Operation of an optical atomic clock with a Brillouin laser subsystem.

Microwave atomic clocks have traditionally served as the 'gold standard' for precision measurements of time and frequency. However, over the past decade, optical atomic clocks1-6 have surpassed the precision of their microwave counterparts by two orders of magnitude or more. Extant optical clocks occupy volumes of more than one cubic metre, and it is a substantial challenge to enable these clocks to operate in field environments, which requires the ruggedization and miniaturization of the atomic reference and clock laser along with their supporting lasers and electronics4,7,8,9. In terms of the clock laser, prior laboratory demonstrations of optical clocks have relied on the exceptional performance gained through stabilization using bulk cavities, which unfortunately necessitates the use of vacuum and also renders the laser susceptible to vibration-induced noise. Here, using a stimulated Brillouin scattering laser subsystem that has a reduced cavity volume and operates without vacuum, we demonstrate a promising component of a portable optical atomic clock architecture. We interrogate a 88Sr+ ion with our stimulated Brillouin scattering laser and achieve a clock exhibiting short-term stability of 3.9 × 10-14 over one second-an improvement of an order of magnitude over state-of-the-art microwave clocks. This performance increase within a potentially portable system presents a compelling avenue for substantially improving existing technology, such as the global positioning system, and also for enabling the exploration of topics such as geodetic measurements of the Earth, searches for dark matter and investigations into possible long-term variations of fundamental physics constants10-12.

Integrated visible-light polarization rotators and splitters for atomic quantum systems.

In this work, we design and experimentally demonstrate the first, to the best of our knowledge, integrated polarization splitters and rotators at blue wavelengths. We develop compact and efficient designs for both a polarization splitter and rotator at a 422-nm wavelength, an important laser-cooling transition for 88Sr+ ions. These devices are fabricated in a 200-mm wafer-scale process and experimentally demonstrated, resulting in a measured polarization-splitter transverse-electric thru-port coupling of 98.0% and transverse-magnetic tap-port coupling of 77.6% for a compact 16-µm-long device and a polarization-rotator conversion efficiency of 92.2% for a separate compact 111-µm-long device. This work paves the way for more sophisticated integrated control of trapped-ion and neutral-atom quantum systems.

Optical frequency averaging of light.

The use of averaging has long been known to reduce noise in statistically independent systems that exhibit similar levels of stochastic fluctuation. This concept of averaging is general and applies to a wide variety of physical and man-made phenomena such as particle motion, shot noise, atomic clock stability, measurement uncertainty reduction, and methods of signal processing. Despite its prevalence in use for reducing statistical uncertainty, such averaging techniques so far remain comparatively undeveloped for application to light. We demonstrate here a method for averaging the frequency uncertainty of identical laser systems as a means to narrow the spectral linewidth of the resulting radiation. We experimentally achieve a reduction of frequency fluctuations from 40 Hz to 28 Hz by averaging two separate laser systems each locked to a fiber resonator. Only a single seed laser is necessary here as acousto-optic modulation is used to enable independent control of the second path. This technique of frequency averaging provides an effective solution to overcome the linewidth constraints of a single laser alone, particularly when limited by fundamental noise sources such as thermal noise, irrespective of the spectral shape of noise.

Experimental Quantum Channel Discrimination Using Metastable States of a Trapped Ion.

We present experimental demonstrations of accurate and unambiguous single-shot discrimination between three quantum channels using a single trapped ^{40}Ca^{+} ion. The three channels cannot be distinguished unambiguously using repeated single channel queries, the natural classical analogue. We develop techniques for using the six-dimensional D_{5/2} state space for quantum information processing, and we implement protocols to discriminate quantum channel analogues of phase shift keying and amplitude shift keying data encodings used in classical radio communication. The demonstrations achieve discrimination accuracy exceeding 99% in each case, limited entirely by known experimental imperfections.

Cooling of an integrated Brillouin laser below the thermal limit.

Photonically integrated resonators are promising as a platform for enabling ultranarrow linewidth lasers in a compact form factor. Owing to their small size, these integrated resonators suffer from thermal noise that limits the frequency stability of the optical mode to ∼100 kHz. Here, we demonstrate an integrated stimulated Brillouin scattering (SBS) laser based on a large mode-volume annulus resonator that realizes an ultranarrow thermal-noise-limited linewidth of 270 Hz. In practice, yet narrower linewidths are required before integrated lasers can be truly useful for applications such as optical atomic clocks, quantum computing, gravitational wave detection, and precision spectroscopy. To this end, we employ a thermorefractive noise suppression technique utilizing an auxiliary laser to reduce our SBS laser linewidth to 70 Hz. This demonstration showcases the possibility of stabilizing the thermal motion of even the narrowest linewidth chip lasers to below 100 Hz, thereby opening the door to making integrated microresonators practical for the most demanding future scientific endeavors.

High-Fidelity Ion State Detection Using Trap-Integrated Avalanche Photodiodes.

Integrated technologies greatly enhance the prospects for practical quantum information processing and sensing devices based on trapped ions. High-speed and high-fidelity ion state readout is critical for any such application. Integrated detectors offer significant advantages for system portability and can also greatly facilitate parallel operations if a separate detector can be incorporated at each ion-trapping location. Here, we demonstrate ion quantum state detection at room temperature utilizing single-photon avalanche diodes (SPADs) integrated directly into the substrate of silicon ion trapping chips. We detect the state of a trapped Sr^{+} ion via fluorescence collection with the SPAD, achieving 99.92(1)% average fidelity in 450 µs, opening the door to the application of integrated state detection to quantum computing and sensing utilizing arrays of trapped ions.

Association between exposure to radioactive iodine after the Chernobyl accident and thyroid volume in Belarus 10-15 years later.

BACKGROUND: While there is a robust literature on environmental exposure to iodine-131 (131I) in childhood and adolescence and the risk of thyroid cancer and benign nodules, little is known about its effects on thyroid volume. METHODS: To assess the effect of 131I dose to the thyroid on the volume of the thyroid gland, we examined the data from the baseline screening of the Belarusian-American Cohort Study of residents of Belarus who were exposed to the Chernobyl fallout at ages ≤18 years. Thyroid dose estimates were based on individual thyroid activity measurements made shortly after the accident and dosimetric data from questionnaires obtained 10-15 years later at baseline screening. During baseline screening, thyroid gland volume was assessed from thyroid ultrasound measurements. The association between radiation dose and thyroid volume was modeled using linear regression where radiation dose was expressed with power terms to address non-linearity. The model was adjusted for attained age, sex, and place of residence, and their modifying effects were examined. RESULTS: The analysis was based on 10,703 subjects. We found a statistically significant positive association between radiation dose and thyroid volume (P < 0.001). Heterogeneity of association was observed by attained age (P < 0.001) with statistically significant association remaining only in the subgroup of ≥18 years at screening (P < 0.001). For this group, increase in dose from 0.0005 to 0.15 Gy was associated with a 1.27 ml (95% CI: 0.46, 2.07) increase in thyroid volume. The estimated effect did not change with increasing doses above 0.15 Gy. CONCLUSIONS: This is the first study to examine the association between 131I dose to the thyroid gland and thyroid volume in a population of individuals exposed during childhood and systematically screened 10-15 years later. It provides evidence for a moderate statistically significant increase in thyroid volume among those who were ≥ 18 years at screening. Given that this effect was observed at very low doses and was restricted to a narrow dose range, further studies are necessary to better understand the effect.

Entanglement with negative Wigner function of almost 3,000 atoms heralded by one photon.

Quantum-mechanically correlated (entangled) states of many particles are of interest in quantum information, quantum computing and quantum metrology. Metrologically useful entangled states of large atomic ensembles have been experimentally realized, but these states display Gaussian spin distribution functions with a non-negative Wigner quasiprobability distribution function. Non-Gaussian entangled states have been produced in small ensembles of ions, and very recently in large atomic ensembles. Here we generate entanglement in a large atomic ensemble via an interaction with a very weak laser pulse; remarkably, the detection of a single photon prepares several thousand atoms in an entangled state. We reconstruct a negative-valued Wigner function--an important hallmark of non-classicality--and verify an entanglement depth (the minimum number of mutually entangled atoms) of 2,910 ± 190 out of 3,100 atoms. Attaining such a negative Wigner function and the mutual entanglement of virtually all atoms is unprecedented for an ensemble containing more than a few particles. Although the achieved purity of the state is slightly below the threshold for entanglement-induced metrological gain, further technical improvement should allow the generation of states that surpass this threshold, and of more complex Schrödinger cat states for quantum metrology and information processing. More generally, our results demonstrate the power of heralded methods for entanglement generation, and illustrate how the information contained in a single photon can drastically alter the quantum state of a large system.

A Multidisciplinary Head-to-Head Comparison of American College of Radiology Thyroid Imaging and Reporting Data System and American Thyroid Association Ultrasound Risk Stratification Systems.

BACKGROUND: Ultrasound plays a critical role in evaluating thyroid nodules. We compared the performance of the two most popular ultrasound malignancy risk stratification systems, the 2015 American Thyroid Association (ATA) guidelines and the American College of Radiology Thyroid Imaging and Reporting Data System (ACR TI-RADS). MATERIALS AND METHODS: We retrospectively identified 250 thyroid nodules that were surgically removed from 137 patients. Their ultrasound images were independently rated using both ATA and ACR TI-RADS by six raters with expertise in ultrasound interpretation. For each system, we generated a receiver operating characteristic curve and calculated the area under the curve (AUC). RESULTS: Sixty-five (26%) nodules were malignant. There was "fair agreement" among raters for both ATA and ACR TI-RADS. Our observed malignancy risks for ATA and ACR TI-RADS categories were similar to expected risk thresholds with a few notable exceptions including the intermediate ATA risk category and the three highest risk categories for ACR TI-RADS. Biopsy of 226 of the 250 nodules would be indicated by ATA guidelines based on nodule size and mean ATA rating. One hundred forty-six nodules would be biopsied based on ACR TI-RADS. The sensitivity, specificity, and negative and positive predictive values were 92%, 10%, 79%, and 27%, respectively, for ATA and 74%, 47%, 84%, and 33%, respectively, for ACR TI-RADS. The AUC for ATA was 0.734 and for ACR TI-RADS was 0.718. CONCLUSION: Although both systems demonstrated good diagnostic performance, ATA guidelines resulted in a greater number of thyroid biopsies and exhibited more consistent malignancy risk prediction for higher risk categories. IMPLICATIONS FOR PRACTICE: With the rising incidence of thyroid nodules, the need for accurate detection of malignancy is important to avoid the overtreatment of benign nodules. Ultrasonography is one of the key tools for the evaluation of thyroid nodules, although the use of many different ultrasound risk stratification systems is a hindrance to clinical collaboration in everyday practice and the comparison of data in research. The first step toward the development of a universal thyroid nodule ultrasound malignancy risk stratification system is to better understand the strengths and weaknesses of the current systems in use.

Dumbell atypical teratoid/rhabdoid tumour (AT/RT) of the cervical spine.

Spinal Atypical Teratoid/Rhabdoid Tumour (AT/RT) is a highly malignant tumour, and its prognosis is dismal especially for very young patients. In this article, we present the case of a teenage boy with AT/RT in the cervical spine and its multimodality management. A review of the literature on ATRT of the spine is also presented.

Development of a new biochip array for APOE4 classification from plasma samples using immunoassay-based methods.

BACKGROUND: Apolipoprotein E (APOE) is a key player in lipid transport and metabolism and exists in three common isoforms: APOE2, APOE3 and APOE4. The presence of the E4 allelic variant is recognized as a major genetic risk factor for dementia and other chronic (neuro)degenerative diseases. The availability of a validated assay for rapid and reliable APOE4 classification is therefore advantageous. METHODS: Biochip array technology (BAT) was successfully applied to identify directly the APOE4 status from plasma within 3 h, through simultaneous immunoassay-based detection of both specific APOE4 and total APOE levels. RESULTS: Samples (n=432) were first genotyped by polymerase chain reaction (PCR), and thereafter, using BAT, the corresponding plasma was identified as null, heterozygous or homozygous for the E4 allele by calculating the ratio of APOE4 to total APOE protein. Two centers based in Austria and Ireland correctly classified 170 and 262 samples, respectively, and achieved 100% sensitivity and specificity. CONCLUSIONS: This chemiluminescent biochip-based sandwich immunoarray provides a novel platform to detect rapidly and accurately an individual's APOE4 status directly from plasma. The E4 genotype of individuals has been shown previously to affect presymptomatic risk, prognosis and treatment response for a variety of diseases, including Alzheimer's disease. The biochip's potential for being incorporated in quantitative protein biomarker arrays capable of analyzing disease stages makes it a superior alternative to PCR-based APOE genotyping and may deliver additional protein-specific information on a variety of diseases in the future.

Factors associated with serum thyroglobulin in a Ukrainian cohort exposed to iodine-131 from the accident at the Chernobyl Nuclear Plant.

BACKGROUND: Serum thyroglobulin (Tg) is associated with the presence of thyroid disease and has been proposed as a biomarker of iodine status. Few studies have examined factors related to serum Tg in populations environmentally exposed to ionizing radiation and living in regions with endemic mild-to-moderate iodine deficiency. METHODS: We screened 10,430 individuals who were living in Ukraine and under 18 years of age at the time of the 1986 Chernobyl Nuclear Power Plant accident for thyroid disease from 2001 to 2003. We estimated the percent change (PC) in serum Tg associated with demographic factors, iodine-131 thyroid dose, and indicators of thyroid structure and function using linear regression. We also examined these relationships for individuals with and without indications of thyroid abnormality. RESULTS: Mean and median serum Tg levels were higher among participants with abnormal thyroid structure/function. Percent change in serum Tg increased among females, smokers and with older age (p-values<0.001), and Tg increased with increasing thyroid volume, and serum thyrotropin (p-values for trend<0.001). We found no evidence of significant associations between iodine-131 thyroid dose and Tg. Serum Tg levels were inversely associated with iodized salt intake (PC=-7.90, 95% confidence interval: -12.08, -3.52), and over the range of urinary iodine concentration, the odds of having elevated serum Tg showed a U-shaped curve with elevated Tg at low and high urinary iodine concentrations. CONCLUSION: Serum Tg may be a useful indicator of population iodine status and a non-specific biomarker of structural and functional thyroid abnormalities in epidemiological studies.

Risk of thyroid follicular adenoma among children and adolescents in Belarus exposed to iodine-131 after the Chornobyl accident.

Several studies reported an increased risk of thyroid cancer in children and adolescents exposed to radioactive iodines, chiefly iodine-131 ((131)I), after the 1986 Chornobyl (Ukrainian spelling) nuclear power plant accident. The risk of benign thyroid tumors following such radiation exposure is much less well known. We have previously reported a novel finding of significantly increased risk of thyroid follicular adenoma in a screening study of children and adolescents exposed to the Chornobyl fallout in Ukraine. To verify this finding, we analyzed baseline screening data from a cohort of 11,613 individuals aged ≤18 years at the time of the accident in Belarus (mean age at screening = 21 years). All participants had individual (131)I doses estimated from thyroid radioactivity measurements and were screened according to a standardized protocol. We found a significant linear dose response for 38 pathologically confirmed follicular adenoma cases. The excess odds ratio per gray of 2.22 (95% confidence interval: 0.41, 13.1) was similar in males and females but decreased significantly with increasing age at exposure (P < 0.01), with the highest radiation risks estimated for those exposed at <2 years of age. Follicular adenoma radiation risks were not significantly modified by most indicators of past and current iodine deficiency. The present study confirms the (131)I-associated increases in risk of follicular adenoma in the Ukrainian population and adds new evidence on the risk increasing with decreasing age at exposure.

Analysis of thyroid malignant pathologic findings identified during 3 rounds of screening (1997-2008) of a cohort of children and adolescents from belarus exposed to radioiodines after the Chernobyl accident.

BACKGROUND: Recent studies of children and adolescents who were exposed to radioactive iodine-131 (I-131) after the 1986 Chernobyl nuclear accident in Ukraine exhibited a significant dose-related increase in the risk of thyroid cancer, but the association of radiation doses with tumor histologic and morphologic features is not clear. METHODS: A cohort of 11,664 individuals in Belarus who were aged ≤18 years at the time of the accident underwent 3 cycles of thyroid screening during 1997 to 2008. I-131 thyroid doses were estimated from individual thyroid activity measurements taken within 2 months after the accident and from dosimetric questionnaire data. Demographic, clinical, and tumor pathologic characteristics of the patients with thyroid cancer were analyzed using 1-way analysis of variance, chi-square tests or Fisher exact tests, and logistic regression. RESULTS: In total, 158 thyroid cancers were identified as a result of screening. The majority of patients had T1a and T1b tumors (93.7%), with many positive regional lymph nodes (N1; 60.6%) but few distant metastases (M1; <1%). Higher I-131 doses were associated with higher frequency of solid and diffuse sclerosing variants of thyroid cancer (P < .01) and histologic features of cancer aggressiveness, such as lymphatic vessel invasion, intrathyroidal infiltration, and multifocality (all P < .03). Latency was not correlated with radiation dose. Fifty-two patients with self-reported thyroid cancers which were diagnosed before 1997 were younger at the time of the accident and had a higher percentage of solid variant cancers compared with patients who had screening-detected thyroid cancers (all P < .0001). CONCLUSIONS: I-131 thyroid radiation doses were associated with a significantly greater frequency of solid and diffuse sclerosing variants of thyroid cancer and various features of tumor aggressiveness.

Histopathological features of papillary thyroid carcinomas detected during four screening examinations of a Ukrainian-American cohort.

BACKGROUND: There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. We evaluated the associations between iodine-131 dose and the histopathological characteristics of post-Chernobyl PTCs, the changes in these characteristics over time, and their associations with selected somatic mutations. METHODS: This study included 115 PTCs diagnosed in a Ukrainian-American cohort (n=13,243) during prescreening and four successive thyroid screenings. Of these PTCs, 65 were subjected to somatic mutation profiling. All individuals were <18 years at the time of the Chernobyl accident and had direct thyroid radioactivity measurements. Statistical analyses included multivariate linear and logistic regression. RESULTS: We identified a borderline significant linear-quadratic association (P=0.063) between iodine-131 dose and overall tumour invasiveness (presence of extrathyroidal extension, lymphatic/vascular invasion, and regional or distant metastases). Irrespective of dose, tumours with chromosomal rearrangements were more likely to have lymphatic/vascular invasion than tumours without chromosomal rearrangements (P=0.020) or tumours with BRAF or RAS point mutations (P=0.008). Controlling for age, there were significant time trends in decreasing tumour size (P<0.001), the extent of lymphatic/vascular invasion (P=0.005), and overall invasiveness (P=0.026). CONCLUSIONS: We determined that the invasive properties of PTCs that develop in iodine-131-exposed children may be associated with radiation dose. In addition, based on a subset of cases, tumours with chromosomal rearrangements appear to have a more invasive phenotype. The increase in small, less invasive PTCs over time is a consequence of repeated screening examinations.

Frequently asked questions in direct pulp capping of permanent teeth.

UNLABELLED: Direct pulp capping is a proven method of preserving tooth vitality of a mature permanent tooth in cases of pulp exposures. The indications for this treatment, treatment modalities and materials are discussed in this paper. CLINICAL RELEVANCE: This paper answers many of the frequently asked questions by general practitioners, dental students and specialists about direct pulp capping.

Radiation Dose Does Not Affect the Predictive Value of Thyroid Biopsy for Diagnosing Papillary Thyroid Cancer in a Belarusian Cohort Exposed to Chernobyl Fallout.

INTRODUCTION: The Chernobyl nuclear accident exposed residents of contaminated territories to substantial quantities of radioiodines and was followed by an increase in thyroid cancer, primarily papillary thyroid cancer (PTC), among exposed children and adolescents. Although thyroid biopsy is an essential component of screening programs following accidental exposure to radioiodines, it is unknown whether the predictive value of biopsy is affected by different levels of environmental exposure. METHODS: A cohort of 11,732 Belarusians aged ≤18 years at the time of the Chernobyl accident with individual thyroid radiation dose estimates was screened at least once 11-22 years later. Paired cytologic conclusions and histopathologic diagnoses were possible for 258 thyroid nodules from 238 cohort members. Cytologic conclusions were divided into five reporting categories, with all follicular lesion aspirates combined into a single indeterminate category. Standard performance indicators, risk of malignancy (ROM), and odds ratios for a correct cytologic conclusion were calculated, both overall and according to quintile of thyroid radiation dose. RESULTS: The arithmetic mean thyroid dose estimate for the study group was 1.73 Gy (range: 0.00-23.64 Gy). The final histopathologic diagnosis was cancer for 136 of 258 biopsies (52.7%; 135 papillary and 1 follicular). The overall ROM was 96.7% for cytologies definite for PTC, 83.7% for suspicious for PTC, 33.0% for indeterminate, 8.1% for benign, and 31.0% for non-diagnostic. The ROM showed little change according to level of radiation exposure. Overall, there was no association between thyroid radiation dose and the odds ratio for a correct cytologic conclusion (p = 0.24). When analyzed according to dose quintile, the odds ratio for a correct conclusion increased two-fold at 0.10-0.29 Gy compared to a dose of 0.00-0.09 Gy and decreased at doses of 0.3-24 Gy (p value for linear trend = 0.99). CONCLUSIONS: At radiation doses received by a cohort of young Belarusians exposed to radioiodines by the Chernobyl accident, the predictive value of thyroid biopsy for diagnosing PTC was not significantly affected by level of radiation exposure.

Prevalence of Thyroid Nodules in Residents of Ukraine Exposed as Children or Adolescents to Iodine-131 from the Chornobyl Accident.

Background: Although childhood exposure to radioactive iodine-131 (I-131) is an established risk factor for thyroid cancer, evidence for an association with thyroid nodules is less clear. The objective of this study is to evaluate the association between childhood I-131 exposure and prevalence of ultrasound-detected thyroid nodules overall and by nodule histology/cytology (neoplastic/suspicious/non-neoplastic), size (<10 mm/≥10 mm), and number (single/multiple). Methods: This is a cross-sectional study of radiation dose (mean = 0.53 gray, range: 0.0003-31 gray) and screen-detected thyroid nodules conducted in 1998-2000 (median population age 21.5 years) in a cohort of 13,243 residents of Ukraine who were under 18 years at the time of the Chornobyl accident on April 26, 1986. Excess odds ratios per gray (excess odds ratio [EOR]/Gy) and confidence intervals (CIs) were estimated using logistic regression. Results: Among 13,078 eligible individuals, we identified 358 (2.7%) with at least one thyroid nodule. Significantly increased dose-response associations were found for all nodules and nodule groups with doses <5 Gy except individuals with non-neoplastic nodules. Among individuals with doses <5 Gy, the EOR/Gy for neoplastic nodules (5.35; CI: 2.19-15.5) was significantly higher than for non-neoplastic nodules (0.24; CI: 0.07-0.74), but the EOR/Gy did not vary by nodule size or number. Conclusions: Childhood exposure to I-131 is associated with an increased risk of thyroid nodules detected 12-14 years following exposure, and the risk for neoplastic nodules is higher than for non-neoplastic nodules. Analyses of incident thyroid nodules may help clarify dose-response patterns by nodule characteristics and provide insights into thyroid nodule etiology.

Factors associated with serum thyroglobulin levels in a population living in Belarus.

OBJECTIVE: Serum thyroglobulin (Tg) has been associated with a number of thyroid disorders and has been proposed as an indicator of iodine deficiency in a population. However, few studies have addressed the epidemiology of Tg in a population-based setting or in the context of exposure to radioactive iodine-131 (I-131). Our objective was to evaluate baseline levels of Tg in relation to sociodemographic characteristics, iodine status and thyroid function for individuals exposed to I-131. DESIGN: A population-based cohort assembled in Belarus following the Chornobyl accident provided demographic factors, clinical data and physiological measurements. PARTICIPANTS: Our analytical sample included 10,344 subjects of whom 7890 had no thyroid disease and 2454 had evidence of structural or functional thyroid abnormality. MEASUREMENTS: Standardized assays were used to measure serum Tg, urinary iodine, TSH and antibodies to Tg and thyroid peroxidase. Ultrasound was used to assess the presence of nodules and estimate thyroid volume. RESULTS: In the fully adjusted model, percent change in Tg was significantly increased among females, smokers and subjects of older age and Tg increased with decreasing urinary iodine concentration, increasing serum TSH and increasing thyroid volume (P-values for trend <0·0001), and presence of thyroid nodules (P < 0·05). We found a complex interaction between region of residence, rural/urban living, presence/absence of thyroid abnormalities and serum Tg (P < 0·0001). CONCLUSIONS: In residents of Belarus, serum Tg is significantly related to presence of thyroid abnormalities as well as indicators of thyroid function and iodine deficiency and, therefore, could be used to characterize the iodine status and thyroid function of individuals in the context of epidemiological study.