Low Cumulative Exposure Research Articles

Lifelong prevention of atherosclerotic cardiovascular disease (ASCVD) through LDL-C control - Means and cost/benefit of sustained very low lifetime LDL-C targets

Central illustration. Coloured bars in the left panel show the impact of age and ethnicity on an individual's lifetime ASCVD risk mediated by cumulative exposure to LDL-C. Even younger individuals with a greater cumulative exposure to LDL-C, despite their age, may have a higher overall risk compared to older individuals with a lower cumulative exposure to LDL-C.Image, graphical abstract.

Comparing pill counts and patient self-reports versus DBS tenofovir concentrations as ART adherence measurements with virologic outcomes and HIV drug resistance in a cohort of adolescents and young adults failing ART in Harare, Zimbabwe

BackgroundMonitoring adherence presents a challenge in adolescents and it is prudent to explore several options for determining their level of adherence. This study sought to determine ART adherence levels in adolescents and young adults (on a tenofovir-containing regimen) failing ART as measured by self-reports, pill counts and DBS tenofovir concentrations and to compare levels of agreement among the methods and determine the ability of each method to predict virological suppression. MethodsThis was a cohort study involving 107 adolescents and young adults between 10 and 24 years failing ART with viral load > 400copies/ml at enrolment. Pill count (PC) records, self-reports (SR) and DBS tenofovir concentrations (done by liquid Chromatography with tandem mass spectrometry (LC-MS/MS)) were used to determine adherence in adolescent participants failing ART in Harare. The latter was used as the reference method with a cut-off of 64 ng/ml. Determination of DBS tenofovir concentrations was also performed to rule out inadequate viral response due to low cumulative drug exposure despite high adherence (≥90 %). Longitudinal analysis was performed to determine the correlation of viral loads (VL) with adherence. The Kappa (k) coefficient was used to evaluate the level of agreement among the 3 methods. ResultsPoor level of agreement was found between PC records and DBS tenofovir concentrations (k = −0.115). Moderate agreement was found between DBS and SR methods (k = 0.0557). Slight agreement was found between PC and SR methods (k = 0.0078). Adherence was dependent on age at HIV diagnosis (p = 0.0184) and ART initiation (p = 0.0265). Participants who were adherent were six times more likely to be suppressed at end point than their non-adherent counterparts (OR=5.7 CI 2.1 – 16.5, p < 0.0001). ConclusionsSelf-reported measure of adherence and pill counts exhibited poor agreement with the reference method used i.e. DBS tenofovir concentrations and are thus not effective methods of predicting virological suppression. Trial identificationParticipants in the present study were a subset of those in the PESU intervention ClinicalTrials.gov Identifier: NCT02833441

Occupational exposure to respirable crystalline silica and incident idiopathic interstitial pneumonias and pulmonary sarcoidosis: a national prospective follow-up study

BackgroundRespirable crystalline silica is a well-known cause of silicosis but may also be associated with other types of interstitial lung disease. We examined the associations between occupational exposure to respirable...

#2477 Longitudinal serum bicarbonate and mortality risk in older patients with advanced chronic kidney disease: analyses from the EQUAL cohort

Abstract Background and Aims Serum bicarbonate (SBC) disorders have been consistently linked to mortality in chronic kidney disease (CKD) patients. Low SBC levels have been extensively associated with increased mortality in CKD patients, possibly due to the detrimental effects of acidosis on various organs and systems. Likewise, several studies have identified high levels of SBC as a risk factor for mortality in the CKD population. To date, most studies have focused on the association between SBC levels and patient survival during the pre-kidney replacement therapy (KRT) period or the period after KRT initiation, considered separately. None have explored this association across the continuum of CKD (e.g., from pre-KRT to post-KRT start), which is relevant since metabolic acidosis is expected to be managed through dialysis in the KRT population, and thus its clinical outcomes might change after KRT initiation. To provide new insights on this topic, we aimed to explore the relationship between SBC and mortality in advanced CKD during three distinct treatment periods: during the pre-KRT period, during the transition phase surrounding the start of KRT (transition-CKD), and during KRT. Method Using the European QUALity Study on treatment in advanced CKD (EQUAL) cohort, which includes patients aged ≥65 years and eGFR ≤20 ml/min per 1.73 m2 from six European countries, we explored the association between longitudinal SBC and all-cause mortality in three separate CKD populations: pre-KRT, transition-CKD and in the KRT populations, using multivariable time-dependent Cox regression models. The cumulative time-averaged, the cumulative exposure of SBC, and the slope of the SBC trajectory during the pre-KRT phase were calculated and evaluated for association with all-cause mortality in the transition-CKD population. Subgroup analysis were used to evaluate the effect modification by pre-specified variables on the relationship between SBC and mortality. Results We included 1485 patients with a median follow-up of 2.9 (IQR 2.7) years, during which 529 (35.6%) patients died. A U-shaped relationship between SBC levels and all-cause mortality was observed in the pre-KRT population (p = 0.03; Fig.). Low cumulative exposure, defined as the area under the SBC trajectory before KRT initiation, was associated with increased mortality risk after transitioning to KRT (p = 0.01). Similarly, in the KRT population, low SBC levels showed a trend towards increased mortality risk (p = 0.13). We observed effect modification on the relationship between SBC and mortality by subjective global assessment category (p-value for interaction = 0.02) and KRT initiation (p-value for interaction = 0.02). Conclusion Our study has provided important insights into the relationship between SBC and mortality in advanced CKD patients. A U-shaped relationship describes the association between SBC and mortality in the advanced CKD pre-KRT population, whereas in patients that initiate KRT only low SBC levels are associated with an increased mortality risk. Our findings suggest that the relationship between SBC and mortality varies across different stages of CKD and that this relationship is modified by KRT initiation. From this point of view, it would be appropriate to consider a personalized management of acid-base balance disorders based on a comprehensive evaluation of the clinical status of the patient.

#2509 Longitudinal haemoglobin levels and mortality in an elderly population with advanced chronic kidney disease: insights from the EQUAL Study

Abstract Background and Aims The relationship between haemoglobin (Hb) levels and clinical outcomes in chronic kidney disease (CKD) is more intricate than previously understood, as both low and high values can have detrimental effects. Although the association between Hb and patient outcomes is widely reported, few studies have focused on older patients with advanced CKD or have explored this relationship both before and after kidney replacement therapy (KRT) initiation. The primary objective of this study is to describe the relationship between Hb levels and mortality in older patients with advanced CKD in the continuum from pre-KRT phase to subsequent KRT initiation, and to evaluate any effect modification by KRT initiation. Method We used data from the European QUALity Study on treatment in advanced CKD (EQUAL) cohort which includes patients aged ≥65 years and eGFR ≤20 ml/min per 1.73 m2 from six European countries. The association between Hb and all-cause and cause-specific mortality (cardiovascular [CV] and non-cardiovascular [non-CV] mortality) was explored in three separate CKD populations: pre-KRT, KRT and transition-CKD (transition phase surrounding the start of KRT) population. Multivariable adjusted time-dependent Cox regression models and natural cubic splines were used to investigate the association between longitudinal Hb levels (as categorical and continuous variable) and mortality risk in the pre-KRT and KRT population. The area under the Hb trajectory (AUC Hb) before KRT initiation was calculated to evaluate the relationship between the cumulative exposure of Hb before KRT initiation and all-cause mortality after KRT initiation in the transition-CKD population. We evaluated effect modification by pre-specified variables on the relationship between Hb and mortality. Results Overall, 1716 CKD patients were included in the study. During a median follow up of 3.0 years (IQR 2.6), 614 patients died, resulting in a 5-year survival probability of 51% (95% CI 48, 55). Low Hb levels were consistently associated with increased mortality risk in all study populations (Figure). A U-shaped association between both the lowest and highest levels of Hb and mortality risk was observed (Figure). A similar association was observed for non-CV mortality, with lower Hb values associated with an increased mortality risk (Figure). Conversely, a trend towards higher risk of cardiovascular death was observed as Hb levels increase, especially in the whole population and pre-KRT population (Figure), albeit not statistically significant. Low cumulative exposure of Hb in the transition-CKD population was associated with increased mortality risk after transitioning to KRT (p = 0.047). In subgroup analysis diabetic patients were more susceptible to low Hb levels (p-value for interaction = 0.003) while patients on ESA therapy (p-value for interaction = 0.005) or initiating KRT (p-value for interaction = 0.024) showed increased mortality risk for high Hb levels. Conclusion The relationship between Hb levels and mortality in advanced CKD patients is complex. Low Hb levels consistently indicate an increased risk of mortality, while high Hb levels also appear to have a negative effect, increasing mortality risk, particularly in patients receiving ESA therapy and after KRT initiation. Our work emphasizes how different stages of advanced kidney disease (i.e., before and after initiating KRT), as well as comorbidities such as diabetes or medications such as ESA therapy can significantly influence the relationship between Hb and mortality.

Risk assessment of multiple pesticide residues in Agrocybe aegerita: Based on a 3-year monitoring survey

The presence of pesticide residues in Agrocybe aegerita has raised an extensive concern. In this paper, based on a 3-year monitoring survey, the dietary exposure risks through A. aegerita consumption for different population subgroups were assessed using both deterministic and semi-probabilistic approaches under the best-case and the worst-case scenarios. Among the 52 targeted pesticides, 28 different compounds were identified in the concentration range of 0.005–3.610 mg/kg, and 87.4 % of samples contained one or more pesticide residues. The most frequently detected pesticide was chlormequat, followed by chlorfenapyr and cyhalothrin. The overall risk assessment results indicated extremely low chronic, acute, and cumulative dietary exposure risks for consumers. Using the ranking matrix, intake risks of pesticides were ranked, revealing endsoluran, chlorpyrifos, and methamidophos to be in the high-risk group. Finally, considering various factors such as the toxicity and risk assessment outcomes of each positive pesticide, use suggestions were proposed for A. aegerita cultivation.

Multiple human activities in coastal benthic ecosystems: Introducing a metric of cumulative exposure

Co-occurring anthropogenic activities influence coastal ecosystems around the world. Notions of ecological exposure are promising indicators to better understand environmental status and enhance ecosystem protection. This study characterized anthropogenic exposure in the context of multiple human activities on coastal benthic ecosystems at a scale of &amp;lt;100 km. Using a particle diffusion model and fishing event data, we developed an exposure index for seven human activities (aquaculture, artificial structures, dredging, fisheries, runoff, sewers and shipping) in a Canadian industrial harbour area. A generally low cumulative exposure was obtained, with the highest values observed directly in front of the city and industrial areas. Derived exposure indices explained a portion of the benthic community structure (R2 = 0.22), suggesting an ecological link between the exposure of species and their vulnerability to human activities. Such tools are relevant in data-poor environments where proxies are required to assess the state of an ecosystem, facilitating the application of ecosystem-based management.

Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 μg and those who received a weight-based dose of 0.45 μg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 μg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

Disease course and treatment outcomes of Crohn's disease patients with early or late surgery - A Danish nationwide cohort study from 1997 to 2015.

Studies on early surgery among Crohn's disease patients are few and focus on ileocolonic resections. The aim of this nationwide cohort study was to investigate the disease course in all Crohn's disease patients who underwent early and late major abdominal surgery. In a Danish nationwide cohort of Crohn's disease patients from 1997 to 2015 we included 493 patients (group 1) resected within 29 days, 472 patients (group 2) resected between 30 and 180 days, and 1,518 patients (group 3) resected after 180 days of diagnosis. Re-operation, hospitalisations and medications were analysed. The cumulative risk of re-operation was lower among patients from group 1 (five-year risk: 16.5% vs. group 2: 18.2% and group 3: 21.2%, p=0.004). Fewer patients from group 2 and 3 required hospitalisations (269 (56.5%) and 803 (52.8%) vs. group 1: 329 (66.8%) p<0.001). Patients from group 3 had a higher cumulative use of immunomodulators in the first three years after initial surgery (one-year risk: 24.6% vs. group 1: 19.4% and group 2: 17.0%, p<0.001). Crohn's disease patients resected within 29 days of diagnosis had a lower cumulative risk of re-operation and a lower cumulative exposure to immunomodulators in the initial years after surgery.

Viral Integration Plays a Minor Role in the Development and Prognostication of Oral Squamous Cell Carcinoma.

Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance.

Neighborhood deprivation and obesity: Sex-specific effects of cross-sectional, cumulative and residential trajectory indicators

Obesity is a long-term health issue that is becoming increasingly prevalent. Very few studies have considered the life course effects of neighborhood characteristics on obesity. In a sample of 35,856 adult participants (representative of the population of the Province of Quebec in Canada), we measured the association between neighborhood deprivation and obesity using logistic modelling on indicators of cross-sectional neighborhood deprivation, cumulative neighborhood deprivation and trajectories of neighborhood deprivation. For cross-sectional exposure, we found that females in our sample had higher odds of being affected by obesity when living in high-deprivation (OR 1.73, CI 1.41–2.13) or medium-deprivation neighborhoods (OR 1.27, CI 1.07–1.51) compared to females living in low-deprivation neighborhoods. Males also had higher odds of being affected by obesity when living in medium or high deprivation. For cumulative exposure to neighborhood deprivation, only females in the second highest category for longitudinal exposure to deprived neighborhoods had significantly higher odds of living with obesity (OR 1.89 CI 1.12–3.19) compared to females in the low cumulative exposure category. Using sequence analysis to determine neighborhood deprivation trajectories for up to 17 years, we found that females with a Deprived upward (OR 1.75 CI 1.10–2.78), an Average downward (OR 1.75 CI 1.08–2.84) or a Deprived trajectory (OR 1.81 CI 1.45–2.86) had higher odds of living with obesity compared to the Privileged trajectory. For males, there were no significant associations. Using trajectory indicators was beneficial to our analyses because this method shows that not only are individuals in low socioeconomic status neighborhoods at the end of their trajectory more susceptible to living with obesity, but so are those exposed to neighborhood deprivation at the beginning of their trajectory. These results could help to more precisely identify individuals at higher risk of developing obesity-related health issues.

Benzene exposure and risk of benzene poisoning in Chinese workers

ObjectivesBenzene is a known haematoxin and leukemogen that can cause benzene poisoning (BP), that is, a persistent reduction in white cell counts that is strongly associated with increased risk of...

Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials.

Angiotensin-receptor blockers (ARBs) are a class of drugs approved for the treatment of several common conditions, such as hypertension and heart failure. Recently, regulatory agencies have started to identify possibly carcinogenic nitrosamines and azido compounds in a multitude of formulations of several ARBs, resulting in progressive recalls. Furthermore, data from several randomized controlled trials suggested that there is also a clinically increased risk of cancer and specifically lung cancer with ARBs; whereas other trials suggested no increased risk. The purpose of this analysis was to provide additional insight into the ARB-cancer link by examining whether there is a relationship between degree of cumulative exposure to ARBs and risk of cancer in randomized trials. Trial-level data from ARB Trialists Collaboration including 15 randomized controlled trials was extracted and entered into meta-regression analyses. The two co-primary outcomes were the relationship between cumulative exposure to ARBs and risk of all cancers combined and the relationship between cumulative exposure and risk of lung cancer. A total of 74,021 patients were randomized to an ARB resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent). 61,197 patients were randomized to control. There was a highly significant correlation between the degree of cumulative exposure to ARBs and risk of all cancers combined (slope = 0.07 [95% CI 0.03 to 0.11], p<0.001), and also lung cancer (slope = 0.16 [95% CI 0.05 to 0.27], p = 0.003). Accordingly, in trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk of all cancers combined (I2 = 31.4%, RR 1.11 [95% CI 1.03 to 1.19], p = 0.006). There was a statistically significant increase in risk of lung cancers in trials where the cumulative exposure was greater than 2.5 years (I2 = 0%, RR 1.21 [95% CI 1.02 to 1.44], p = 0.03). In trials with lower cumulative exposure to ARBs, there was no increased risk of all cancers combined or lung cancer. Cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme inhibitor treatment or the type of control (i.e. placebo or non-placebo control). Since this is a trial-level analysis. the effects of patient characteristics such as age and smoking status could not be examined due to lack of patient-level data. In conclusion, this analysis, for the first time, reveals that risk of cancer with ARBs (and specifically lung cancer) increases with increasing cumulative exposure to these drugs. The excess risk of cancer with long-term ARB use has public health implications.

Low-dose oral corticosteroids in asthma associates with increased morbidity and mortality.

Long-term oral corticosteroid (OCS) treatment for severe asthma is known to cause significant adverse effects, but knowledge on effects of lower exposures in general asthma populations is limited. We aimed to explore this in a nationwide Danish asthma population. Users of asthma medication aged 18-45 years were identified in the Danish nationwide registers during 1999-2018 and followed prospectively in an open-cohort design. Incident OCS users were matched 1:4 to nonusers by propensity scores with replacement. Associations between OCS use and incident comorbidities were examined by Cox regression. Mortality rates, causes of death and rates of unscheduled hospital visits were assessed. OCS users (n=30 352) had, compared with nonusers (n=121 408), an increased risk of all outcomes with evident dose-response relationships starting at cumulative doses of ≤500 mg (prednisolone-equivalent). Hazard ratios ranged from 1.24 (95% CI 1.18-1.30) for fractures to 8.53 (95% CI 3.97-18.33) for adrenal insufficiency. Depression/anxiety had the highest incidence rate difference at 4.3 (95% CI 3.6-5.0) per 1000 person-years. Asthma-specific mortality rates were generally low at 0.15 (95% CI 0.11-0.20) and 0.04 (95% CI 0.02-0.06) per 1000 person-years for OCS users and nonusers, respectively. Mortality rates and unscheduled hospital visits increased with increasing OCS exposure. The study findings should be interpreted with their observational nature in mind. However, we found that even at low cumulative exposure, OCS use in asthma management was associated with increased risk of comorbidities, mortality and unscheduled hospital visits. Effective strategies for optimising asthma control and reducing OCS use are pivotal in asthma management.

Cumulative exposure characteristics of vegetable farmers exposed to Chlorpyrifos in Central Java \u2013 Indonesia; a cross-sectional study

BackgroundAgriculture is a major economic sector in Indonesia. Chemical pesticides are widely being used in agriculture for controlling pest. There is a growing concern that pesticide exposure, particularly chlorpyrifos (CPF) exposure, combined with other occupational characteristics that determine the level of exposure, can lead to further health impacts for farmers. Our objective was to evaluate the cumulative exposure characteristics among farmers exposed to CPF by using a validated algorithm.MethodsWe conducted a cross-sectional study of 152 vegetable farmers aged 18–65 who actively used CPF for at least 1 year in Central Java, Indonesia. Subject characteristics were obtained using a structured interviewer-administered questionnaire, addressed for sociodemographic and work-related characteristics. The cumulative exposure level (CEL) was estimated as a function of the intensity level of pesticide exposure (IL), lifetime years of pesticide use and the number of days spraying per year. CEL was subsequently classified into two groups, high and low exposure groups. The difference in characteristics of the study population was measured using Chi-square, independent-t or Mann-Whitney test. Association between CEL and its characteristics variables were performed by multiple linear regression.ResultsSeventy-one subjects (46.7%) were classified as the high exposure group. The use of multiple pesticide mixtures was common among our study population, with 94% of them using 2 or more pesticides. 73% reported direct contact with concentrated pesticides product, and over 80% reported being splashed or spilt during preparation or spraying activity. However, we found that the proportion of proper personal protective equipment (PPE) use in our subjects was low. Higher volume of mixture applied (p < 0.001) and broader acres of land (p = 0.001) were associated with higher cumulative exposure level, while using long-sleeved clothes and long pants (p < 0.05) during pesticide spraying were associated with lower cumulative exposure after adjusted for age and gender.ConclusionsThese findings indicate an inadequate knowledge of using pesticides properly. Thus, we recommend comprehensive training on pesticide usage and encourage proper PPE to reduce the exposure level.

DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters.

Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military “breachers” —exposed to controlled, low-level blast during a 3-days explosive breaching course.Methods: We screened epigenetic profiles in peripheral blood samples from 59 subjects (in two separate U.S. Military training sessions) using Infinium MethylationEPIC BeadChips. Participants had varying numbers of exposures to blast over their military careers (empirically defined as high ≥ 40, and conversely, low < 39 breaching exposures). Daily self-reported physiological symptoms were recorded. Tinnitus, memory problems, headaches, and sleep disturbances are most frequently reported.Results: We identified 14 significantly differentially methylated regions (DMRs) within genes associated with cumulative blast exposure in participants with high relative to low cumulative blast exposure. Notably, NTSR1 and SPON1 were significantly differentially methylated in high relative to low blast exposed groups, suggesting that sleep dysregulation may be altered in response to chronic cumulative blast exposure. In comparing lifetime blast exposure at baseline (prior to exposure in current training), and top associated symptoms, we identified significant DMRs associated with tinnitus, sleep difficulties, and headache. Notably, we identified KCNN3, SOD3, MUC4, GALR1, and WDR45B, which are implicated in auditory function, as differentially methylated associated with self-reported tinnitus. These findings suggest neurobiological mechanisms behind auditory injuries in our military warfighters and are particularly relevant given tinnitus is not only a primary disability among veterans, but has also been demonstrated in active duty medical records for populations exposed to blast in training. Additionally, we found that differentially methylated regions associated with the genes CCDC68 and COMT track with sleep difficulties, and those within FMOD and TNXB track with pain and headache.Conclusion: Sleep disturbances, as well as tinnitus and chronic pain, are widely reported in U.S. military service members and veterans. As we have previously demonstrated, DNA methylation encapsulates lifetime exposure to blast. The current data support previous findings and recapitulate transcriptional regulatory alterations in genes involved in sleep, auditory function, and pain. These data uncovered novel epigenetic and transcriptional regulatory mechanism underlying the etiological basis of these symptoms.

Respiratory Health and Inflammatory Markers-Exposure to Cobalt in the Swedish Hard Metal Industry.

To study the relationship between inhalable dust and cobalt, and respiratory symptoms, lung function, exhaled nitric oxide in expired air, and CC16 in the Swedish hard metal industry. Personal sampling of inhalable dust and cobalt, and medical examination including blood sampling was performed for 72 workers. Exposure-response relationships were determined using logistic, linear, and mixed-model analysis. The average inhalable dust and cobalt concentrations were 0.079 and 0.0017 mg/m, respectively. Statistically significant increased serum levels of CC16 were determined when the high and low cumulative exposures for cobalt were compared. Nonsignificant exposure-response relationships were observed between cross-shift inhalable dust or cobalt exposures and asthma, nose dripping, and bronchitis. Our findings suggest an exposure-response relationship between inhalable cumulative cobalt exposure and CC16 levels in blood, which may reflect an injury or a reparation process in the lungs.

THE EFFECTS OF INTERNAL JUGULAR VEIN COMPRESSION FOR PRESERVING WHITE MATTER INTEGRITY IN HIGH SCHOOL FOOTBALL PLAYERS COMPARISON OF HIGH VS LOW

Background:Repetitive head impacts experienced during competitive sports contribute to neurologic changes over the course of a season. Internal jugular vein compression, by means of an externally worn neck collar device has shown efficacy in mitigating white matter (WM) alterations following repeated head impact exposure. However, its relative effectiveness in high versus low head impact exposures is unknown.Hypothesis/Purpose:The purpose of this study was to investigate the effectiveness of an externally worn neck collar device in limiting WM alterations over a season of high school football in players who receive high and low cumulative head impact exposures over 90 g.Methods:213 male high-school football athletes were prospectively assigned to two study groups: a control group (non-collar; n=106) and an experimental group who wore the jugular vein compression collar during all practices and games (collar; n=107). MRI data was collected from all participants pre- and post-season. Fractional anisotropy (FA), and mean, axial and radial diffusivity (MD/AD/RD) were calculated to assess WM integrity at both time points. Cumulative head impact exposure was monitored by accelerometers attached to each athlete’s left mastoid process during every exposure. Participants were dichotomized into subgroups based on accumulated exposures to hits over 90 g, which divided the entire cohort into four subgroups, using a cut-off of 40 hits : (1) non-collar group (≥40 hits, n=57); (2) collar group (≥40 hits, n=51); (3) non-collar group (<40 hits, n=49); (4) collar group (<40 hits, n=56).Results:As seen in Table 1, in athletes with ≥40 hits, both the non-collar and collar group showed significant pre- to post- season reductions in MD, AD, and/or RD. The non-collar group with ≥40 hits also showed a significant increase in FA, MD, and AD. RD, FA, and MD changes were greater in the non-collar group compared to the control group with ≥40 hits, while AD changes were greater in the collar group compared to the non-collar group with ≥ 40 hits. The non-collar group with <40 hits presented significant pre- to post-season reductions in MD, AD, and RD that were greater than the collar group with < 40 hits (whom did not show pre-to post-season changes).Discussion & Conclusion:The present results provide support for internal jugular vein compression to protect the brain from both low- and high-level repeated head impact exposure. However, less consistent changes were observed for athletes exposed to repeated, high-level head impacts, warranting further investigation.Table 1.Number of WM voxels (1x1x1mm) with significant (p < .05 after correcting for multiple comparisons) pre- to post-season DTI changes and/or significant group difference (red indicates group difference for non-collar group; blue indicates group difference for collar group) for high and low head impact exposure FA ↓ MD↓ AD↓ RD↓ FA↑ MD↑ AD↑ RD↑ #hits ≥ 40 Noncollar,n= 5701390381 702965186110Collar, n=51013313350 0000Grp_diff-011511 24660-#hits <40 Noncollar,n= 4905925956340 0000Collar, n=560000 0000Grp_diff-308627611 ----

The effects of psychosocial stress on dopaminergic function and the acute stress response.

Chronic psychosocial adversity induces vulnerability to mental illnesses. Animal studies demonstrate that this may be mediated by dopaminergic dysfunction. We therefore investigated whether long-term exposure to psychosocial adversity was associated with dopamine dysfunction and its relationship to psychological and physiological responses to acute stress. Using 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F]-DOPA) positron emission tomography (PET), we compared dopamine synthesis capacity in n = 17 human participants with high cumulative exposure to psychosocial adversity with n = 17 age- and sex-matched participants with low cumulative exposure. The PET scan took place 2 hr after the induction of acute psychosocial stress using the Montréal Imaging Stress Task to induce acute psychosocial stress. We found that dopamine synthesis correlated with subjective threat and physiological response to acute psychosocial stress in the low exposure group. Long-term exposure to psychosocial adversity was associated with dampened striatal dopaminergic function (p=0.03, d = 0.80) and that psychosocial adversity blunted physiological yet potentiated subjective responses to acute psychosocial stress. Future studies should investigate the roles of these changes in vulnerability to mental illnesses.