Persistence of headache and its relation to other major sequelae following traumatic brain injury at 2-8 years after deployment-related traumatic brain injury in veterans of Afghanistan and Iraq wars.

OBJECTIVE: This study deals with headache in relation to other major sequelae of traumatic brain injury (TBI) in veterans of Iraq and Afghanistan wars over 8 years after experiencing a deployment-related TBI (DTBI). BACKGROUND: TBI occurred in 14%-23% of veterans deployed to the Iraq or Afghanistan campaigns. This study evaluates sequelae of TBI (STBI) over 1-8 years after a DTBI. METHODS: This is a secondary, cross-sectional analysis of previously collected data, which was taken from review of medical records of the first 500 veterans with a DTBI seen in the TBI clinic of the Oklahoma City Veterans Health Center. This report deals with five of the most common STBIs and represents the presence and severity of, or absence of, the particular symptom at the time of a patient's initial visit to the clinic. All subjects were evaluated between June 1, 2008, and April 30, 2011. The STBI used here include: headache, dizziness, balance, coordination difficulties, and difficulty with decisions. In the TBI clinic, the burden of these symptoms was evaluated with a Likert Scale of none, mild, moderate, severe, or very severe. For this report, the scale was compressed into three categories: none, mild/moderate, and severe/very severe. Data were complete for age at TBI and mechanism of TBI in 500 subjects, for symptom severity in 497 subjects, for TBI severity in 491 subjects, and for presence of prior TBI in 496 subjects. RESULTS: For the 497 subjects with complete symptom severity data, headache was seen in 476 (95.8%) and absent in 21 (4.2%). Regarding headache severity, 236 (47.5%) reported mild/moderate and 240 (48.3%) reported severe/very severe headache burden. For other sequelae, including severity of dizziness, balance, and coordination problems, these symptoms were absent in 85 (17.1%), 85 (17.1%), and 106 (21.3%) patients, respectively; of mild/moderate severity in 356 (71.6%), 355 (71.4%), and 321 (64.6%) patients; and of severe/very severe intensity in 56 (11.3%), 57 (11.5%), and 70 (14.1%) patients. Difficulty with decisions, which was used as an indication of cognitive difficulty, was noted in 429 (86.3%) of the subjects, of which 252 (50.7%) noted mild/moderate and 177 (35.6%) severe/very severe intensity. To evaluate changes over time, the subjects were divided into 2-year cohorts of 1-2, 3-4, 5-6, and 7-8 years since DTBI. Comparing symptom burden within these four 2-year cohorts, there was no statistically significant change in symptom burden analyzing by time interval from DTBI to TBI clinic evaluation. For analysis by severity of the DTBI in 491 subjects with complete data, categories were constructed based on alteration of consciousness (AOC) or duration of loss of consciousness (LOC) as follows: AOC (264/491 [53.8%]); LOC <1 min (95/491 [19.4%]); LOC, 1-30 min (115/491 [23.4%]); and LOC >30 min (17/491 [3.5%]). The proportion of subjects with severe/very severe symptom intensity increased as the severity of the DTBI increased (from p = 0.043 to p = 0.001). Additional evaluations included groupings by age at DTBI (20-29, 30-39, and ≥40 years), by presence or absence of a TBI prior to the DTBI, and by causation of the DTBI (blast or direct head trauma). No significant differences were observed with any of these comparisons. CONCLUSION: For veterans experiencing a DTBI, these TBI-related sequelae persist with little improvement over time up to 8 years. A trend toward symptoms becoming worse as DTBI severity increased was observed. Headache was the most frequent sequela of TBI, occurring in 96% of the patients with almost half of these reporting severe/very severe intensity of headache burden. The basis for the prolonged persistence of these STBI is not known.

Distinguishing Alzheimer's Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis.

It is important to develop minimally invasive biomarker platforms to help in the identification and monitoring of patients with Alzheimer's disease (AD). Assisting in the understanding of biochemical mechanisms as well as identifying potential novel biomarkers and therapeutic targets would be an added benefit of such platforms. This study utilizes a simplified and novel serum profiling platform, using mass spectrometry (MS), to help distinguish AD patient groups (mild and moderate) and controls, as well as to aid in understanding of biochemical phenotypes and possible disease development. A comparison of discriminating sera mass peaks between AD patients and control individuals was performed using leave one [serum sample] out cross validation (LOOCV) combined with a novel peak classification valuation (PCV) procedure. LOOCV/PCV was able to distinguish significant sera mass peak differences between a group of mild AD patients and control individuals with a p value of 10-13. This value became non-significant (p = 0.09) when the same sera samples were randomly allocated between the two groups and reanalyzed by LOOCV/PCV. This is indicative of physiological group differences in the original true-pathology binary group comparison. Similarities and differences between AD patients and traumatic brain injury (TBI) patients were also discernable using this novel LOOCV/PCV platform. MS/MS peptide analysis was performed on serum mass peaks comparing mild AD patients with control individuals. Bioinformatics analysis suggested that cell pathways/biochemical phenotypes affected in AD include those involving neuronal cell death, vasculature, neurogenesis, and AD/dementia/amyloidosis. Inflammation, autoimmunity, autophagy, and blood-brain barrier pathways also appear to be relevant to AD. An impaired VWF/ADAMTS13 vasculature axis with connections to F8 (factor VIII) and LRP1 and NOTCH1 was indicated and is proposed to be important in AD development.

Occupational Exposure to Secondhand Cannabis Smoke Among Law Enforcement Officers Providing Security at Outdoor Concert Events.

OBJECTIVES: Numerous states within the USA have legalized cannabis for medical or non-medical (adult/recreational) use. With the increased availability and use of cannabis, occupational and environmental exposures to secondhand cannabis smoke (SHCS) raise concerns over whether non-users may be at risk for a 'contact high', impaired neurocognitive function, harm from irritants and carcinogens in smoke, or potentially failing a cannabis screening test. The extent of health effects from potential occupational exposure to SHCS is unknown. This is a study of occupational exposures to SHCS among law enforcement officers (LEOs) providing security at outdoor concerts on a college campus in a state where adult use of cannabis is legal. METHODS: Investigators evaluated a convenience sample of LEOs' potential exposure to SHCS and symptoms experienced while providing security during two open-air stadium rock-n-roll concerts on consecutive days in July 2018. During each event, full-shift area and LEO personal air samples were collected for Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of cannabis. Urine (pre- and postevent; n = 58) and blood (postevent; n = 29) were also collected and analyzed for Δ9-THC and two of its metabolites [11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and 11-nor-hydroxy-delta-9-tetrahydrocannabinol (OH-THC)]. Urine samples were analyzed using ultrahigh performance liquid chromatography coupled with positive electrospray ionization tandem mass spectrometry and results were compared with the Department of Transportation guidelines for urine screening for cannabis. Blood (postevent) samples were also collected and the plasma fraction was tested for Δ9-THC, THC-COOH, and OH-THC using high-performance liquid chromatography coupled with mass spectrometry. LEOs also completed a medical questionnaire asking about symptoms experienced during the concerts. RESULTS: Twenty-nine LEOs participated in the evaluation. Measurable amounts of Δ9-THC were found in area (concentrations ranged from non-detectable to 330 ng m-3) and personal air samples (53-480 ng m-3). Small amounts (<1.0 ng ml-1) of a Δ9-THC metabolite (THC-COOH) were found in the postevent urine of 34% of LEOs. Neither Δ9-THC nor its metabolites were detected in any blood sample. LEOs reported experiencing non-specific symptoms during the concerts, such as burning, itchy, or red eyes (31%); dry mouth (21%); headache (21%); and coughing (21%). CONCLUSIONS: Identification of Δ9-THC in the breathing zone for some LEOs indicates the potential for airborne exposure to the psychoactive component of cannabis. However, the magnitude of these exposures was small compared with those that would result in a dose of Δ9-THC associated with psychotropic effects. Similarly, THC-COOH was found in the postevent urine of some LEOs at concentrations that were orders of magnitude below active use cut-points used during a cannabis screening test (50 ng ml-1). Exposure to SHCS was not high enough to detect concentrations of THC, THC-COOH, to OH-THC in the blood, which could be due to differences between the limits of detection for the tests employed. The ocular and respiratory symptoms reported by LEOs may be related to irritants in SHCS. However, the health effects of SHCS remain unclear, and further research concerning occupational and environmental exposures is warranted.

Review of NIOSH Cannabis-Related Health Hazard Evaluations and Research.

Since 2004, the National Institute for Occupational Safety and Health (NIOSH) has received 10 cannabis-related health hazard evaluation (HHE) investigation requests from law enforcement agencies (n = 5), state-approved cannabis grow operations (n = 4), and a coroner's office (n = 1). Earlier requests concerned potential illicit drug exposures (including cannabis) during law enforcement activities and criminal investigations. Most recently HHE requests have involved state-approved grow operations with potential occupational exposures during commercial cannabis production for medicinal and non-medical (recreational) use. As of 2019, the United States Drug Enforcement Administration has banned cannabis as a Schedule I substance on the federal level. However, cannabis legalization at the state level has become more common in the USA. In two completed cannabis grow operation HHE investigations (two investigations are still ongoing as of 2019), potential dermal exposures were evaluated using two distinct surface wipe sample analytical methods. The first analyzed for delta-9-tetrahydrocannabinol (Δ9-THC) using a liquid chromatography and tandem mass spectrometry (LC-MS-MS) method with a limit of detection (LOD) of 4 nanograms (ng) per sample. A second method utilized high performance liquid chromatography with diode-array detection to analyze for four phytocannabinoids (Δ9-THC, Δ9-THC acid, cannabidiol, and cannabinol) with a LOD (2000 ng per sample) which, when comparing Δ9-THC limits, was orders of magnitude higher than the LC-MS-MS method. Surface wipe sampling results for both methods illustrated widespread contamination of all phytocannabinoids throughout the tested occupational environments, highlighting the need to consider THC form (Δ9-THC or Δ9-THC acid) as well as other biologically active phytocannabinoids in exposure assessments. In addition to potential cannabis-related dermal exposures, ergonomic stressors, and psychosocial issues, the studies found employees in cultivation, harvesting, and processing facilities could potentially be exposed to allergens and respiratory hazards through inhalation of organic dusts (including fungus, bacteria, and endotoxin) and volatile organic compounds (VOCs) such as diacetyl and 2,3-pentanedione. These hazards were most evident during the decarboxylation and grinding of dried cannabis material, where elevated job-specific concentrations of VOCs and endotoxin were generated. Additionally, utilization of contemporary gene sequencing methods in NIOSH HHEs provided a more comprehensive characterization of microbial communities sourced during cannabis cultivation and processing. Internal Transcribed Spacer region sequencing revealed over 200 fungal operational taxonomic units and breathing zone air samples were predominantly composed of Botrytis cinerea, a cannabis plant pathogen. B. cinerea, commonly known as gray mold within the industry, has been previously associated with hypersensitivity pneumonitis. This work elucidates new occupational hazards related to cannabis production and the evolving occupational safety and health landscape of an emerging industry, provides a summary of cannabis-related HHEs, and discusses critical lessons learned from these previous HHEs.

Potential occupational and respiratory hazards in a Minnesota cannabis cultivation and processing facility.

BACKGROUND: Cannabis has been legalized in some form for much of the United States. The National Institute for Occupational Safety and Health (NIOSH) received a health hazard evaluation request from a Minnesota cannabis facility and their union to undertake an evaluation. METHODS: NIOSH representatives visited the facility in August 2016 and April 2017. Surface wipe samples were collected for analysis of delta-9 tetrahydrocannabinol (Δ9-THC), delta-9 tetrahydrocannabinol acid (Δ9-THCA), cannabidiol, and cannabinol. Environmental air samples were collected for volatile organic compounds (VOCs), endotoxins (limulus amebocyte lysate assay), and fungal diversity (NIOSH two-stage BC251 bioaerosol sampler with internal transcribed spacer region sequencing analysis). RESULTS: Surface wipe samples identified Δ9-THC throughout the facility. Diacetyl and 2,3-pentanedione were measured in initial VOC screening and subsequent sampling during tasks where heat transference was greatest, though levels were well below the NIOSH recommended exposure limits. Endotoxin concentrations were highest during processing activities, while internal transcribed spacer region sequencing revealed that the Basidiomycota genus, Wallemia, had the highest relative abundance. CONCLUSIONS: To the authors' knowledge, this is the first published report of potential diacetyl and 2,3-pentanedione exposure in the cannabis industry, most notably during cannabis decarboxylation. Endotoxin exposure was elevated during grinding, indicating that this is a potentially high-risk task. The findings indicate that potential health hazards of significance are present during cannabis processing, and employers should be aware of potential exposures to VOCs, endotoxin, and fungi. Further research into the degree of respiratory and dermal hazards and resulting health effects in this industry is recommended.

Distinguishing and phenotype monitoring of traumatic brain injury and post-concussion syndrome including chronic migraine in serum of Iraq and Afghanistan war veterans.

Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI "most affected" group) vs healthy controls, TBI "most affected" vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10-10, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI "most affected" vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer's disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.

Microbial hazards during harvesting and processing at an outdoor United States cannabis farm.

Cannabis cultivation is an emerging industry within the United States. Organic dust derived in part from naturally occurring microorganisms is known to cause byssinosis in the hemp industry. In this pilot study, bacteria and fungi encountered by workers at an outdoor cannabis farm that utilized organic practices were elucidated by 16 S ribosomal RNA (rRNA) and Internal Transcribed Spacer (ITS) region sequencing, respectively. Area (n = 14) and personal air samples (n = 12) were collected during harvesting and processing activities. 16 S rRNA and ITS regions of extracted bacterial and fungal genomic DNA were amplified and sequenced using Sanger sequencing. Bacterial sequencing resolved 1,077 sequences that were clustered into 639 operational taxonomic units (OTUs) and predominantly placed in the phylum, Actinobacteria (46%). Personal air samples revealed higher bacterial and Actinobacteria diversity compared to outdoor area samples collected within the facility (p < 0.05). A high degree of dissimilarity between bacteria was identified within and between samples. Fungal sequences (n = 985) were identified and predominantly clustered in the phylum Ascomycota (53%). Of the 216 fungal OTUs elucidated, the cannabis plant pathogenic species, Botrytis cinerea, was the most prevalent and accounted for 34% of all fungal sequences. The relative abundance of B. cinerea was highest in personal air samples (59%) compared to area samples collected in the drying room (19%), greenhouse (18%), and outdoor environment (6%). There was 49% sample similarity between fungi identified within personal air samples, but higher dissimilarity coefficients were observed within and between greenhouse, drying room, and outdoor area air samples. The results of this pilot study suggest that the cannabis farm workers are potentially exposed to Actinobacteria as well as the cannabis plant pathogen, B. cinerea during harvesting, bud-stripping, and hand-trimming processes.

Is beryllium-induced lung cancer caused only by soluble forms and high exposure levels?

OBJECTIVES: The US Occupational Safety and Health Administration (OSHA) recently proposed a permissible exposure limit of 0.2 µg/m3 for beryllium, based partly on extrapolated estimates of lung cancer risk from a pooled occupational cohort. The purpose of the present analysis was to evaluate whether cohort members exposed at lower levels to mainly insoluble forms of beryllium exhibit increased risk of lung cancer. METHODS: We conducted Cox proportional hazards regression analyses among 75 lung cancer cases in age-based risk sets within two lower exposure plants in the pooled cohort followed from 1940 to 2005. We used categorical and power models to evaluate exposure-response patterns for mean and cumulative beryllium exposures in the two-plant cohort, comparing findings with the full pooled cohort. We also evaluated the distribution of exposure-years in each cohort by solubility class (soluble, insoluble and mixed). RESULTS: 98% of workers in the two-plant cohort were hired between 1955 and 1969. The mean beryllium exposure averaged 1.3 µg/m3 and the predominant form was insoluble. Adjusting for confounders, we observed a monotonic increase in lung cancer mortality across exposure categories in the two-plant cohort. The exposure-response coefficients (per unit ln exposure) were 0.270 (p=0.061) for mean exposure and 0.170 (p=0.033) for cumulative exposure, compared with 0.155 and 0.094 (respectively) in the full cohort. CONCLUSION: The low-exposure levels at these two plants and the predominance of insoluble beryllium suggest that the overall pooled cohort findings on which OSHA's lung cancer risk assessment is based are relevant for current workers exposed to any form of beryllium.

Headache Prevalence at 4-11 Years After Deployment-Related Traumatic Brain Injury in Veterans of Iraq and Afghanistan Wars and Comparison to Controls: A Matched Case-Controlled Study.

OBJECTIVE: Evaluate the extent and severity of headache following deployment-related TBI (D-TBI) in veterans of the Iraq (OIF) and Afghanistan (OEF) wars over a follow-up period of 4-11 years with comparison to age, sex, race, and time of deployment matched controls. BACKGROUND: TBI has been recognized as the "signature Injury" of the OEF/OIF campaigns occurring in 14-20% of deployed soldiers. Currently, there are very few data on the longer term follow-up of soldiers with D-TBI. This study deals with prevalence and severity of headache and headache burden at 4-11 years following D-TBI for OEF/OIF veterans with comparison to controls without D-TBI. METHODS: This is a matched case controlled-study. All subjects were recruited from Operation New Dawn (OND), a voluntary program for OEF/OIF Veterans at the Oklahoma VAMC designed to assist with re-integrating into civilian life. On entry into OND a medical questionnaire was administered that included a brief screen for D-TBI, and those with a possible D-TBI were referred to a TBI clinic, For this study, the first 500 TBI clinic patients who were found to have had a D-TBI (TBIS) were matched by age, sex, race, and time of deployment to control subjects (CS), drawn from the 4411 OND program members with no D-TBI, creating a pool of 500 TBIS/CS pairs. From this pool, 55 pairs (11%) were randomly selected for this study. Data were collected from both TBIS and CS by telephone interview with questionnaires regarding the DTBI, headache, depression, and PTSD. TBI severity was measured by duration of loss of consciousness (LOC) as: [a] Very Mild (VMTBI, dazed only, no LOC), [b] Mild (MTBI, LOC 1-30 minutes), and [c] Moderate-Severe (MSTBI, LOC > 30 minutes). Intensity for individual headaches was measured by disability produced by the headache as: [a] Disabling (must be in bed), [b] Severe (50-90% decrease in activity), or [c] Mild-Moderate (>50% of usual activity possible). Statistical analysis employed Fisher's exact test and odds ratio. RESULTS: The 55 TBIS/CS pairs were segregated by severity of TBI for the TBIS. For the TBIS there were no significant differences among these three subgroups as to mechanism producing the TBI (blast injury or direct head trauma). Comparing TBIS vs CS for phenotypic classification of headaches, for TBIS - 89% had migraine, 2% probable migraine, 9% had tension, and 0% had no headaches, while for CS - 36% had migraine, 15% probable migraine, 27% tension, and 22% no headache (P < .0001). Migraine with aura occurred in 38% of TBIS and 6% of CS (P < .0001). As to headache frequency, for TBIS - chronic daily headache (CDH) occurred in 44%, frequent headache in 33%, and infrequent or no headache in 23%, while for CS - CDH occurred in 7%, frequent headache in 13%, and infrequent or no headache in 80% (P < .0001). For TBIS, 54% had severe or disabling headache ≥2 days/week as opposed to only 16% of CS (OR 6.13 [2.5-14.9]). As to onset of most severe and frequent headaches, this occurred shortly after TBI in 89% of TBIS while only 27% of CS reported most severe headaches starting during deployment. There was no correlation of severity of headache problem with severity of TBI. Comparing TBIS at 4-7 vs 8-11 years after injury, there was no difference in frequency or severity of headache between these groups. CONCLUSIONS: At 4-11 years after D-TBI for TBIS, or after deployment for CS, the TBIS as compared to CS suffered much more frequent and severe headaches. For TBIS, there was no relation of headache intensity or phenotype to severity or cause of the TBI, and the Headache Burden has not improved over time up to 11 years after D-TBI. The process initiated by the D-TBI that relates to the headache has a prolonged effect up to and beyond 11 years.

Treatment of headache following triptan failure after successful triptan therapy.

OPINION STATEMENT: Triptans should remain the first choice in migraine abortive treatment. They are not always effective or adequate for specific patients. Before declaring a triptan in appropriate for a given patient, the provider ought to be analytical about the rationale and especially the use of objective efficacy outcome measures and ensure that treatment is prescribed and used appropriately. Other ergot derivatives, especially dihydroergotamine, may on one hand share common contraindications of triptans but on the other hand can be quite effective where triptans failed. Non-steroids are simple, readily available, and overall safe, and evidence for their efficacy in migraine is plentiful. Opioid analgesics are blatantly overprescribed especially in non-complicated migraine patients. These should be used with great care and restraint and closely monitored. Frequent opioid usage often leads to tolerance, dependence, and medication overuse headache. Neurostimulation is gaining momentum in the armamentarium of migraine management but at the present time remains primarily focused on prophylaxis, yet abortive use is expected to grow.

Risk of lung cancer associated with quantitative beryllium exposure metrics within an occupational cohort.

OBJECTIVES: Beryllium has been identified as a human carcinogen on the basis of animal and epidemiological studies. The authors recently reported updated associations between lung cancer and beryllium exposure in a large, pooled occupational cohort. The authors conducted the present study to evaluate the shape of exposure-response associations between different exposure metrics and lung cancer in this cohort, considering potential confounders (race, plant, professional and short-term work status, and exposure to other lung carcinogens). METHODS: The authors conducted Cox proportional hazards regression analyses of lung cancer risk with cumulative, mean and maximum 'daily weighted average' (DWA) exposure among 5436 workers, using age-based risk sets. Different exposure-response curves were fitted to the exposure metrics, including categorical, power, restricted cubic spline and piecewise log-linear fits. RESULTS: The authors found significant positive associations between lung cancer and mean (p < 0.0001) and maximum (p < 0.0001) exposure, adjusting for age, birth cohort and plant, and for cumulative (p = 0.0017) beryllium exposure, adjusting for these factors plus short-term work status and exposure to asbestos. The best-fitting models were generally categorical or piecewise log-linear, with the steepest increase in lung cancer risk between 0 and 10 µg/m(3) for both mean and maximum DWA exposure and between 0 and 200 µg/m(3)-days for cumulative DWA exposure. The estimated mean DWA beryllium exposure associated with 10(-3) excess lifetime risk based on the piecewise log-linear model is 0.033 µg/m(3). CONCLUSION: This study provides evidence that lung cancer risk is elevated at levels near the current US Occupational Safety and Health Administration beryllium exposure limit of 2.0 µg/m(3) DWA for workers.

Update on chronic daily headache.

OPINION STATEMENT: Chronic daily headache (CDH), defined as a primary headache occurring at least 15 days per month, is a problem of worldwide scope, which is seen in 3% to 5% of the population. Though it has been recognized since ancient times, only recently have there been attempts to define and classify it. CDH usually consists of a mixture of migraine and tension-type headaches (TTH), with the more severe headaches having migraine features and the less severe headaches fitting the definition of TTH. Some patients have pure chronic TTH and no migrainous features, and others have only migraine, but most have a mixed migraine-TTH pattern. New daily persistent headache, a CDH pattern that comes on over a few days, constitutes 9% to 10% of this group and is otherwise indistinguishable from CDH. Hemicrania continua (1% of CDH) appears to be unique in being absolutely responsive to indomethacin. Accurate diagnosis of CDH is critical to management, as all organic etiologies of chronic headache must be ruled out. Problems often associated with CDH and complicating the diagnosis are head injury or medication overuse (rebound-withdrawal headache). These accompanying issues must be recognized and treated appropriately in the management plan. Finally, psychiatric problems (unipolar depression, bipolar disease, generalized anxiety disorder, and obsessive/compulsive disorder) often accompany CDH, as they are comorbid with migraine. These conditions must be recognized and treated along with the headache itself for treatment to succeed fully. Treatment of CDH is multimodal. The cornerstone of therapy is the use of prophylactic antimigraine medications to prevent or modulate the next headache. Amitriptyline, topiramate, valproic acid, and gabapentin have all had class I studies showing effectiveness in reducing headache occurrence. Recent studies with botulinum toxin have also shown effectiveness in reducing the headache burden. Recognition and treatment of medication overuse headache (MOH) must be carried out as part of the initial approach. Use of acute symptomatic treatments such as triptans or NSAIDs must be undertaken with care, as frequent use of these agents can lead to MOH. Educating the patient about the condition and reasonable expectations for therapy is essential to success. Recognition and appropriate treatment of psychiatric disorders is likewise essential. Adjunctive nondrug therapies and lifestyle changes round out the requirements for a management plan. The chances for long-term remission or significant improvement are up to 65%. The patient and physician must understand that CDH is a long-term process with relapses and remissions. A strong and trusting relationship between patient and physician is a major asset in managing this condition.

Development of retrospective quantitative and qualitative job-exposure matrices for exposures at a beryllium processing facility.

OBJECTIVES: To construct a job-exposure matrix (JEM) for an Ohio beryllium processing facility between 1953 and 2006 and to evaluate temporal changes in airborne beryllium exposures. METHODS: Quantitative area- and breathing-zone-based exposure measurements of airborne beryllium were made between 1953 and 2006 and used by plant personnel to estimate daily weighted average (DWA) exposure concentrations for sampled departments and operations. These DWA measurements were used to create a JEM with 18 exposure metrics, which was linked to the plant cohort consisting of 18,568 unique job, department and year combinations. The exposure metrics ranged from quantitative metrics (annual arithmetic/geometric average DWA exposures, maximum DWA and peak exposures) to descriptive qualitative metrics (chemical beryllium species and physical form) to qualitative assignment of exposure to other risk factors (yes/no). Twelve collapsed job titles with long-term consistent industrial hygiene samples were evaluated using regression analysis for time trends in DWA estimates. RESULTS: Annual arithmetic mean DWA estimates (overall plant-wide exposures including administration, non-production, and production estimates) for the data by decade ranged from a high of 1.39 µg/m(3) in the 1950s to a low of 0.33 µg/m(3) in the 2000s. Of the 12 jobs evaluated for temporal trend, the average arithmetic DWA mean was 2.46 µg/m(3) and the average geometric mean DWA was 1.53 µg/m(3). After the DWA calculations were log-transformed, 11 of the 12 had a statistically significant (p < 0.05) decrease in reported exposure over time. CONCLUSIONS: The constructed JEM successfully differentiated beryllium exposures across jobs and over time. This is the only quantitative JEM containing exposure estimates (average and peak) for the entire plant history.

Amitriptyline in the prophylactic treatment of migraine and chronic daily headache.

OBJECTIVE AND BACKGROUND: Amitriptyline is one of the most commonly used medications in migraine prophylaxis. There have been relatively few placebo-controlled studies of amitriptyline in migraine prophylaxis or in treatment of chronic daily headache (CDH). This report deals with a large placebo-controlled trial of amitriptyline vs placebo of 20 weeks duration that included subjects with intermittent migraine (IM) as well as CDH. The study was carried out between 1976 and 1979; however, results have never been fully reported. METHODS: Patients with a history of migraine as defined by the 1962 Ad Hoc Committee report were recruited for this study. Subjects had at least 2 headaches per month, and no limit was placed on the number of headaches per month that could be experienced. The study format included a 4-week baseline period (Period A) in which all subjects received placebo in a dose of 2 pills per day for one week, 3 pills per day for one week and then 4 pills per day for 2 weeks. Subjects with at least 2 migraine headaches in this period were then entered into Period B and randomized into either amitriptyline or placebo tracks. Medication consisted of identical tablets containing either 25 mg amitriptyline or placebo. Period B was 4 weeks in duration with dose titration identical to Period A. The dose could be reduced if necessary to reduce side effects. The minimum dose was one pill per day. Period C was a 12-week maintenance or stabilization period in which the patient continued the dose established by week 8 with visits at weeks 12, 16, and 20. Patients kept a headache calendar that was used for data collection. Headache frequency (per month), severity, and duration (hours) were the primary measurement parameters employed for data analysis. RESULTS: For the entire group, 391 subjects were entered into Period A, 338 were randomized into Period B, 317 (81%) subjects completed the first post-randomization visit (8 weeks), 255 (65%) completed week 12, 210 (54%) completed week 16, and 186 (48%) completed week 20. Using headache frequency and evaluating parameters of (a) improvement, (b) no change, or (c) worsening relative to baseline, there was a significant improvement in headache frequency for amitriptyline over placebo at 8 weeks (P = .018) but not at 12, 16, or 20 weeks. When amitriptyline and placebo patients were compared for headache frequency at 8, 12, 16, and 20 weeks to their own placebo stabilization period at 4 weeks, statistically significant improvement vs worsening was seen in headache frequency at each evaluation point for both amitriptyline and placebo groups (P ≤ .01) reaching 50% reporting a decrease in frequency in each group and approximately 10% reporting worsening by week 20. There were no significant differences in headache severity or duration between amitriptyline and placebo groups at anytime during the study. Within the study sample, there were 36 amitriptyline and 22 placebo subjects who had headaches ≥ 17 days/month that fit the current definition of CDH by the Silberstein-Lipton criteria. These were analyzed separately as a subgroup for comparison of amitriptyline vs placebo using a metric of (1) no change or worsening; (2) up to a 50% improvement; and (3) ≥ 50% improvement in headache frequency. Amitriptyline was superior to placebo in number with improvement in frequency of ≥ 50% at 8 weeks (25% vs 5% [P = .031]) and at 16 weeks (46% vs 9% [P = .043]). There was a trend for amitriptyline to be superior to placebo at 12 and 20 weeks but this did not reach significance. CONCLUSIONS: In this study, using headache frequency as the primary metric, for the entire group, amitriptyline was superior to placebo in migraine prophylaxis at 8 weeks but, because of a robust placebo response, not at subsequent time points. For the subgroup with CDH, amitriptyline was statistically significantly superior to placebo at 8 weeks and 16 weeks with a similar but nonsignificant trend at 12 and 20 weeks. Compared with placebo amitriptyline is effective in CDH. Amitriptyline was also significantly effective in IM compared intragroup to its own baseline; however, placebo was equally effective in the same analysis. The reason for the robust placebo response in the IM group is not clear, but has been occasionally reported.

Cohort mortality study of workers at seven beryllium processing plants: update and associations with cumulative and maximum exposure.

OBJECTIVES: To extend follow-up of cause-specific mortality in workers at seven beryllium processing plants and to estimate associations between mortality risk and beryllium exposure. METHODS: 9199 workers were followed for mortality from 1940 through 2005. Standardised mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers. RESULTS: Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was ≥ 10 µg/m(3) had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. Significant positive trends with cumulative exposure were observed for nervous system cancers (p = 0.0006) and, when short-term workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p = 0.003) and COPD (p < 0.0001). CONCLUSION: These findings reaffirm that lung cancer and CBD, and suggest that COPD and nervous system and urinary tract cancers, are related to beryllium exposure. Cigarette smoking and exposure to other lung carcinogens are unlikely to explain these elevations.

Sumatriptan-naproxen fixed combination for acute treatment of migraine: a critical appraisal.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen and naproxen sodium, are effective yet nonspecific analgesic and anti-inflammatory drugs, which work for a variety of pain and inflammatory syndromes, including migraine. In migraine, their analgesic effect helps relieve the headache, while their anti-inflammatory effect decreases the neurogenic inflammation in the trigeminal ganglion. This is the hypothesized mechanism by which they prevent the development of central sensitization. Triptans, including sumatriptan, work early in the migraine process at the trigeminovascular unit as agonists of the serotonin receptors (5-HT receptors) 1B and 1D. They block vasoconstriction and block transmission of signals to the trigeminal nucleus and thus prevent peripheral sensitization. Therefore, combining these two drugs is an attractive modality for the abortive treatment of migraine. Sumatriptan-naproxen fixed combination tablet (Treximet [sumatriptan-naproxen]) proves to be an effective and well tolerated drug that combines these two mechanisms; yet is far from being the ultimate in migraine abortive therapy, and further research remains essential.