Estimating impacts of reducing acrylonitrile exposure on lung cancer mortality in an occupational cohort with the parametric g-formula.

OBJECTIVES: To inform the potential human carcinogenicity of acrylonitrile, we estimate associations between acrylonitrile exposures and lung cancer mortality in US workers with the objectives of (1) assessing potential for healthy worker survivor bias and (2) adjusting for this bias while assessing the expected lung cancer mortality under different hypothetical occupational exposure limits on acrylonitrile exposure using the parametric g-formula. METHODS: We used data from a cohort of 25 460 workers at facilities making or using acrylonitrile in the USA. We estimated HRs to quantify associations between employment and lung cancer mortality, and exposure and leaving employment. Using the parametric g-formula, we estimated cumulative lung cancer mortality at hypothetical limits on acrylonitrile exposure. RESULTS: Recent and current employment was associated with lung cancer, and exposure was associated with leaving employment, indicating potential for healthy worker survivor bias. Relative to no intervention, reducing the historical exposure under limits of 2.0, 1.0 and 0.45 parts per million would have been expected to reduce lung cancer mortality by age 90 by 4.46 (95% CI 0.78 to 8.15), 5.03 (95% CI 0.96 to 9.11) and 6.45 (95% CI 2.35 to 10.58) deaths per 1000 workers, respectively. A larger lung cancer mortality reduction would be expected under elimination of exposure: 7.21 (95% CI 2.72 to 11.70) deaths per 1000 workers. CONCLUSIONS: Healthy worker survivor bias likely led to underestimation of excess risk. Our results corroborate previous study findings of an excess hazard of lung cancer among the highest exposed workers.

Adjustment for duration of employment in occupational epidemiology.

PURPOSE: In occupational epidemiology, the healthy worker survivor effect can manifest as a time-dependent confounder because healthier workers can accrue greater amounts of exposure over longer periods of employment. For example, in occupational studies of radiation exposure that focus on cumulative annualized radiation dose, workers can accrue greater amounts of cumulative radiation exposure over longer periods of employment, while workers with longer periods of employment can transition into jobs with a reduced potential for annualized radiation exposure. The extent to which confounding arising from the healthy worker survivor effect impacts radiation risk estimates is unknown. METHODS: We assessed the impact of the healthy worker survivor effect on estimates of radiation risk among nuclear workers in a Million Person Study cohort. In simulation studies, we contrasted the ability of marginal structural Cox models with inverse probability weighting and Cox proportional hazards models to account for time-dependent confounding arising from the healthy worker survivor effect. RESULTS: Marginal structural Cox models and Cox proportional hazards models with flexible functional forms for duration of employment provided reliable results. CONCLUSIONS: It is crucial to flexibly adjust for duration of employment to account for confounding arising from the healthy worker survivor effect in occupational epidemiology.

Tip of the iceberg: unveiling the impact on back disorders from cumulative physical job exposure and evaluating bias from the healthy worker effect using a nationwide longitudinal cohort study.

PURPOSE: Longitudinal studies across various sectors with physically demanding jobs are notably absent in back disorder risk research. This study aimed to investigate the relationship between cumulative physical job exposure (PJE) and hospital-diagnosed back disorders among individuals in Denmark. To assess the healthy worker effect, we compared the cumulative risk estimate with results from a naive cross-sectional model ignoring PJE history. METHODS: A nationwide longitudinal cohort study was conducted using Danish registers, encompassing individuals born between 1975 and 1978 and working in 1996. Cumulative PJE was measured with a 10-year look-back period for each year 2006-2017. PJE consisted of lower-body occupational exposures, including the total weight lifted, stand/sit ratio, and the frequency of lifting more than 20 kg per day from a job exposure matrix. Odds ratio for back disorders was estimated for each year and all years combined. RESULTS: The results unveiled a significant 31% increase in the risk of hospital-diagnosed back disorders after 4 years of cumulative PJE. The lowest risk (7%) was observed for incident back disorders with 1 year of exposure, suggesting a healthy worker effect. Nevertheless, this risk is still significantly elevated. This cumulative estimate is fourfold the estimate from the 2006 naive cross section model. CONCLUSION: Our study clearly demonstrates an 31% increase in the risk of hospital-diagnosed back disorders with just 4 years of PJE over a 10-year period. Further, we find that cross-sectional studies strongly underestimate the risk of back disorders due to the healthy worker effect.

A comparison of meta-analysis results with and without adjustment for the healthy worker effect: cancer mortality among workers in the semiconductor industry.

OBJECTIVES: This study compared the results of meta-analysis with and without adjustment for the healthy worker effect on the association between working in the semiconductor industry and cancer mortality. METHODS: Six studies that reported standardized mortality ratios (SMRs) for cancers were selected for meta-analysis. Using a random-effects model, the SMR results from each study were combined for all cancers and leukemias to estimate the summary SMRs (95% confidence interval, CI). To adjust for the healthy worker effect, the relative standardized mortality ratio (rSMR=SMRx/SMRnot x) were calculated using observed and expected counts for the specific cause of interest (i.e., all cancers and leukemias) and the observed and expected counts for all other causes of mortality. Then, the rSMR results were combined to estimate the summary rSMRs (95% CIs). RESULTS: The SMRs for all causes of mortality among semiconductor industry workers ranged from 0.25 to 0.80, which reflects a significant healthy worker effect. A remarkable difference was found between the summary SMRs and the summary rSMRs. The summary SMR for all cancers was 0.70 (95% CI, 0.63 to 0.79) whereas the summary rSMR was 1.38 (95% CI, 1.20 to 1.59). The summary SMR for leukemia was 0.88 (95% CI, 0.72 to 1.07), and the summary rSMR was 1.88 (95% CI, 1.20 to 2.95). CONCLUSIONS: Our results suggest that adjustment for the healthy worker effect (i.e., rSMR) may be useful in meta-analyses of cohort studies reporting SMRs.

COVID-19 mortality among migrants living in Italy.

We aimed to compare COVID-19-specific and all-cause mortality rates among natives and migrants in Italy and to investigate the clinical characteristics of individuals dying with COVID-19 by native/migrant status. The mortality rates and detailed clinical characteristics of natives and migrants dying with COVID-19 were explored by considering the medical charts of a representative sample of patients deceased in Italian hospitals (n = 2,687) between February 21st and April 29th, 2020. The migrant or native status was assigned based on the individual's country of birth. The expected all-cause mortality among natives and migrants living in Italy was derived by the last available (2018) dataset provided by the Italian National Institute of Statistics. Overall, 68 individuals with a migration background were identified. The proportions of natives and migrants among the COVID-19-related deaths (97.5% and 2.5%, respectively) were similar to the relative all-cause mortality rates estimated in Italy in 2018 (97.4% and 2.6%, respectively). The clinical phenotype of migrants dying with COVID-19 was similar to that of natives except for the younger age at death. International migrants living in Italy do not have a mortality advantage for COVID-19 and are exposed to the risk of poor outcomes as their native counterparts.

Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions.

OBJECTIVES: To assess if improvement of working conditions related to heat stress was associated with improved kidney health outcomes among sugarcane harvest workers in Chichigalpa, Nicaragua, a region heavily affected by the epidemic of chronic kidney disease of non-traditional origin. METHODS: Based on our findings during the 2017-2018 harvest (harvest 1), recommendations that enhanced the rest schedule and improved access to hydration and shade were given before the 2018-2019 harvest (harvest 2). Actual work conditions during harvest 2 were then observed. Serum creatinine (SCr) was measured before and at end-harvest, and cross-harvest changes in estimated glomerular filtration rate (eGFR) and incident kidney injury (IKI, ie, SCr increase by ≥0.30 mg/dL or ≥1.5 times the baseline value) were compared between harvest 1 and harvest 2 for three jobs with different physical workloads using regression modelling. Workers who left during harvest were contacted at home, to address the healthy worker selection effect. RESULTS: In burned cane cutters, mean cross-harvest eGFR decreased 6 mL/min/1.73 m2 (95% CI 2 to 9 mL/min/1.73 m2) less and IKI was 70% (95% CI 90% to 50%) lower in harvest 2 as compared with harvest 1 data. No such improvements were seen among seed cutters groups with less successful intervention implementation. CONCLUSION: Kidney injury risk was again elevated in workers with strenuous jobs. The results support further efforts to prevent kidney injury among sugarcane workers, and other heat-stressed workers, by improving access to water, rest and shade. The distinction between design and implementation of such interventions should be recognised.

Associations between exposure to ethylene oxide, job termination, and cause-specific mortality risk.

BACKGROUND: Previous analyses of mortality were conducted in a large cohort of ethylene oxide (EtO) exposed workers employed at 13 sterilization facilities throughout the U.S. and followed from the start of operation through 1998. Statistically significant elevated mortality was reported from hematopoietic cancer in men and breast cancer in women compared to the general population. Possible healthy worker survivor bias was not addressed. METHODS: To examine survivor bias in this cohort, employment termination was analyzed with statistical models stratified on sex and race that included age, employment duration, and cumulative EtO exposure. To reduce survivor bias employment duration was included in Poisson regression model specifications for estimating standardized mortality ratios for several cancer outcomes. RESULTS: Strong statistically significant effects of unlagged cumulative EtO exposure were observed on rate of employment termination, indicating potential healthy worker survivor effect bias. Adjustment for employment duration in analyses of mortality resulted in statistically significant and stronger associations between cumulative EtO exposure and lung cancer, female breast cancer and hematopoietic cancer. There was a striking reduction in nonmalignant respiratory disease mortality risk with increasing employment duration with a further (nonsignificant) reduction with cumulative EtO, suggesting that EtO itself is driving termination of workers with respiratory morbidity even though the average EtO exposures in this population were generally far below odor and acute irritancy thresholds. CONCLUSIONS: Important survivor bias was present in this EtO cohort and may be present in many occupational settings involving irritant exposures.

Respiratory health, occupation and the healthy worker effect.

BACKGROUND: Workers are exposed to physical, chemical and other hazards in the workplace, which may impact their respiratory health. AIMS: To examine the healthy worker effect in the Canadian working population and to identify the association between occupation and respiratory health. METHODS: Data from four cycles of the Canadian Health Measures Survey were utilized. The current occupation of employed participants was classified into 10 broad categories based on National Occupation Category 2011 codes. Data relating to 15 400 subjects were analysed. RESULTS: A significantly lower proportion of those in current employment than those not in current employment reported respiratory symptoms or diseases or had airway obstruction. Similarly, those currently employed reported better general health and had greater mean values for percent-predicted forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow between 25% and 75% of FVC (FEF25-75%) and FEV1/FVC ratio. Among males, females and older age groups, significant differences were observed for almost all the respiratory outcomes for those in current employment. Those in 'Occupations unique to primary industry' had a significantly greater likelihood of regular cough with sputum and ever asthma and had lower mean values of percent-predicted FEV1/FVC and FEF25-75% than those in 'Management occupations'. Those in 'Health occupations' had the highest proportion of current asthma. CONCLUSIONS: Participants in current employment were healthier than those not in current employment providing further support for the healthy worker effect. Those in 'Occupations unique to primary industry' had an increased risk of adverse respiratory outcomes and reducing workplace exposures in these occupations has the potential to improve their respiratory health.

Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort.

OBJECTIVES: To examine the association between workload and kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest, and to assess whether the existing heat prevention efforts at a leading occupational safety and health programme are sufficient to mitigate kidney injury. METHODS: Biological and questionnaire data were collected before (n=545) and at the end (n=427) of harvest among field support staff (low workload), drip irrigation workers (moderate), seed cutters (high) and burned sugarcane cutters (very high). Dropouts were contacted (87%) and reported the reason for leaving work. Cross-harvest incident kidney injury (IKI) was defined as serum creatinine increase ≥0.30 mg/dL or ≥1.5 times the baseline value, or among dropouts reporting kidney injury leading to leaving work. RESULTS: Mean cross-harvest estimated glomerular filtration rate change was significantly associated with workload, increasing from 0 mL/min/1.73 m2 in the low-moderate category to -5 mL/min/1.73 m2 in the high and -9 mL/min/1.73 m2 in the very high workload group. A similar pattern occurred with IKI, where low-moderate workload had 2% compared with 27% in the very high workload category. A healthy worker selection effect was detected, with 32% of dropouts reporting kidney injury. Fever and C reactive protein elevation were associated with kidney injury. CONCLUSIONS: Workers considered to have the highest workload had more cross-harvest kidney damage than workers with less workload. Work practices preventing heat stress should be strengthened and their role in preventing kidney damage examined further. Future occupational studies on chronic kidney disease of unknown aetiology should account for a healthy worker effect by pursuing those lost to follow-up.

Assessment of the healthy worker survivor effect in the relationship between psychosocial work-related factors and hypertension.

OBJECTIVES: The healthy worker survivor effect (HWSE) usually leads to underestimation of the effects of harmful occupational exposures. HWSE is characterised by the concomitance of three associations: (1) job status-subsequent exposure, (2) job status-disease and (3) previous exposure-job status. No study has reported the coexistence of these associations in the relationship between psychosocial work-related factors and health. We assessed if HWSE is present when measuring the effects of cumulative exposure to psychosocial work-related factors on the prevalence of hypertension in white-collar workers. METHODS: Data were obtained from two timepoints (1991-1993 at baseline and 1999-2001 at follow-up) of a prospective cohort study. At baseline, the population was composed of 9188 white-collar employees (women: 49.9%) in Quebec City. Job strain as psychosocial work-related factor and blood pressure were measured using validated methods. Job status (retirees vs employees) at follow-up was self-reported. Multiple multilevel robust Poisson regressions were used to estimate prevalence ratios of hypertension and risk ratios of retirement separately by gender. We performed multiple imputations to control selection bias due to missing values. RESULTS: Retirement eliminated the subsequent exposure to job strain de facto and was associated with the reduction in the prevalence of hypertension in younger (-33%) and older (-11%) men and in older women (-39%). Job strain was associated with job status in younger men and in women of any age. CONCLUSION: Data showed the presence of HWSE in younger men and older women given the coexistence of the three structural associations.

Healthy workers or less healthy leavers? Mortality in military veterans.

BACKGROUND: The 'healthy worker effect' predicts that longer employment is positively associated with reduced mortality, but few studies have examined mortality in military veterans irrespective of exposure to conflict. AIMS: To examine mortality in a large national cohort of Scottish veterans by length of service. METHODS: Retrospective cohort study comparing survival in up to 30-year follow-up among 57 000 veterans and 173 000 people with no record of service, matched for age, sex and area of residence, who were born between 1945 and 1985. We compared antecedent diagnoses in the two groups to provide information on probable risk factors. RESULTS: By the end of follow-up, 3520 (6%) veterans had died, compared with 10 947 (6%) non-veterans. Cox proportional hazard analysis confirmed no significant difference overall unadjusted or after adjusting for deprivation. On subgroup analysis, those who left prematurely (early service leavers) were at significantly increased risk of death (hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.09-1.24, P < 0.001), although the increase became non-significant after adjusting for socioeconomic status (HR 1.05, 95% CI 0.99-1.12). Longer-serving veterans were at significantly lower risk of death than non-veterans; the risk decreased both with length of service and in more recent birth cohorts. Smoking-related disease was the greatest contributor to increased mortality in early leavers. CONCLUSIONS: Among longer-serving veterans, there was evidence of a HWE partly attributable to selective attrition of early service leavers, but birth cohort analysis suggests improvements over time which may also reflect a causal effect of improved in-service health promotion.

Self-reported skin problems and the healthy worker effect in the general working population of Norway: a three-year prospective study.

Objectives This study aimed to assess whether the occurrence of skin problems in 2006 (baseline) was associated with response frequency, quitting a job due to health problems, and change in occupational skin exposures in 2009. Methods We conducted a three-year prospective study of the general working population of Norway. Associations between baseline indicators (sex, age, education, occupation), and occurrence of skin problems with response frequency at follow-up were assessed with Chi-square test and unconditional logistic regression. Associations between the occurrence of skin problems at baseline with quitting a job due to health problems and skin exposure at follow-up were also assessed with unconditional logistic regression. Results We found no evidence of an association between the occurrence of skin problems at baseline and a lower response frequency at follow-up. Age, sex, education, and occupation were the most important predictors for response at follow-up. Skin problems at baseline consistently predicted quitting a job due to health problems at follow-up. No evidence of change in the patterns of occupational skin exposures at follow up in 2009 was found for workers reporting skin problems in 2006. Conclusion While skin problems at baseline were not related to a lower response frequency at follow-up, our results suggest that workers reporting skin problems may quit their jobs due to health problems. Preventive efforts are still needed to reduce hazardous occupational skin exposures among workers reporting skin problems.

Mortality and cancer incidence among female Australian firefighters.

OBJECTIVES: To investigate the mortality and cancer incidence of female firefighters, a group where there are limited published findings. METHODS: Participating fire agencies supplied records of individual firefighters including the number and type of incidents attended. The cohort was linked to the Australian National Death Index and Australian Cancer Database. Standardised mortality ratios and standardised cancer incidence ratios were calculated separately for paid and volunteer firefighters. Volunteer firefighters were grouped into tertiles by the duration of service and by a number of incidents attended and relative mortality ratios and relative incidence ratios calculated. RESULTS: For volunteer firefighters (n=37 962), the overall risk of mortality and risk from all major causes of death were reduced when compared with the general population whether or not they had ever attended incidents. Volunteer firefighters had a similar cancer incidence when compared with the general population for most major cancer categories. Female volunteer firefighters have usually attended few fires. Of those who had turned out to incidents, only one-third had attended more than 12 fires about half the number for male volunteers. Mortality and cancer incidence for paid female firefighters (n=1682) were similar to the general population but the numbers were small and so power was limited. CONCLUSIONS: Female volunteer firefighters have a cancer incidence similar to the general population but a reduced risk of mortality which is likely to be a result of a 'healthy volunteer' effect.Most of the paid female firefighters were relatively recent recruits and it will be important to monitor the health of this group as more women are recruited to front-line firefighting roles.

Suicides of Male Portuguese Police Officers - 10 years of National Data.

Background: Police officers, as first responders to difficult situations with ready access to firearms, are frequently considered to be at increased suicide risk. Aims: We aimed to calculate the suicide rate for male officers of the Portuguese National Police (PSP) and compare it with the Portuguese general population. Method: Retrospective review of the PSP male officers' suicides between 2005 and 2014 and comparison with the suicide rate for the general Portuguese population, adjusted for sex and age. Results: A total of 39 suicides were identified, with 34 using a firearm - mostly the service one (30 cases). The average truncated (20-59 years) suicide rate for male officers was 20.6 per 100,000 person-years (95% CI =14.2-27.1). Over the same period, the rate for the general Portuguese population was 13.9 per 100,000 person-years (95% CI = 13.5-14.3). The standardized rate ratio was 1.5 (95% CI = 0.9-2.4). Limitations: Despite the 10-year period of observation, this is a small sample and there are issues with missing data, such as lack of information for retired or dismissed police officers. Denominators were converted to estimates of person-years observations and we should be mindful of the limitations in the validity of the reported rates. Conclusion: Portuguese male police officers mostly die by suicide using service firearms. The suicide rates among them were not statistically different from those of the sex- and age-adjusted general population. However, given that police officers are healthy workers, we would expect lower rates - thus, similar rates could suggest an increased risk in the study sample.

Switchability of Gabapentin Formulations: A Randomized Trial to Assess Bioequivalence Between Neurontin and Gabasandoz on the Individual Subject Level.

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800 mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between-batch and between-formulation variability in exposure play a significant role in the within-subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being -2.01 and -2.31 for area under the concentration-time curve from zero to infinity (AUC0-inf ) and peak plasma concentration (Cmax ), respectively. Subject-by-formulation variability (1.35%) was negligible compared with the within-subject variability of AUC0-inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within-subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800 mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.

Mortality by cause of death and risk behaviors in farmers versus non-farmers: the importance of avoiding the healthy worker effect.

OBJECTIVES: To compare mortality by cancer sites and by other specific causes of death, and the prevalence of risk behaviors in farmers and non-farmers in Spain. METHODS: Mortality by cause of death was calculated based on a longitudinal study with 10-years follow-up of 9.5 million men and 6 million women aged 20-64 years who were employed in 2001. The prevalence of risk behaviors was calculated from the 2001 National Health Survey in the 6464 employed men and 5573 employed women aged 20-64. The study subjects were grouped as farmers and non-farmers. For each cause of death, we estimated the ratio of age-standardized mortality rates, and for each risk behavior we estimated the age-standardized prevalence ratio in farmers versus non-farmers. RESULTS: In men, the mortality rate for most cancer sites did not differ significantly between farmers and non-farmers, except for cancers of the lip, oral cavity, stomach, larynx and skin epidermoid carcinoma-which was higher in farmers-and cancers of the liver, pancreas and mesothelioma-which was lower in farmers. In contrast, farmers had a higher rate of mortality from most other diseases and from external causes of death. In women, farmers showed lower mortality from lung cancer, breast cancer and chronic lower respiratory disease, and higher mortality from external causes. The prevalence of smoking, excessive alcohol consumption, physical inactivity and obesity was higher in farmers than in non-farmers, except smoking and excessive alcohol consumption in women where prevalence was lower in farmers. CONCLUSIONS: Findings are different from those found in other studies. In men, greater exposure to the sun and the higher prevalence of risk behaviors in farmers could explain their excess mortality from some cancer sites and the other causes of death. However, other factors may be behind this excess risk of mortality from these causes, given that farmers did not show higher mortality from some cancers related to smoking. In women, no differences were observed in mortality rate for majority of causes of death between farmers and non-farmers.

Analysis of the association between ionizing radiation and mortality in uranium workers from five plants involved in the nuclear fuel production cycle in France.

PURPOSE: The aim is to investigate associations between mortality and exposure to ionizing radiation in a cohort of uranium workers with potential for internal and external radiation exposures. METHODS: Workers employed for at least 6 months between 1958 and 2006 in five plants involved in the French nuclear fuel cycle were included and followed up between 1968 and 2013. Cause-specific standardized mortality ratios were calculated. Analyses of associations between individual cumulative radiation dose (both internal and external, lagged by 5-15 years) and mortality were conducted using Poisson regression. RESULTS: The cohort includes 4541 workers. The mean cumulative external dose was 11.12 mGy. Mean cumulative internal doses ranged, depending on modelling hypotheses, from 0.05 to 0.09 mGy (liver) and from 4.22 to 10.90 mGy (lung). At the end of the follow-up, 838 workers were deceased and 28 lost to follow-up. A healthy worker effect was observed. The risk of prostate and lung cancers mortality was significantly higher for workers exposed to cumulative external dose above 50 mGy compared to non-exposed, but these associations were based only on three cases and became non-significant, although of similar magnitude, after adjustment for smoking. Associations with internal dose showed no consistent pattern. CONCLUSIONS: For the first time, a study was conducted in a French cohort of uranium workers with a complete reconstruction of internal dose. Results are preliminary and must be interpreted with caution because of the limited cohort size and significant sources of uncertainty. Future steps of this study will overcome these limitations.

Structure and Control of Healthy Worker Effects in Studies of Pregnancy Outcomes.

Much of the literature on the healthy worker effect focuses on studies of chronic disease and mortality; however, when studying pregnancy outcomes, these effects might differ because of the short, defined risk periods of most pregnancy outcomes. Three pregnancy-specific healthy worker effects have also been described, but the structure of these effects has not yet been investigated when occupational exposure, and not employment status, is the exposure of interest. We used directed acyclic graphs to examine healthy worker effects in studies of occupational exposures and pregnancy outcomes: the healthy hire effect, the healthy worker survivor effect, the desperation/privilege effect (differential workforce reentry after pregnancy), the reproductively unhealthy worker effect (women with live births leave the workforce, while women with nonlive births do not), and the insecure pregnancy effect (women with adverse pregnancy outcomes reduce their exposures in subsequent pregnancies). Given our assumptions, we conclude that the healthy hire effect, the desperation/privilege effect, the reproductively unhealthy worker effect, and the insecure pregnancy effect result from confounding that can be addressed if data on measured confounders, such as employment status, are available. The presence of the healthy worker survivor effect, however, varies by study design. Different types of healthy worker effects can be present in studies of occupational exposure and pregnancy outcomes, and many of them are easily addressed analytically.

Interactive effects of conditioned pain modulation and temporal summation of pain-the role of stimulus modality.

Conditioned pain modulation (CPM) and temporal summation of pain (TSP) are 2 experimental paradigms capturing endogenous pain modulation, which have repeatedly demonstrated clinical relevance. Conditioned pain modulation describes the inhibition of the pain response to a test stimulus (Ts) when a second noxious stimulus, the conditioning stimulus (CS), is concurrently applied. Temporal summation of pain describes the enhanced pain response to a series of stimuli compared with single stimuli. Temporal summation of pain-limiting effects of CPM are likely but may depend on the stimulus modality of the Ts. This study aimed at investigating these differential effects of stimulus modality. Thirty-five healthy volunteers completed 2 experimental blocks (Ts modality: pressure vs heat) in balanced order. Both blocks consisted of 3 conditions: baseline (no CS), CPM1 (nonpainful CS: 42°C water bath), and CPM2 (painful CS: 46°C water bath). Single stimuli and series of stimuli were alternatingly applied to assess TSP by means of a Numerical Rating Scale. Both TSP and CPM were successfully induced with no difference between the 2 Ts modalities. We also detected a significant interaction between TSP and CPM, with higher pain reduction for a series of Ts compared with single Ts during the painful CS. Interestingly, this interaction was modality-dependent: TSP for heat Ts was completely abolished by CPM, whereas this was not the case for pressure Ts. Our findings suggest different forms of central sensitization induced by TSP using either heat or pressure stimuli, which differ in their susceptibility to CPM. Clinical implications and directions for future research are discussed.