributable to sugar consumption in Israel along with the effects of reducing sugar consumption. METHODS: Gender specific relative risks of many diseases from overweight (25 < =BMI < 30) and obesity (BMI > =30) were applied to the national gender specific prevalence rates of overweight and obesity in order to calculate the population attributable fraction (PAF) from overweight and obesity. National expenditure on these related diseases was calculated by applying disease-specific data from a recent Canadian study to estimates of disease specific general hospital expenditures in Israel. Disease specific costs attributable to overweight and obesity were estimated from the product of these expenditures and PAF. In addition national costs of treating caries in persons under 18 years of age from sugar were calculated. Similar calculations were made to estimate the burden from sugar in terms of mortality and hospital utilisation. A recent UK modelling study was used to estimate the effect of a national program to reduce calorific consumption of sugar from 12.45 to 10% in 5 years. RESULTS: Conditions associated with overweight or obesity accounted annually for 6402 deaths (95% CI 3296-8760) and 268,009 hospital days. Dental costs attributable to sugar consumption were 264 million NIS. In total, obesity, overweight and sugar consumption accounted for 2449 million in direct treatment costs (0.21% of GDP), rising to 4027 million (0.35% of GDP) when indirect costs were included. A national program of reducing energy from sugar consumption from 12.45 to 10% over 5 years is considered have a very feasible short-term goal. Even if the program does not impose taxes on sugar consumption, this would save 778 million NIS as well as 1184 lives. CONCLUSION: Sugar consumption causes a huge monetary and mortality burden. Estimates of potential decreases in this burden justify the current prioritisation given by the health minister of creating and implementing a national program to reduce sugar consumption, which is likely to be cost-saving (ie: averted treatment costs will exceed intervention costs).

Mitigating dietary arsenic exposure: Current status in the United States and recommendations for an improved path forward.

Inorganic arsenic (iAs) is a well-characterized carcinogen, and recent epidemiologic studies have linked chronic exposures to non-cancer health outcomes, including cardiovascular disease, diabetes, skin lesions and respiratory disorders. Greater vulnerability has been demonstrated with early life exposure for health effects including lung and bladder cancer, immunotoxicity and neurodevelopment. Despite its well-known toxicity, there are important gaps in the regulatory oversight of iAs in food and in risk communication. This paper focuses on the US regulatory framework in relation to iAs in food and beverages. The state of existing regulatory agency toxicological assessments, monitoring efforts, standard setting, intervention policies and risk communication are explored. Regarding the approach for standard setting, risk-based evaluations of iAs in particular foods can be informative but are insufficient to create a numeric criterion, given current uncertainties in iAs toxicology and the degree to which traditional risk targets can be exceeded by dietary exposures. We describe a process for prioritizing dietary exposures for different lifestages and recommend a relative source contribution-based approach to setting criteria for arsenic in prioritized foods. Intervention strategies begin with an appropriately set criterion and a monitoring program that documents the degree to which this target is met for a particular food. This approach will promote improvements in food production to lower iAs contamination for those foods which initially do not meet the criterion. Risk communication improvements are recommended to ensure that the public has reliable information regarding sources and alternative dietary choices. A key recommendation is the consideration of meal frequency advice similar to what is currently done for contaminants in fish. Recent action level determinations by FDA for apple juice and infant rice cereal are evaluated and used as illustrations of how our recommended approach can further the goal of exposure mitigation from key sources of dietary iAs in the US.

Should Men who have sex with Men be allowed to donate blood in Israel?

BACKGROUND: The present permanent deferral policy in Israel for MSM was established in 1977 and was based on the previous (now outdated) USA Food and Drug Administration standards. This study analyses epidemiological data regarding blood donations among MSM, in order to estimate the risk for HIV transfusion transmitted infection (TTI) if the policy is changed to allow at-risk MSM to donate blood. METHODS: An Excel based spreadsheet model integrated demographic, epidemiological data from the HIV National Register, laboratory, blood donation and testing data in order to calculate TTI due to false-negatives in known HIV+ donors, windows period donations, asymptomatic carriers and laboratory misclassification errors. A sensitivity analysis of our estimated TTIs for deferral periods for MSM was performed based on a literature review regarding this overall policy issue worldwide. RESULTS: MSM in Israel have a considerably higher relative risk (RR) of both prevalence (115) and incidence (143) of being HIV+ than persons without a risk factor. Allowing MSM to donate blood, without any deferral period, will add an additional five HIV TTI cases over the next decade. Imposition of a 1 or 5 years deferral of abstinence will increase the number of HIV TTI cases only by 0.10 and 0.05 cases, respectively. CONCLUSION: A 1 year deferral period for blood donations from MSM in Israel is recommended.

Mortality, hospital days and expenditures attributable to ambient air pollution from particulate matter in Israel.

BACKGROUND: Worldwide, ambient air pollution accounts for around 3.7 million deaths annually. Measuring the burden of disease is important not just for advocacy but also is a first step towards carrying out a full cost-utility analysis in order to prioritise technological interventions that are available to reduce air pollution (and subsequent morbidity and mortality) from industrial, power generating and vehicular sources. METHODS: We calculated the average national exposure to particulate matter particles less than 2.5 µm (PM2.5) in diameter by weighting readings from 52 (non-roadside) monitoring stations by the population of the catchment area around the station. The PM2.5 exposure level was then multiplied by the gender and cause specific (Acute Lower Respiratory Infections, Asthma, Circulatory Diseases, Coronary Heart Failure, Chronic Obstructive Pulmonary Disease, Diabetes, Ischemic Heart Disease, Lung Cancer, Low Birth Weight, Respiratory Diseases and Stroke) relative risks and the national age, cause and gender specific mortality (and hospital utilisation which included neuro-degenerative disorders) rates to arrive at the estimated mortality and hospital days attributable to ambient PM2.5 pollution in Israel in 2015. We utilised a WHO spread-sheet model, which was expanded to include relative risks (based on more recent meta-analyses) of sub-sets of other diagnoses in two additional models. RESULTS: Mortality estimates from the three models were 1609, 1908 and 2253 respectively in addition to 184,000, 348,000 and 542,000 days hospitalisation in general hospitals. Total costs from PM2.5 pollution (including premature burial costs) amounted to $544 million, $1030 million and $1749 million respectively (or 0.18 %, 0.35 % and 0.59 % of GNP). CONCLUSIONS: Subject to the caveat that our estimates were based on a limited number of non-randomly sited stations exposure data. The mortality, morbidity and monetary burden of disease attributable to air pollution from particulate matter in Israel is of sufficient magnitude to warrant the consideration of and prioritisation of technological interventions that are available to reduce air pollution from industrial, power generating and vehicular sources. The accuracy of our burden estimates would be improved if more precise estimates of population exposure were to become available in the future.

Correlates of well-being among caregivers of long-term community-dwelling stroke survivors.

Although caregiving for stroke survivors is usually long-term, most studies on caregivers have generally involved only the first year following the event. We assessed and compared the long-term level of well-being measures among stroke survivors and their caregivers at more than 1 year following the stroke event and examined the associations between well-being, survivors' characteristics, and caregiver burden. We interviewed a convenience sample of 51 community-dwelling stroke survivors, at least 1 year after the last stroke event, and their primary caregivers. Disability of survivors was assessed using the Barthel index and the modified Rankin Scale; health-related quality of life by the SF-36 questionnaire; and depression and anxiety using the Hospital Anxiety Depression Scale. Caregivers filled the SF-36 questionnaire, Hospital Anxiety Depression Scale questionnaire, and the Zarit Burden Interview, which assesses caregiver burden. Caregivers reported low levels of health-related quality of life and high levels of burden, anxiety, and depression. Caregivers' anxiety level was higher than that of the survivors (7.7±5.1 vs. 5.8±4.5, respectively; P=0.02). Anxiety was the only characteristic of caregivers that was associated with overall caregiver burden. Our study suggests that there is a spillover effect of the disease on stroke patients' primary caregivers. Intervention programs for caregivers should focus on their mental state and address their specific needs.