Direct Exposure Measurements Research Articles

Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.

Direct measurement of spatial-temporal drug penetration and exposure in the human central nervous system (CNS) and brain tumors is difficult or infeasible. This study aimed to develop an innovative mechanistic modeling platform for quantitative prediction of spatial pharmacokinetics of systemically administered drugs in the human CNS and brain tumors. A nine-compartment CNS (9-CNS) physiologically-based pharmacokinetic model was developed to account for general anatomical structure and pathophysiological heterogeneity of the human CNS and brain tumors. Drug distribution into and within the CNS and tumors is driven by plasma concentration-time profiles and governed by drug properties and CNS pathophysiology. The model was validated by comparisons of model predictions and clinically observed data of six drugs (abemaciclib, ribociclib, pamiparib, olaparib, temuterkib, and ceritinib) in glioblastoma patients. As rigorously validated, the 9-CNS model allows reliable prediction of spatial pharmacokinetics in different regions of the brain parenchyma (i.e., parenchyma adjacent to CSF and deep parenchyma), tumors (i.e., tumor rim, bulk tumor, and tumor core), and CSF (i.e., ventricular CSF, cranial and spinal subarachnoid CSF). By considering inter-individual plasma pharmacokinetic variability and CNS/tumor heterogeneity, the model well predicts the inter-individual variability and spatial heterogeneity of drug exposure in the CNS and tumors as observed for all six drugs in glioblastoma patients. The 9-CNS model is a first-of-its kind, mechanism-based computational modeling platform that enables early reliable prediction of spatial CNS and tumor pharmacokinetics based on plasma concentration-time profiles. It provides a valuable tool to assist rational drug development and treatment for brain cancer.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0–128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2–20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

CNS Viral Infections-What to Consider for Improving Drug Treatment: A Plea for Using Mathematical Modeling Approaches.

Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood-brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.

Serum Prestin and Otolin-1 Levels in Pilots of Helicopter-Based Emergency Medical Services: Potential Markers for Ear Injury.

Occupational noise exposure is a major public health concern, impacting a large workforce worldwide. In this study, we sought to evaluate the serum concentrations of prestin, a cochlear protein that diminishes following noise exposure, and otolin-1, a protein secreted into the bloodstream subsequent to inner ear damage, among three diverse professional categories, each exposed to varying degrees of noise. Helicopter emergency medical service (HEMS) pilots and construction workers were considered high-risk groups due to their elevated exposure to occupational noise, whereas office workers were regarded as a low-risk group, reflecting their comparatively minimal noise exposure. The study sample included 60 males, encompassing helicopter pilots, construction laborers, and office workers (n=20, each). Recruitment occurred during standard occupational health visits, with all participants presenting normal clinical audiograms. Serum levels of prestin and otolin-1 were measured in duplicate using commercially available immunoassays and compared across the three professional categories. HEMS pilots had the lowest mean serum prestin level at 211±27 pg/mL, followed by construction workers at 234±29 pg/mL, and office workers at 269±42 pg/mL (p<0.001, one-way analysis of variance), with all inter-group differences statistically significant (p<0.05, Tukey'spost hoctests). For otolin-1, HEMS pilots showed the highest mean at 216±20 pg/mL, with construction workers at 196±22 pg/mL, and office workers at 181±20 pg/mL (p<0.001, one-way analysis of variance). Statistically significant differences were found between HEMS pilots and both other groups for otolin-1 levels (p<0.05, Tukey'spost hoctests), but not between construction workers and office workers. Serum concentrations of prestin and otolin-1 may differ among healthy individuals according to their occupational noise exposure and have the potential to act as indicators of subclinical inner ear injury. To substantiate these preliminary observations, incorporating exposure assessment, especially via direct measurements of noise and vibration exposure, would markedly improve the reliability of our findings.

Societal determinants of flood-induced displacement.

What explains human consequences of weather-related disaster? Here, we explore how core socioeconomic, political, and security conditions shape flood-induced displacement worldwide since 2000. In-sample regression analysis shows that extreme displacement levels are more likely in contexts marked by low national income levels, nondemocratic political systems, high local economic activity, and prevalence of armed conflict. The analysis also reveals large residual differences across continents, where flood-induced displacement in the Global South often is much more widespread than direct human exposure measures would suggest. However, these factors have limited influence on our ability to accurately predict flood displacement on new data, pointing to important, hard-to-operationalize heterogeneity in flood impacts across contexts and critical data limitations. Although results are consistent with an interpretation that the sustainable development agenda is beneficial for disaster risk reduction, better data on societal consequences of natural hazards are critically needed to support evidence-based decision-making.

Labour‐saving automation: A direct measure of occupational exposure

AbstractThis article represents one of the first attempts at building a direct measure of occupational exposure to robotic labour‐saving technologies. After identifying robotic and labour‐saving robotic patents, the underlying 4‐digit CPC (Cooperative Patent Classification) code definitions, together with O*NET (Occupational Information Network) task descriptions, are employed to detect functions and operations which are more directed to substituting the labour input and their exposure to labour‐saving automation. This measure allows us to obtain fine‐grained information on tasks and occupations according to their text similarity ranking. Occupational exposure by wage and employment dynamics in the United States is then studied, and complemented by investigating industry and geographical penetration rates.

Mainstreaming the populist radical right? Online news exposure and voting behavior in the 2019 European Parliament election

AbstractHow does media exposure relate to support for radical right populist parties (RRPPs)? We contribute to this classic debate by analyzing the web browsing histories and survey responses of six thousand study participants in France, Germany, Italy, Spain, and the UK during the 2019 European Parliament election. Linking direct measures of online news exposure to voting behavior allows us to assess the effects of the salience of issues politicized by RRPPs on their electoral support. The likelihood to vote for RRPPs was higher when the EU was more salient in individual media diets, while exposure to the less salient issue of immigration did not increase the propensity to vote for RRPPs. Alongside consistent results for other party families and interactions with pre-existing voting intentions, the findings indicate that the electoral effects of online media are contingent on the overall salience of a specific issue and voters’ predispositions.

Shoulder Tendinopathies and Occupational Biomechanical Overload: A Critical Appraisal of Available Evidence.

The aim of this study is to evaluate the association between occupational exposure to biomechanical risk factors and shoulder tendinopathies. We updated recent systematic reviews about specific shoulder disorders and work-related risk factors. MEDLINE was searched up to September 2022. Studies satisfying the following criteria were included: i) the diagnosis was based on physical examination plus imaging data (when available), and ii) the exposure assessment was based on video analysis and/or directly measured. Five studies met the inclusion criteria: three cross-sectional studies identified from published systematic reviews and two cohort studies retrieved from the update. Two studies investigated shoulder tendinitis, one supraspinatus tendinitis, and the other two rotator cuff syndrome. The diagnosis was based on physical examination, not supported by imaging techniques for all the included studies. In four out of five studies, the exposure was assessed by experienced ergonomists with the support of video recordings. In two studies, the exposure assessment was further supplemented by force gauge measurements or direct measurements of upper arm elevation. Only the combined exposure of working with arms above shoulder level with forceful hand exertion appears to be associated with rotator cuff syndrome: i) a cohort study reported an HR=1.11 (95%CI 1.01-1.22) for each unit increase in forceful repetition rate when the upper arm is flexed ≥45° for ≥29% of the working time; and ii) a cross-sectional study showed an OR=2.43 (95%CI 1.04-5.68) for the combination of upper arm flexion ≥45° for more than 15% of the time with a duty cycle of forceful exertions more than 9% of the time. There is moderate evidence of a causal association between shoulder tendinopathy and combined exposures of working above shoulder level with forceful hand exertion. The evidence is insufficient for any single biomechanical exposure on its own. High-quality cohort studies with direct exposure measures and objective diagnostic criteria are needed. The occupational origin of shoulder tendinopathies is still an open question that must be properly answered.

Associations Between Surface Mining Airsheds and Birth Outcomes in Central Appalachia at Multiple Spatial Scales.

A considerable body of research exists outlining ecological impacts of surface coal mining, but less work has explicitly focused on human health, and few studies have examined potential links between health and surface coal mining at fine spatial scales. In particular, relationships between individual birth outcomes and exposure to air contaminants from coal mining activities has received little attention. Central Appalachia (portions of Virginia, West Virginia, Kentucky, and Tennessee, USA), our study area, has a history of resource extraction, and epidemiologic research notes that the region experiences a greater level of adverse health outcomes compared to the rest of the country that are not fully explained by socioeconomic and behavioral factors. The purpose of this study is to examine associations between surface mining and birth outcomes at four spatial scales: individual, Census tract, county, and across county‐sized grid cells. Notably, this study is among the first to examine these associations at the individual scale, providing a more direct measure of exposure and outcome. Airsheds were constructed for surface mines using an atmospheric trajectory model. We then implemented linear (birthweight) and logistic (preterm birth [PTB]) regression models to examine associations between airsheds and birth outcomes, which were geocoded to home address for individual analyses and then aggregated for areal unit analyses, while controlling for a number of demographic variables. This study found that surface mining airsheds are significantly associated with PTB and decreased birthweight at all four spatial scales, suggesting that surface coal mining activities impact birth outcomes via airborne contaminants.

Early developmental vulnerabilities following exposure to domestic violence and abuse: Findings from an Australian population cohort record linkage study

Early life exposure to Domestic Violence and Abuse (DVA) is associated with poor psychosocial and cognitive development in childhood. However, most prior research uses mother-reported involvement in DVA as a proxy indicator of child exposure; studies using direct measures of child exposure to DVA are scarce, especially among representative population-based samples. We address this gap by using longitudinal, population-based data from an Australian record linkage study of children to examine the associations between early life exposure to DVA and early childhood developmental vulnerability. Exposure to DVA was measured using police contact records for children involved in a DVA incident either as a victim or witness. Developmental vulnerability at school entry was measured using the Australian Early Development Census, providing indices of five broad domains of function and person-centred classes of developmental risk (referred to as ‘mild generalized risk’, ‘misconduct risk’, and ‘pervasive risk’, each compared to a group showing ‘no risk’). Children exposed to DVA showed significantly greater odds of developmental vulnerability on all five domains and were more likely to be members of the three developmental risk classes. Girls who were victims of DVA (OR = 1.65) had significantly poorer developmental outcomes than boys who were victims (OR = 1.26) within the domain of communication skills and general knowledge (d = 0.29 [SE = 0.16], p = .04). No other sex differences were found. These preliminary findings hold important implications for policy regarding the early intervention and implementation of support services for young children exposed to DVA.

The effect of laboratory-verified smoking on SARS-CoV-2 infection: results from the Troina sero-epidemiological survey

Previous research yielded conflicting results on the association between cigarette smoking and risk of SARS-CoV-2 infection. Since the prevalence of smoking is high globally, the study of its impact on COVID-19 pandemic may have considerable implications for public health. This study is the first to investigate the association between the SARS-CoV-2 antibody sero-positivity and biochemically verified smoking status, to refine current estimates on this association. SARS-CoV-2-specific IgG and serum cotinine levels (a well-known marker of tobacco exposure) were assessed in a large sero-epidemiological survey conducted in the town of Troina (Sicily, Italy). A propensity score matching was carried out to reduce the effect of possible factors on SARS-CoV-2 infection risk among study participants. Of the 1785 subjects included in our study, one-third was classified as current smokers, based on serum cotinine levels. The overall proportion of subjects with positive serology for SARS-CoV-2 IgG was 5.4%. The prevalence of SARS-CoV-2 antibody positivity and previous COVID-19 diagnosis were reduced in smokers. This reduced prevalence persisted after adjusting for possible confounders (such as sex, age, previous infection, chronic conditions, and risk group) at regression analyses, and the point estimates based on the PS-matched models resulted consistent with those for the unmatched population. This study found a lower proportion of positive SARS-CoV-2 serology among current smokers, using direct laboratory measures of tobacco exposure and thus avoiding possible bias associated with self-reported smoking status. Results may also serve as a reference for future clinical research on potential pharmaceutical role of nicotine or nicotinic-cholinergic agonists against COVID-19.

Dietary ethanol ingestion by free-ranging spider monkeys (Ateles geoffroyi).

Ethanol within ripe and over-ripe fruit is produced naturally through the metabolic activity of fermentative yeasts. As a consequence, frugivorous animals may chronically consume ethanol as part of their routine diet, although direct measurements of such exposure are lacking. Here, we present data on ethanol concentrations within fruits of Spondias mombin (Anacardiaceae) that are eaten by black-handed spider monkeys (Ateles geoffroyi) on Barro Colorado Island, Panama. Of collected fruits that were partially consumed and then dropped by foraging monkeys, pulp-ethanol content was typically in the range of 1–2%; the percentage of pulp for consumed fruits was not significantly correlated with the ethanol concentration of the pulp remaining within each fruit. Urine samples from foraging spider monkeys were also evaluated for the ethanol metabolites ethyl glucuronide and ethyl sulfate; five of six samples tested positive for both compounds. In aggregate, these data indicate natural exposure to fruit-associated ethanol in a wild primate species.

Reflux-related Extraesophageal Symptoms Until Proven Otherwise: A Direct Measurement of Abnormal Proximal Exposure Based on Hypopharyngeal Multichannel Intraluminal Impedance as a Reliable Indicator for Successful Treatment Outcomes

Background/AimsThe Lyon Consensus defined parameters based on upper endoscopy and 24-hour combined multichannel intraluminal impedance-pH (MII-pH), that conclusively establish the presence of gastroesophageal reflux disease (GERD). However, the true role of upper endoscopy and MII-pH to evaluate patients with extraesophageal symptoms (EES) has not been well established. Hypopharyngeal MII (HMII), which directly measures laryngopharyngeal reflux (LPR) events, has been utilized to evaluate patients with EES suggestive of LPR.MethodsThis was a retrospective study involving patients with EES for > 12 weeks despite proton pump inhibitor therapy, and had no endoscopic confirmatory evidence for GERD and negative MII-pH. All patients were subsequently referred for further evaluation of EES with “unknown” etiology and underwent laryngoscopy and HMII. Based on HMII, abnormal proximal exposure (APE) was defined as LPR ≥ 1/day and/or full column reflux (reflux 2 cm distal to the upper esophageal sphincter) > 4/day. Patients with APE were offered antireflux surgery (ARS) and the outcome of ARS was objectively assessed using Reflux Symptom Index.ResultsOf 21 patients with EES which was thought to be GERD-unrelated based on endoscopy and MII-pH, 17 patients (81%) had APE. Eight patients with APE who had undergone ARS had significant symptomatic improvement in the Reflux Symptom Index score (19.6 ± 4.9 pre-ARS to 5.8 ± 1.4 post-ARS, P = 0.008).ConclusionsA conventional diagnostic approach using endoscopy and MII-pH may not be sufficient to evaluate patients with EES suggestive of LPR. HMII is essential to evaluate patients with EES, and APE could be a reliable indicator for successful treatment outcomes.

Subconcussive changes in youth football players: objective evidence using brain vital signs and instrumented accelerometers.

Brain vital signs, measured by EEG, were used for portable, objective, neurophysiological evaluation of cognitive function in youth tackle football players. Specifically, we investigated whether previously reported pre- and post-season subconcussive changes detected in youth ice hockey players were comparably detected in football. The two objectives were to: (i) replicate previously published results showing subconcussive cognitive deficits; and (ii) the relationship between brain vital sign changes and head-impact exposure. Using a longitudinal design, 15 male football players (age 12.89 ± 0.35 years) were tested pre- and post-season, with none having a concussion diagnosis during the season. Peak latencies and amplitudes were quantified for Auditory sensation (N100), Basic attention (P300) and Cognitive processing (N400). Regression analyses tested the relationships between these brain vital signs and exposure to head impacts through both number of impacts sustained, and total sessions (practices and games) participated. The results demonstrated significant pre/post differences in N400 latencies, with ∼70 ms delay (P < 0.01), replicating prior findings. Regression analysis also showed significant linear relationships between brain vital signs changes and head impact exposure based on accelerometer data and games/practices played (highest R = 0.863, P < 0.001 for overall sessions). Number of head impacts in youth football (age 12–14 years) findings corresponded most closely with prior Junior-A ice hockey (age 16–21 years) findings, suggesting comparable contact levels at younger ages in football. The predictive relationship of brain vital signs provided a notable complement to instrumented accelerometers, with a direct physiological measure of potential individual exposure to subconcussive impacts.

Development of a new hand-held type thyroid monitor using multiple GAGG detectors for young children following a nuclear accident

One of the most important lessons learned from the Fukushima Daiichi Nuclear Power Plant accident is that direct (in vivo) measurements of thyroid exposure to radioiodine (mainly, 131I) in the affected populations should be initiated in a timely manner. Furthermore, the existing commercial detectors are not necessarily suitable for the measurement of young children, who are especially vulnerable to radiation exposure and therefore important to screen. This paper presents the development of a new thyroid monitor for such measurements and the results from phantom-based experiments. The monitor has two unique probes having multiple high-energy-resolution type Gd3(Al,Ga)5O12(Ce) (GAGG) detectors that can be placed directly on the young subject's anterior neck. The crystal size of the GAGG detector is 1 cm3, and a probe consisting of a 4 × 1 or 4 × 2 detector array can be selected depending on the subject's body size. The thickness of the 4 × 1 array probe is 24 mm, which is less than that for a conventional NaI(Tl) survey meter having a crystal 1 inch in diameter and 1 inch long (38 mm). Experimental and computational calibrations of the new monitor using existing and virtual phantoms allowed us to determine the full energy peak efficiency for the 131I thyroid contents of different age groups from 3-mo-old to 10-yr-old and minimum detectable activity (MDA) values under various conditions. As a result, the attainable MDA for subjects age ≤5 years under a normal background level (∼0.05 μSv h−1) was found to be ∼30 Bq, which was low enough to identify children with thyroid-equivalent doses over 10 mSv up to about 25 days after the 131I intake. Our new monitor would be useful in direct thyroid measurements for vulnerable young children following a large nuclear accident.

Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth outcomes

Human health effects of airborne lower-chlorinated polychlorinated biphenyls (LC-PCBs) are largely unexplored. Since PCBs may cross the placenta, maternal exposure could potentially have negative consequences for fetal development. We aimed to determine if exposure to airborne PCB during pregnancy was associated with adverse birth outcomes. In this cohort study, exposed women had lived in PCB contaminated apartments at least one year during the 3.6 years before conception or the entire first trimester of pregnancy. The women and their children were followed for birth outcomes in Danish health registers. Logistic regression was performed to estimate odds ratios (OR) for changes in secondary sex ratio, preterm birth, major congenital malformations, cryptorchidism, and being born small for gestational age. We performed linear regression to estimate difference in birth weight among children of exposed and unexposed mothers. All models were adjusted for maternal age, educational level, ethnicity, and calendar time. We identified 885 exposed pregnancies and 3327 unexposed pregnancies. Relative to unexposed women, exposed women had OR 0.97 (95% CI 0.82, 1.15) for secondary sex ratio, OR 1.13 (95% CI 0.76, 1.67) for preterm birth, OR 1.28 (95% CI 0.81, 2.01) for having a child with major malformations, OR 1.73 (95% CI 1.01, 2.95) for cryptorchidism and OR 1.23 (95% CI 0.88, 1.72) for giving birth to a child born small for gestational age. The difference in birth weight for children of exposed compared to unexposed women was − 32 g (95% CI—79, 14). We observed an increased risk of cryptorchidism among boys after maternal airborne LC-PCB exposure, but due to the proxy measure of exposure, inability to perform dose–response analyses, and the lack of comparable literature, larger cohort studies with direct measures of exposure are needed to investigate the safety of airborne LC-PCB exposure during pregnancy

Extreme Exposure Levels of PCDD/Fs Inhaled from Biomass Burning Activity for Cooking in Typical Rural Households.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), emitted during biomass combustion, are carcinogenic chemicals. The association between indoor biomass burning and PCDD/Fs inhalation exposure levels is still poorly understood. This study first reports direct measurement of personal exposure to PCDD/Fs in real-world households with wood combustion. In homes where biomass burning is used for cooking, toxic equivalent quantity (TEQ) PCDD/Fs concentrations were found to be 545 ± 251 fg I-TEQ/m3 in kitchens, with levels of 4.5-, 6.9-, and 13.3-fold higher than those in living rooms (122 ± 92 fg I-TEQ/m3), bedrooms (79 ± 27 fg I-TEQ/m3), and ambient air (41 ± 15 fg I-TEQ/m3), respectively. PCDD/Fs exposure levels in populations using biomass fuels for cooking (353 ± 110 fg I-TEQ/m3) were 4.3-fold higher than those in the control groups (82 ± 32 fg I-TEQ/m3). Additionally, the average cancer risks for biomass cooking person were approximately 3.1-fold higher than those in factory workers. Overall, residents of household that use biomass fuels for cooking have the highest known risk of PCDD/Fs exposure. These results highlight that aiming to mitigate the PCDD/Fs exposure risk in the general population, the focus of dioxin emission source control measures should shift from industrial sectors to residential biomass combustion.

Efficient study design to estimate population means with multiple measurement instruments.

Outcomes from studies assessing exposure often use multiple measurements. In previous work, using a model first proposed by Buonoccorsi (1991), we showed that combining direct (eg, biomarkers) and indirect (eg, self-report) measurements provides a more accurate picture of true exposure than estimates obtained when using a single type of measurement. In this article, we propose a tool for efficient design of studies that include both direct and indirect measurements of a relevant outcome. Based on data from a pilot or preliminary study, the tool, which is available online as a shiny app at https://michalbitan.shinyapps.io/shinyApp/, can be used to compute: (1) the sample size required for a statistical power analysis, while optimizing the percent of participants who should provide direct measures of exposure (biomarkers) in addition to the indirect (self-report) measures provided by all participants; (2) the ideal number of replicates; and (3) the allocation of resources to intervention and control arms. In addition we show how to examine the sensitivity of results to underlying assumptions. We illustrate our analysis using studies of tobacco smoke exposure and nutrition. In these examples, a near-optimal allocation of the resources can be found even if the assumptions are not precise.

Testing and Validating Semi-automated Approaches to the Occupational Exposure Assessment of Polycyclic Aromatic Hydrocarbons.

When it is not possible to capture direct measures of occupational exposure or conduct biomonitoring, retrospective exposure assessment methods are often used. Among the common retrospective assessment methods, assigning exposure estimates by multiple expert rater review of detailed job descriptions is typically the most valid, but also the most time-consuming and expensive. Development of screening protocols to prioritize a subset of jobs for expert rater review can reduce the exposure assessment cost and time requirement, but there is often little data with which to evaluate different screening approaches. We used existing job-by-job exposure assessment data (assigned by consensus between multiple expert raters) from a large, population-based study of women to create and test screening algorithms for polycyclic aromatic hydrocarbons (PAHs) that would be suitable for use in other population-based studies. We evaluated three approaches to creating a screening algorithm: a machine-learning algorithm, a set of a priori decision rules created by experts based on features (such as keywords) found in the job description, and a hybrid algorithm incorporating both sets of criteria. All coded jobs held by mothers of infants participating in National Birth Defects Prevention Study (NBDPS) (n = 35,424) were used in developing or testing the screening algorithms. The job narrative fields considered for all approaches included job title, type of product made by the company, main activities or duties, and chemicals or substances handled. Each screening approach was evaluated against the consensus rating of two or more expert raters. The machine-learning algorithm considered over 30,000 keywords and industry/occupation codes (separate and in combination). Overall, the hybrid method had a similar sensitivity (87.1%) as the expert decision rules (85.5%) but was higher than the machine-learning algorithm (67.7%). Specificity was best in the machine-learning algorithm (98.1%), compared to the expert decision rules (89.2%) and hybrid approach (89.1%). Using different probability cutoffs in the hybrid approach resulted in improvements in sensitivity (24-30%), without the loss of much specificity (7-18%). Both expert decision rules and the machine-learning algorithm performed reasonably well in identifying the majority of jobs with potential exposure to PAHs. The hybrid screening approach demonstrated that by reviewing approximately 20% of the total jobs, it could identify 87% of all jobs exposed to PAHs; sensitivity could be further increased, albeit with a decrease in specificity, by adjusting the algorithm. The resulting screening algorithm could be applied to other population-based studies of women. The process of developing the algorithm also provides a useful illustration of the strengths and potential pitfalls of these approaches to developing exposure assessment algorithms.

Limitations in Japanese Public Health Research and Policy: Lessons from Fukushima and Covid-19

Background/AimThe Covid-19 pandemic revealed national differences in public health systems. Japan suppressed PCR tests, did not conduct urban lockdown, and relied on contact tracing. As a result of these unique measures, in early stage, the number of patients and deaths from Covid-19 seemed small, but as of April 30, 2020, they reached 13,929 and 415 cases, respectively, and outbreaks are ongoing. In South Korea, they ware 10,765 and 247, respectively and peak was passed in early March. The purpose of this study is to clarify why the Japanese public health system (including research, policymaking, and implementation) failed to implement Covid-19 measures and to discuss remedial measures.MethodsIn this study, we compare the responses to the Fukushima nuclear disaster and Covid-19 in terms of measurement, information disclosure, policy planning, and risk communication. Since the two cases are currently on-going, a narrative analysis will be conducted using public documents.ResultsIn Fukushima, direct measurement of thyroid exposure was limited to only 1060 children, and PCR testing was also suppressed at Covid-19. Although, in UK and US, forecast of the number of infections and deaths caused by Covid-19 are published with the models used, they are not disclosed in Japan. In both Fukushima and Covid-19, experts such as epidemiologist who appointed to advisory councils of the government, tend to provide advice that is in line with the government's desire to minimize the economic impact, rather than providing scientific advice. Due to diffusion of social media, circulation of false information such as “PCR testing is harmful due to false positives” were more serious in Covid-19 than FukushimaConclusionsIn this study, we clarified common problems in public health in Japan that would be common in Hiroshima, Nagasaki, and Minamata. There is an urgent need to improve the public health system.