Risk of lymphoma subtypes by occupational exposure in Southern Italy

Background

Occupational exposure is known to play a role in the aetiology of lymphomas. The aim of the present work was to explore the occupational risk of the major B-cell lymphoma subtypes using a case–control study design.

Methods

From 2009 to 2014, we recruited 158 lymphoma cases and 76 controls in the provinces of Bari and Taranto (Apulia, Southern Italy). A retrospective assessment of occupational exposure based on complete work histories and the Carcinogen Exposure (CAREX) job-exposure matrix was performed.

Results

After adjusting for major confounding factors, farmers showed an increased risk of diffuse large B-cell lymphoma (DLBCL) [odds ratio (OR)?=?10.9 (2.3–51.6)] and multiple myeloma (MM) [OR?=?16.5 (1.4–195.7)]; exposure to the fungicide Captafol was significantly associated with risk of non-Hodgkin lymphoma (NHL) [OR?=?2.6 (1.1–8.2)], particularly with the risk of DLBCL [OR?=?5.3 (1.6–17.3)].

Conclusions

Agricultural activity seems to be a risk factor for developing lymphoma subtypes, particularly DLBCL, in the provinces of Bari and Taranto (Apulia Region, Southern Italy). Exposure to the pesticides Captafol, Paraquat and Radon might be implicated.

Trial registration

Protocol number UNIBA 2207WEJLZB_004 registered 22/09/2008.

     

An updated historical cohort mortality study of workers exposed to asbestos in a refitting shipyard, 1947�C2007

Purpose

To evaluate the long-term health effects of occupational asbestos exposure, an updated historical cohort mortality study of workers at a refitting shipyard was undertaken.

Methods

The cohort consisted of 249 male ship repair workers (90 laggers, 159 boiler repairers). To determine relative excess mortality, standardized mortality ratios (SMRs) were calculated using mortality rates among the Japanese male population. Mortality follow-up of study subjects was performed for the period from 1947 till the end of 2007.

Results

We identified the vital status of 87 (96.7%) laggers and 150 (94.3%) boiler repairers. Of these, 63 (72.4%) and 95 (63.3%), respectively, died. Laggers, who had handled asbestos materials directly, showed a significantly elevated SMR of 2.64 (95% confidence interval [CI]: 1.06?C5.44) for lung cancer and 2.49 (95% CI: 1.36?C4.18) for nonmalignant respiratory diseases. Boiler repairers, who had many opportunities for secondary exposure to asbestos and a few for direct exposure, showed no significant elevation in SMR for lung cancer but a significantly elevated SMR of 1.78 (95% CI: 1.06?C2.81) for nonmalignant respiratory diseases. In an analysis according to duration of employment, there was a significantly elevated SMR of nonmalignant respiratory diseases in the longer working years group. Among workers from both jobs, no deaths caused by mesothelioma in addition to those in the original study were found and no subject died from larynx cancer.

Conclusion

This updated study confirmed a significant excess of asbestos-related mortality from diseases such as lung cancer and nonmalignant respiratory diseases among workers in a refitting shipyard in Japan.     

Migration and geographical inequalities in health in the Netherlands: an investigation of age patterns

Objectives

This paper estimates, for six different age groups, whether and how migration influences inequalities in health between deprived and non-deprived neighbourhoods in the Netherlands.

Methods

Data were accessed from the Netherlands Housing Survey 2006. Using multi-level logistic regression analyses, we compared the health of migrants with that of nonmigrants in the area of origin and assessed the role of demographic and socioeconomic characteristics. Next, we assessed the magnitude of health differences between deprived versus non-deprived areas among migrants and non-migrants.

Results

For many age groups, migrants into non-deprived areas were healthier and migrants into deprived areas had similar levels of health compared with non-migrant populations in the area of origin. These differences in health were not explained by demographic and socio-economic characteristics. For all ages and for people aged 25–34 years we found smaller area inequalities in health among migrants compared with non-migrants. For most other age groups, about equally large differences were observed.

Conclusions

For most age groups, the results do not provide empirical support to the expectation that migration would enlarge health differences between deprived and non-deprived neighbourhoods.     

Air pollution exposure estimation using dispersion modelling and continuous monitoring data in a prospective birth cohort study in the Netherlands

Background

High temperature and humidity conditions are associated with short-term elevations in the mortality rate in many United States cities. Previous research has quantified this relationship in an aggregate manner over large metropolitan areas, but within these areas the response may differ based on local-scale variability in climate, population characteristics, and socio-economic factors.

Methods

We compared the mortality response for 48 Zip Code Tabulation Areas (ZCTAs) comprising Philadelphia County, PA to determine if certain areas are associated with elevated risk during high heat stress conditions. A randomization test was used to identify mortality exceedances for various apparent temperature thresholds at both the city and local scale. We then sought to identify the environmental, demographic, and social factors associated with high-risk areas via principal components regression.

Results

Citywide mortality increases by 9.3% on days following those with apparent temperatures over 34°C observed at 7:00 p.m. local time. During these conditions, elevated mortality rates were found for 10 of the 48 ZCTAs concentrated in the west-central portion of the County. Factors related to high heat mortality risk included proximity to locally high surface temperatures, low socioeconomic status, high density residential zoning, and age.

Conclusions

Within the larger Philadelphia metropolitan area, there exists statistically significant fine-scale spatial variability in the mortality response to high apparent temperatures. Future heat warning systems and mitigation and intervention measures could target these high risk areas to reduce the burden of extreme weather on summertime morbidity and mortality.     

Predictors of 3-year mortality in subjects over 95 years of age. The nonasantfeliu study

Objectives

To examine the survival rates of subjects aged 95 or over after a follow-up period of 3 years, and to determine predictive factors for mortality risk.

Design

A prospective cohort study.

Setting

A community-based study.

Participants

Forty-eight subjects aged 95 or over.

Measurements

Sociodemographic data, Barthel Index, Lawton-Brody Index, Spanish version of the Mini-Mental State Examination, short version of the Mini Nutritional Assessment, comorbidity (Charlson Index), and prevalent chronic diseases were evaluated. Patients who died were compared with the rest.

Results

Thirty-six deaths (75%) were recorded during follow-up. The Cox multivariate analysis showed that lower Barthel Index scores and a history of heart failure were independently associated with long-term mortality.

Conclusions

In subjects aged 95 or over, poor functional status and history of heart failure were the two independent risk factors for 3-year mortality.     

Open source GIS for HIV/AIDS management

Background

A growing body of research suggests that the suburbanization of food retailers in North America and the United Kingdom in recent decades has contributed to the emergence of urban 'food deserts', or disadvantaged areas of cities with relatively poor access to healthy and affordable food. This paper explores the evolution of food deserts in a mid-sized Canadian city (London, Ontario) by using a geographic information system (GIS) to map the precise locations of supermarkets in 1961 and 2005; multiple techniques of network analysis were used to assess changing levels of supermarket access in relation to neighbourhood location, socioeconomic characteristics, and access to public transit.

Results

The findings indicate that residents of inner-city neighbourhoods of low socioeconomic status have the poorest access to supermarkets. Furthermore, spatial inequalities in access to supermarkets have increased over time, particularly in the inner-city neighbourhoods of Central and East London, where distinct urban food deserts now exist.

Conclusion

Contrary to recent findings in larger Canadian cities, we conclude that urban food deserts exist in London, Ontario. Policies aimed at improving public health must also recognize the spatial, as well as socioeconomic, inequities with respect to access to healthy and affordable food. Additional research is necessary to better understand how supermarket access influences dietary behaviours and related health outcomes.     

„Primary Health Care“ und Urbanisierung

Background

The world of the twenty-first century will be a predominantly urban world. By the year 2008, for the first time in human history, more people were residing in cities than in rural areas. The process of urbanization was mostly completed in the industrialized countries by the mid-twentieth century. In developing countries, however, both number and proportion of city dwellers are increasing.

Methods

To review the process of urbanization in developing countries, its relevance for the social and health situation of urban populations and the consequences arising thereof for the concept of Primary Health Care (PHC).

Results

A rapid urbanization poses great challenges to city councils, e. g. concerning infrastructure and distribution of societal wealth. Today, the process of urbanization is accompanied by a lack of jobs in the formal sector and a change in lifestyle which is not conducive to health, e.g. high calorie and fatty foods. A disaggregation of the health situation shows strong intra-city differentials between wealthy neighbourhoods and slum areas. Slum dwellers remain exposed to communicable diseases and are in addition at risk for non-communicable, chronic diseases. Many of the most prevalent health problems have social causes. Such health problems will persist as long as their social causes are not mended. Evidence-based interventions for tackling social causes of illness are lacking, however.

Discussion

Urbanization poses new challenges to PHC. The present strategies, e.g. prevention, are often restricted to health symptoms and reach the middle classes rather than the urban poor. Instead, strategies directed towards a more human urbanization are required. They would have to make full use of the primary health care approach.     

Is obesity a marker of robustness in vulnerable hospitalized aged populations? Prospective,multicenter cohort study of 1 306 acutely ill patients

Background

The “obesity paradox” is poorly understood in vulnerable older hospitalized populations.

Objectives

To prospectively analyze the impact of body mass index (BMI) and comorbidities on early (6-week), one- and two-year mortality.

Design

Prospective multicenter study with a two-year follow-up of old patients participating in the SAFES cohort study.

Settings

Nine university hospitals in France.

Participants

Patients aged 75 or older hospitalized in medical divisions through the emergency department.

Measurement

Inpatients’ characteristics were obtained through a comprehensive geriatric assessment of inpatients, conducted in the first week of hospitalization. All-cause mortalities at 6-week, one- and two-year were determined using bivariable and multivariable Cox proportional hazard model.

Results

The SAFES cohort included 1,306 patients, aged 85±6 years, with a majority of women (65%). One- and two-year mortality were inversely associated with BMI ≥30 kg/m2 while early mortality was not, and positively associated with age, burden of comorbidities, walking disorders, level of dependency and presence of a dementia syndrome. Survival rates between patients in low (< 18.0 kg/m2) and intermediate (18–24.9 and 25–29.9 kg/m2) BMI categories were not significant.

Conclusion

While our findings seem to confirm the reality of the “obesity paradox” in vulnerable older hospitalized population, the exact understanding of underlying mechanisms and even the truthfulness of this paradoxical relationship are still fraught with considerable methodological, epidemiological and metabolic challenges.     

Blood lead,cadmium and mercury among children from urban,industrial and rural areas of Fez Boulemane Region (Morocco): Relevant factors and early renal effects

Objectives

To describe blood lead (Pb-B), cadmium (Cd-B) and mercury (Hg-B) levels in children living in urban, industrial and rural areas in Fez city (north of Morocco) and to identify the determinants and some renal effects of exposure.

Material and Methods

The study was conducted from June 2007 to January 2008 in 209 school children (113 girls, 96 boys), aged 6–12 years, from urban, industrial and rural areas in Fez city. Interview and questionnaires data were obtained. Blood and urinary samples were analyzed.

Results

The mean of blood lead levels (Pb-B) in our population was 55.53 μg/l (range: 7.5–231.1 μg/l). Children from the urban area had higher blood lead levels (BLLs) mean (82.36 μg/l) than children from industrial and rural areas (48.23 and 35.99 μg/l, respectively); with no significant difference between boys and girls. BLLs were associated with traffic intensity, passive smoking and infancy in the urban area. The mean of blood cadmium levels (BCLs) was 0.22 μg/l (range: 0.06–0.68 μg/l), with no difference between various areas. Rural boys had higher BCLs mean than rural girls, but no gender influence was noticed in the other areas. BCLs were associated with the number of cigarettes smoked at children’s homes. The blood mercury levels (BMLs) mean was 0.49 μg/l (range: 0.01–5.31 μg/l). The BMLs mean was higher in urban and industrial areas than in the rural area with no gender-related difference. BMLs were associated with amalgam fillings and infancy in the urban area. About 8% of the children had BLLs ≥ 100 μg/l particularly in the urban area, microalbuminuria and a decrease in height were noticed in girls from the inner city of Fez and that can be related to high BLLs (89.45 μg/l).

Conclusions

There is a need to control and regulate potential sources of contamination by these trace elements in children; particularly for lead.     

Distributed lag associations between respiratory illnesses and mortality with suspended particle concentration in Tula, a highly polluted industrial region in Central Mexico

Purpose

We aimed to evaluate the association between changes in airborne particulate matter concentration (PM) with changes in cases of mortality, acute respiratory infections (ARI) and asthma over 2004–2008 in an industrialized and polluted region in central Mexico.

Methods

A generalized linear model with a Poisson distribution and a negative binomial analysis was used to evaluate the influence of PM and temperature on all-cause mortality (All-cause-M), cause-specific mortality (Cause-specific-M), ARI and asthma, using cubic spline functions and distributed lags of PM. Estimated changes in relative risk were calculated for an exposure corresponding to each increase of 10 μg/m³ in PM level.

Results

Associations between PM and mortality and morbidity were statistically most consistent for total suspended particulate (TSP) than for particulate matter <10 μM aerodynamic diameter (PM₁₀). The greatest effects in mortality were observed with a 3-week lag, and effects were greater for Cause-specific-M. We also found a displacement effect up to 4-week lag for Cause-specific-M and TSP. The greatest effects in morbidity were observed at 0-week lag, yet they were statistically marginal and were greater for asthma. We found a displacement effect at 4–5–6-week lag for asthma and TSP. All associations of mortality and morbidity, expressed as change in relative risk, were greater with PM₁₀; however, all of them were statistically marginal.

Conclusions

Increased respiratory morbidity and mortality is associated with weekly changes of PM air pollution in the region. A reduction in air pollutants from industrial sources would benefit life quality and health of the exposed population.     

Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka

Background

The alarming rise in the prevalence of chronic kidney disease of uncertain etiology (CKDu) among the low socioeconomic farming community in the North Central Province of Sri Lanka has been recognized as an emerging public health issue in the country.

Methods

This study sought to determine the possible factors associated with the progression and mortality of CKDu. The study utilized a single-center cohort registered in 2003 and followed up until 2009 in a regional clinic in the endemic region, and used a Cox proportional hazards model.

Results

We repeatedly found an association between disease progression and hypertension. Men were at higher risk of CKDu than women. A significant proportion of the patients in this cohort were underweight, which emphasized the need for future studies on the nutritional status of these patients.

Conclusions

Compared with findings in western countries and other regions of Asia, we identified hypertension as a major risk factor for progression of CKDu in this cohort.     

Malnutrition in Turkish nursing homes: A correlate of short term mortality

Objective

Elderly nursing home residents are under high risk of malnutrition. Early interventions to prevent malnutrition may play a critical role in malnutrition-mortality correlation. This study aimed to obtain insight into the prevalence of malnutrition in nursing homes in the capital city of Turkey and the role of malnutrition in predicting the risk for short-term mortality.

Design

This study was conducted in seven different residential care facilities in Ankara.

Measurements

Nutritional status was evaluated by Mini Nutritional Assessment-Short Form.

Results

The mean age of the 534 participants was 79.46±7.22 years. Nutritional assessment revealed that 15.9% of all older adults suffered from malnutrition and another 53.6% were at risk of malnutrition. The mortality rate for all subjects was 118 (22.1%) over 18 months, which was significantly higher in participants with malnutrition.

Conclusions

We noted a high prevalence of malnutrition and a strong correlation of increased mortality with malnutrition in nursing home residents. Given the negative impact of malnutrition on mortality and morbidity, an emphasis should be placed on an effective nutritional policy in nursing homes.     

Neighbourhood context and abuse among immigrant and non-immigrant women in Canada: findings from the Maternity Experiences Survey

Objectives

To examine the relationship between neighbourhood deprivation and concentration of immigrants, and abuse among immigrant women versus non-immigrant women.

Methods

Using data from the Canadian Maternity Experiences Survey (un-weighted sample N?=?5,679 and weighted sample N?=?68,719) linked to the neighbourhoods Census data, we performed contextual analysis to compare abuse prevalence among: immigrants ≤5?years, immigrants >5?years and Canadian-born. We identified two level effect modifiers: living in high (≤15?% of households at or below low-income cut-off- [LICO]) versus low-income (>15?% below LICO) neighbourhoods and living in high (≥25?%) versus low immigrant (<25?%) neighbourhoods. Individual socioeconomic position (SEP), family variables and neighbourhood SEP or percentage of immigrants were considered in different logistic regression models.

Results

Immigrant women were less likely to experience abuse even upon adjustment for individual SEP, family variables and neighbourhood characteristics. The protective effect of the neighborhood was stronger among immigrant women living in low-income and high immigrant neighborhoods, irrespective of length of stay in Canada.

Conclusion

Policies and interventions to reduce abuse among immigrant women need to consider neighbourhood’s SEP and concentration of immigrants.     

Moderate alcohol consumption predicts long-term mortality in elderly subjects with chronic heart failure

Objective

Moderate alcohol consumption is related to a reduction of mortality. However, this phenomenon is not well established in the elderly, especially in the presence of chronic heart failure (CHF). The aim of the study was to verify the effect of moderate alcohol consumption on 12-year mortality in elderly community-dwelling with and without CHF.

Settings

community-dwelling from 5 regions of Italy.

Participants

A cohort of 1332 subjects aged 65 and older.

Measurement

Mortality after 12-year follow-up in elderly subjects (≥65 years old) with and without CHF was studied. Moderate alcohol consumption was considered ≤250 ml/day (drinkers).

Results

In the absence of CHF (n=947), mortality was 42.2% in drinkers vs. 53.7% in non-drinker elderly subjects (p=0.021). In contrast, in the presence of CHF (n=117), mortality was 86.5% in drinkers vs. 69.7% in non-drinker elderly subjects (p=0.004). Accordingly, Cox regression analysis shows that a moderate alcohol consumption is protective of mortality in the absence (HR=0.79; CI 95% 0.66–0.95; p<0.01) but it is predictive of mortality in the presence of CHF (HR=1.29; CI 95% 1.05–1.97; p<0.05).

Conclusions

Our data demonstrates that moderate alcohol consumption is associated with an increased long-term mortality risk in the elderly in the presence of CHF.     

Dairy intake in relation to cardiovascular disease mortality and all-cause mortality: the Hoorn Study

Purpose

Existing data from prospective cohort studies on dairy consumption and cardiovascular diseases are inconsistent. Even though the association between total dairy and cardiovascular diseases has been studied before, little is known about the effect of different types of dairy products on cardiovascular diseases (CVD). The objective of this study was to examine the relationship between (type of) dairy intake and CVD mortality and all-cause mortality in a Dutch population.

Methods

We examined the relationship between dairy intake and CVD mortality and all-cause mortality in 1956 participants of the Hoorn Study (aged 50–75 years), free of CVD at baseline. Hazard ratios with 95 % CIs were obtained for CVD mortality and all-cause mortality per standard deviation (SD) of the mean increase in dairy intake, with adjustment for age, sex, BMI, smoking, education, total energy intake, alcohol consumption, physical activity, and dietary intakes.

Results

During 12.4 years of follow-up, 403 participants died, of whom 116 had a fatal CVD event. Overall dairy intake was not associated with CVD mortality or all-cause mortality. Each SD increase in high-fat dairy intake was associated with a 32 % higher risk of CVD mortality (95 % CI; 7–61 %).

Conclusion

In this prospective cohort study, the intake of high-fat dairy products was associated with an increased risk of CVD mortality.     

Three-year follow-up of physical activity in Norwegian youth from two ethnic groups: associations with socio-demographic factors

Background

Effective promotion of physical activity in low income communities is essential given the high prevalence of inactivity in this sector.

Methods

This study explored determinants of engaging in physical activity in two Irish city based neighbourhoods using a series of six focus groups and twenty five interviews with adult residents. Data were analysed using constant comparison methods with a grounded theory approach.

Results

Study findings centred on the concept of 'community contentment'. Physical activity was related to the degree of contentment/comfort within the 'self' and how the 'self' interacts within the neighbourhood. Contemporary focus on outer bodily appearance and pressure to comply with societal expectations influenced participants' sense of confidence and competence. Social interaction, involvement, and provision of adequate social supports were viewed as positive and motivating. However normative expectations appeared to affect participants' ability to engage in physical activity, which may reflect the 'close knit' culture of the study neighbourhoods. Access to suitable local facilities and amenities such as structured and pleasant walking routes was regarded as essential. Indeed participants considered walking to be their preferred form of physical activity which may relate to the minimal skill requirement, ease of access and low financial costs incurred.

Conclusion

In the context of physical activity, health promoters need to be conscious of the difficulties that individuals feel in relation to bodily appearance and the pressure to comply with societal standards. This may be particularly relevant in low income settings where insufficient allocation of resources and social supports means that individuals have less opportunity to attend to physical activity than individuals living in higher income settings.     

Distribution and trends in mesothelioma mortality in Italy from 1974 to 2006

Purpose

Using the epidemiological data of pleural cancer mortality, the authors estimated time trends and distribution of malignant mesothelioma in Italy during the period 1974–2006.

Methods

To describe temporal trends of the standardized mortality ratios (SMRs) in all the 20 Italian regions, we applied the Joinpoint Regression Model, developed by the National Cancer Institute (USA). The 107 provincial SMRs are represented on maps by using the Arcview GIS software (version 3.2).

Results

The high values from mesothelioma mortality in construction and shipbuilding sectors, previously reported, are confirmed by our analyses. Furthermore, data show that the annual percentage change is still growing: statistically significant increments in time trends are observed for 11 of 20 Italian regions. Of additional concern has been the identification of changes in 9 of 20 trends partially due to the misdiagnosis in the past.

Conclusions

Given the long latency of mesothelioma, preventive and legal measures with the ban of asbestos in Italy since 1992 are still not giving effects on mesothelioma mortality trends.     

The short-form mini-nutritional assessment is as effective as the full-mini nutritional assessment in predicting follow-up 4-year mortality in elderly Taiwanese

Objective

To compare the mortality-predictive ability of the full- and short-form (SF) Mini Nutritional Assessment (MNA).

Design

A prospective cohort study.

Setting

Population-representative sample.

Participants

2872 ≥65-year old men and women.

Measurements

The study analyzed 1999 and 2003 datasets of the Taiwan Longitudinal Survey on Aging (TLSA). Subjects were graded for nutritional status with the full-MNA and MNA-SF of a Taiwanese-specific version (T2, containing calf circumference instead of BMI) at baseline (1999) and tracked their survival status for 4 years. Mortality-predictive abilities of the full-MNA and MNA-SF were compared using Cox regression analysis and Net Reclassification Improvement (NRI).

Results

The full-MNA and MNA-SF have comparable abilities in predicting follow-up 4-year mortality risk according to the hazard ratios (all p<0.001) and Akaike information criterion (AIC). It also showed a slight improvement (not significant) if the full-MNA in a predictive model was replaced by the MNA-SF (NRI=0.09%, p=0.956).

Conclusion

The MNA-SF has at least comparable or even slightly better ability in predicting follow-up 4-year mortality risk of elderly Taiwanese. Results suggest that MNA-SF with calf circumference may possess some basic characteristics of a comprehensive and universal geriatric screening scale.     

Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg)

Purpose

To prospectively evaluate the association of vitamin/mineral supplementation with cancer, cardiovascular, and all-cause mortality.

Methods

In the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), which was recruited in 1994–1998, 23,943 participants without pre-existing cancer and myocardial infarction/stroke at baseline were included in the analyses. Vitamin/mineral supplementation was assessed at baseline and during follow-up. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

After an average follow-up time of 11?years, 1,101 deaths were documented (cancer deaths?=?513 and cardiovascular deaths?=?264). After adjustment for potential confounders, neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer, cardiovascular, or all-cause mortality. However, baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality (HR: 0.52; 95% CI: 0.28, 0.97) and all-cause mortality (HR: 0.58; 95% CI: 0.38, 0.88). In comparison with never users, baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality (HR: 1.74; 95% CI: 1.09, 2.77) and all-cause mortality (HR: 1.58; 95% CI: 1.17, 2.14).

Conclusions

Based on limited numbers of users and cases, this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality. The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a “sick-user effect,” which researchers should be cautious of in future observational studies.