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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress 6 HEALTH EFFECTS The studies discussed in this chapter demonstrate that veterans’ reactions to deployment to a war zone and its inherent stressors are varied. Some veterans suffer no ill consequences and may even benefit from deployment, and some experience initial distress but become acclimated to some of the stressors; but the body of evidence suggests that most veterans perceive deployment to a war zone as stressful (Gifford et al. 2006; MHAT 2006b). Given that few studies provide a good indication of the deployment-related stressors to which veterans were exposed and the amount of stress experienced during those exposures, the committee decided that deployment to a war zone itself was sufficient to elicit a stress response and that deployment would serve as a surrogate for deployment-related stress (the stress response is discussed in detail in Chapter 4). Therefore, military personnel deployed to a war zone would constitute the study group of interest and military personnel serving at the same time but not deployed to a war zone would be the appropriate comparison group. The studies reviewed in this chapter generally compared Gulf War veterans or veterans of other deployments, such as to Vietnam, with veterans who were deployed during the same period to noncombat areas within the United States or elsewhere (for example, Germany). In some cases, the committee included studies of other military personnel, such as peacekeepers, or civilians that had similar exposures if the studies appeared to be relevant to the discussion. ORGANIZATION OF THIS CHAPTER The committee discusses health effects in the order they occur in the International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10,)1 except for the last section, which examines the many reports of increased health symptoms in deployed veterans. The committee did not examine health effects related to or resulting from infectious and parasitic diseases as the Institute of Medicine (IOM) Committee on Gulf War and Health: Infectious Diseaseshas examined those outcomes and released its report (IOM 2007). The committee also did not consider health effects that are most likely to be associated with exposures to environmental agents—such as sarin nerve gas, the defoliant Agent Orange, or combustion products from oil-well fires—or with the use of various vaccines and other 1 The International Statistical Classification of Diseases and Related Health Problems (ICD) provides a detailed description of known diseases and injuries. Every disease (or group of related diseases) is given a unique code. ICD is periodically revised and is currently in its 10th edition (ICD-10) and available at http://www.who.int/classifications/apps/icd/icd10online/.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress prophylactic measures, although anticipation of exposure to such agents may be a deployment-related stressor, as indicated in Chapter 3. Those stressors have already been thoroughly evaluated by other IOM committees. In general, for each health effect presented in this chapter, the committee identifies first the primary studies and then the secondary or supporting studies, as defined by the criteria in Chapter 2. A primary study had to include information about the putative exposure (deployment) and specific health effects, demonstrate rigorous methods, include details of its methods, include an appropriate control or reference group, have adequate statistical power to detect effects, and provide appropriate adjustment for confounders. Many of the large cohort studies examined multiple effects and so might be referred to in more than one place. A given study might be deemed a primary study for one or more health effects and be a secondary study for another effect, as determined by how the particular health effects were defined and measured. For example, a study that was well designed for assessing a neurobehavioral effect might not be well designed for assessing a psychiatric disorder. In general, only primary studies appear in the evidence tables that accompany the discussions of health effects. A secondary study was typically a study that had methodologic limitations, such as not including a rigorous or well-defined measure of exposure, that is, deployment to a war zone or posttraumatic stress disorder (PTSD) as a marker of trauma (see Chapter 1). Some studies assessed past trauma that was not necessarily peculiar to war-zone deployment, so they were included as secondary studies. The secondary studies were reviewed and included in the discussion because they evaluated the same health effects and in some cases provided useful information on veteran populations from the same conflicts as the primary studies; they add information that might increase or decrease confidence in the conclusions based on the primary studies. Confidence in a secondary study is substantially reduced if the statistical analysis did not adjust for confounders, if the data were obtained from self-reported cross-sectional surveys or from screening instruments that relied solely on self-reported answers, or if response rates were unacceptably low. Without evidence from primary studies, the potential for unreliable findings due to bias, chance, or multiple comparisons may outweigh the extent to which secondary studies may contribute, even collectively, to the overall conclusion of the committee about an association between deployment-related stress and any specific health effect. Understanding the relationship between a health effect and deployment-related stress may be hampered by the exposure not being explicitly defined as deployment or, more commonly, by many potentially harmful exposures being compared with multiple effects. With rare exceptions, the chapter excludes studies of participants in Gulf War registries established by the Department of Veterans Affairs (VA) or the Department of Defense (DoD), which were not intended to be representative of the entire group of Gulf War veterans. Registry participants can not be considered representative of all Gulf War veterans in that they are self-selected subjects, many of whom have joined the registries because they believe that they have symptoms of a new medical syndrome; they were not randomly selected from all Gulf War military personnel, and there is no nondeployed control group. One main exception to the use of registries occurs for studies in which the groups of interest are veterans with and without PTSD. As discussed in Chapter 5, PTSD can be diagnosed only after exposure to a traumatic event, thus, the committee agreed that studies of veterans with deployment-related PTSD compared with deployed veterans who had not developed PTSD were appropriate comparison populations when determining whether health effects were associated with deployment-related PTSD.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Many of the studies had other limitations. Few studies measured the stress that troops experienced during deployment; rather, most asked veterans about exposure to possible stressors after their return from deployment. Some studies—such as the congressionally mandated National Vietnam Veterans Readjustment Study (NVVRS), the Vietnam Experience Study (VES), and some Gulf War studies—assessed veterans’ war-zone exposures many years after they had returned home. Furthermore, many studies did not verify veterans’ reported exposures against military records. Finally, although many studies used various scales, such as the Combat Exposure Scale, to determine possible exposures during deployment, the scales did not ascertain the emotional response of the veterans to the exposures; that is, the studies asked only whether exposure to a stressor occurred and not about the degree to which the veterans found the experience to be stressful. Studies that did ascertain veterans’ reactions to stressors, such as seeing a comrade wounded or firing a gun at the enemy, and that asked veterans to rate their responses on a scale, such as “never” to “always,” are rare. The committee acknowledges that many of the health effects associated with deployment were discussed in a previous volume of the Gulf War and Health series, Volume 4: Health Effects of Serving in the Gulf War. In that volume, the health effects that had been found in deployed Gulf War veterans were identified, and their prevalence compared with the prevalence of the same effects in nondeployed Gulf War veterans. However, that review was restricted to Gulf War veterans; veterans of other conflicts—such as the Vietnam War, World War II, the Korean War, and Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF)—were not considered. Furthermore, that report did not seek to establish whether there was any association between being deployed and specific health effects. As a consequence, although the present committee reviewed many of the same studies as the committee that prepared Volume 4, the assessment process used here is different, as are some of the conclusions because a broader array of studies were considered using defined categories of association. CANCER Each year over a million people receive a diagnosis of cancer in the United States. About one of two American men and one of three American women will have cancer at some point in their lives. Cancer can develop at any age, but about 77% of all cancers are diagnosed in people 55 years old or older. Military personnel during the Gulf War had a mean age of 28 years and therefore are now in their mid-40s. Insufficient time had elapsed for most forms of cancer to be detected among Gulf War veterans by surveys conducted in the 1990s and early 2000s. That is not the case, however, for veterans of the Vietnam War, many of whom are now at an age when most cancers are likely to be diagnosed. Therefore, given the substantial differences in ages between veterans of the Vietnam War and the Gulf War, the studies are discussed separately. Primary studies for this health effect were those that compared deployed vs nondeployed veteran populations from either the Vietnam War or the Gulf War. A primary study must have indicated that the presence of cancer or death from cancer was confirmed, as by physical examination, medical record review, or death certificates. Of particular concern in studies of Vietnam veterans is possible confounding from exposure to Agent Orange, a toxic herbicide sprayed on foliage in Vietnam. Most of the studies reviewed in this section did not distinguish between the type of cancers that were seen in or reported by veterans, so the occurrence of cancer is addressed as a specific endpoint. The few studies reporting specific results on testicular cancer, which occurs
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress predominantly in younger men, and on skin cancer, which is relatively common, are discussed in separate sections. The occurrence of cancer in veterans with PTSD is discussed at the end of the section. The primary studies for cancer are summarized in Table 6-1 at the end of the section. All Cancers Vietnam War The committee identified three primary studies that examined the effect of deployment to Vietnam on the development of cancer in veterans of the Vietnam War (CDC 1988b; Selected Cancers Cooperative Study Group 1990a,b,c; Watanabe and Kang 1995). Two other primary studies (Dalager et al. 1995; Kang et al. 2000c) focused exclusively on cancers in female Vietnam veterans. In response to a congressional mandate, Centers for Disease Control and Prevention (CDC) undertook the VES to assess the health status of the 5 million Vietnam-theater and Vietnam-era veterans who served in the U.S. Army during 1965-1971; the study was completed in 1988, about 15-20 years after the war (CDC 1988b). It consisted of a nationally representative random sample of 7924 theater veterans and 7364 era veterans who completed a phase 1 telephone interview. In phase 2, a random subsample of 2490 theater veterans and 1972 era veterans also completed physical- and psychologic-health screening examinations in 1985-1986 at a medical facility. On examination, 1.9% of theater veterans and 1.3% of era veterans had cancers (unspecified); the study findings were not significant (odds ratio [OR] 1.4, 95% confidence interval [CI] includes 1.0, p > 0.05). The OR was adjusted for age at enlistment, race, year of enlistment, enlistment status, score on a general technical test, and primary military occupational specialty. The study had the advantage of including a physical examination and a large study population, but it is limited in that information on exposure to herbicides, particularly Agent Orange, was not provided, the types of cancer that were screened for were not indicated, the study was not designed to assess the presence of relatively rare cancers, and the participation rate of 75% and 63% for the theater and era veterans, respectively. As a followup to the VES, CDC conducted a further population-based case-control assessment for six cancers in Vietnam-theater and Vietnam-era veterans: non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, soft-tissue and other sarcomas, nasal cancer, nasopharyngeal cancer, and primary liver cancer. Those cancers were chosen because cancers of the liver, nasal cavity, and nasopharnyx, and Hodgkin’s disease have been associated with exposure to phenoxy herbicides, such as Agent Orange, in some animal studies and a few human studies. Study participants were all men born in 1929-1953 who were first diagnosed as having cancer in 1984-1988 and were listed in any of eight city or state cancer registries—those in Atlanta, Detroit, San Francisco, Seattle, Miami, Connecticut, Iowa, and Kansas. Controls were selected by random-digit telephone dialing in the relevant locations and frequency-matched by age to the men with cancer. All cancers were confirmed pathologically. An analysis of 1157 men with NHL and 1776 controls found that the risk of NHL in men who served in Vietnam compared with those who served in the military in 1964-1972 but not in Vietnam was 1.52 (95% CI 1.00-2.32, p = 0.01) when adjusted for registry, age group in 1968, ethnicity, education, and other covariates, including reported exposures to pesticides, reported medical history and medication use, smoking, marital status, and being raised as Jewish (Selected Cancers Cooperative Study Group 1990a). There was no suggestion of an increasing trend in risk of NHL
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress corresponding to service in support units (OR 1.50, 95% CI 1.02-2.21), combat-support units (OR 1.18, 95% CI 0.65-2.15), or combat units (OR 1.25, 95% CI 0.63-2.45). With respect to soft-tissue and other sarcomas, the same eight cancer registries showed that 342 men had confirmed cancers compared with the 1776 controls. The OR for soft-tissue and other sarcomas in Vietnam-theater veterans compared with Vietnam-era veterans is a nonsignificant 0.74 (95% CI 0.39-1.41) with the same adjustment factors as for NHL (Selected Cancers Cooperative Study Group 1990b). Again, there was no trend in cancer risk in men who served in support units (OR 0.76, 95% CI 0.37-1.53), combat-support units (OR 1.03, 95% CI 0.44-2.41), or combat units (OR 0.76, 95% CI 0.25-2.28). Combining data from the eight cancer registries shows that 28 of the 310 men with Hodgkin’s disease had served in Vietnam, two of the 48 with nasal carcinoma, three of the 80 with nasopharyngeal carcinoma, and eight of the 130 with primary liver cancer (Selected Cancers Cooperative Study Group 1990c). Although the power of the study was good for Hodgkin’s disease (96%), it was less robust for the other cancers. In comparisons of Vietnam-theater veterans with Vietnam-era veterans with the same adjustments as for NHL, the OR was 1.23 for Hodgkin’s disease (95% CI 0.65-2.32), 0.31 for nasal carcinoma (95% CI 0.04-2.20, additionally adjusted for occupational exposures), and 0.53 for primary liver cancer (95% CI 0.14-1.94, additionally adjusted for occupational exposures); the OR for nasopharyngeal carcinoma could not be calculated with conditional logistic regression. There was no trend (p = 0.17) in risk of Hodgkin’s disease related to serving in Vietnam in a support unit (OR 1.58, 95% CI 0.90-2.77), a combat-support unit (OR 0.50, 95% CI 0.14-1.76), or a combat unit (OR 0.94, 95% CI 0.34-2.59). The relationship of combat to the other three cancers was not assessed. Although the authors did not sample blood for possibly elevated dioxin levels, they asserted that, based on their locations and occupations during the war, the Vietnam-veteran study participants were not at greater risk of exposure to Agent Orange than the nondeployed veterans. Those studies are limited by the small sample sizes for some cancers. Postservice mortality was assessed in 10,716 Marines who served in Vietnam and 9346 Marines who were not deployed to Vietnam (Watanabe and Kang 1995). An analysis of death certificates showed that as of 1991, for Marines who had served in Vietnam, there were no statistically significant increases in all-cancer mortality (rate ratio 1.08, 95% CI 0.84-1.39), cancer of the larynx (rate ratio 2.60, 95% CI 0.27-25.0), lung cancer (rate ratio 1.12, 95% CI 0.71-1.76), or lymphosarcoma and reticulosarcoma (rate ratio 1.21, 95% CI 0.27-5.41). No statistically significant increase was seen for all cancers or for lung cancer. The relative-risk (RR) estimates based on the Cox proportional-hazards model were 1.20 (95% CI 0.93-1.55) for all cancers and 1.33 (95% CI 0.84-2.10) for lung cancer, adjusted for year of birth and military rank. Death certificates were obtained from VA regional offices, federal records centers, and state vital-statistics offices. Comparisons with the U.S. male population showed slightly increased standardized mortality ratios for laryngeal cancer and for lymphosarcoma and reticulosarcoma, but the increases were not statistically significant. The authors considered the latent period for many cancers to be 15-20 years but found no difference in RRs in cancer deaths whether veterans were followed for less than or more than 16 years. The authors suggested that there may have been insufficient observation time since the war to detect excess deaths from cancer and that there was insufficient statistical power to detect rare causes of death. They also noted that many of the Marines were posted to areas in Vietnam where Agent Orange was used. A similar study of cancer mortality was conducted in female Vietnam veterans (Dalager et al. 1995). The vital status of 4586 female Vietnam veterans and 5325 female Vietnam-era
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress veterans was compared more than 20 years after the war. Vital status as of 1991 was determined from VA beneficiary records, information from the Social Security Administration and the Internal Revenue Service, the National Death Index, and military personnel records; copies of official death certificates were used to determine cause of death. The Cox proportional-hazard multivariate regression model was used to derive cause-specific mortality risks for female Vietnam theater veterans vs female Vietnam-era veterans adjusted for rank, nursing status, duration of military service, and age at entry into followup. The RR for all cancer mortality was 1.00 (95% CI 0.75-1.34). The authors noted that there were increased risks of cancer of the pancreas, uterine corpus, brain, and other parts of the central nervous system in female Vietnam veterans, but the number of deaths was small and did not reach statistical significance, and adjustment for confounders was not possible. Female theater veterans had a lower mortality than female era veterans from lymphopoietic cancer and lung cancer. This study and that by Watanabe and Kang (1995) discussed above had the advantage of being conducted after a sufficient latent period for many cancers to be evident, however the number of cancer cases was small in each study, and their study populations were to small to have much potential to identify changes in the incidence of relatively rare cancers. Not all cancers result in death, so a second study of the prevalence of gynecologic cancers among female Vietnam veterans was undertaken (Kang et al. 2000c). The prevalence of malignant tumors was ascertained in 4140 female Vietnam-theater veterans and 4140 female Vietnam-era veterans. Participants were given a structured health questionnaire via telephone interview, and self-reported gynecologic (breast, ovarian, uterine, or cervical) cancer was confirmed by review of medical or hospital records. The response rate of the 6430 women interviewed was 83-87%. A multivariate logistic model was used to calculate the ORs and 95% CIs. The adjusted OR was 1.14 (95% CI 0.94-1.40) for any gynecologic cancer; 1.18 (95% CI 0.91-1.51) for breast cancer, 1.83 (95% CI 0.72-4.61) for ovarian cancer, 1.00 (95% CI 0.61-1.61) for uterine cancer, and 1.11 (95% CI 0.74-1.66) for cervical cancer. Adjustments included age, race, branch of service, pay grade, marital status, nursing occupation, smoking, drinking, family history of cancer, use of birth-control pills, and postmenopausal estrogen and progestin use. Medical records were used to confirm self-reported cancer; 222 records were reviewed, and 99% of self-reported breast cancers, 76% of cervical cancers, 78% of ovarian cancers, and 61% of uterine cancers were confirmed. However, 10% of the self-reported cancers were not confirmed, and 5% of the medical records had no information on cancer. This study indicates that service in Vietnam did not increase the risk of gynecologic cancer in female Vietnam veterans. The study had a high response rate and relatively high validation rate for the diagnosis of gynecologic cancers that had a sufficient latent period for detection. It is limited by lack of information on possible exposures during service in Vietnam, including exposure to Agent Orange. Gulf War There was only one primary study in Gulf War-deployed veterans compared with their nondeployed counterparts, which indicated an increased risk of cancer. McCauley et al. (2002b) looked at cancer rates in Gulf War veterans residing in Oregon, Washington, California, Georgia, and North Carolina in 1999 as part of a larger study to assess neurologic and neurophysiologic signs and symptoms in veterans who may have been exposed to chemical-warfare agents as a result of the destruction of munitions at Khamisiyah, Iraq. Names of possible participants were obtained from the Defense Manpower Data Center (DMDC) maintained by the DoD. Gulf War-
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress deployed veterans were categorized as those who were within a 50-km radius of Khamisiyah between March 4 and March 13, 1991, and were therefore potentially exposed to chemical agents (n = 653), and Gulf War veterans who were deployed to Southwest Asia but outside of the 50-km radius (n = 610). A control group consisted of nondeployed veterans in the military at that time but not deployed to Southwest Asia (n = 516). A structured telephone interview asked veterans about physician-diagnosed medical conditions, hospitalizations, and disability during and after return from the Gulf War. The frequency of any cancer was 1.2% for veterans deployed in the Khamisiyah region, and 2.1% for those deployed outside the Khamisiyah region, for an OR of 0.4 (95% CI 0.1-1.4); the frequency of any cancer for nondeployed veterans was 0.6%. When the 21 cases of cancer among all deployed veterans (Khamisiyah region or elsewhere in the gulf combined) were compared with the 3 among nondeployed veterans, there was a nonsignificant increase in cancer frequency among the deployed troops (OR 3.0, 95% CI 1.0-13.1). All statistics were adjusted for age, gender, race, and region of residence. Twenty of the 24 deployed and nondeployed veterans reporting a diagnosis of cancer were asked for details on year of diagnosis and cancer type. When the 7 cases of skin cancer and the 4 cases of cancer for which details were not obtained were removed from the analysis, the resulting OR for non-skin cancers in deployed vs nondeployed was 4.94 (95% CI 0.6-38.1); there was no apparent trend for any specific type of cancer among the remaining 9 cancer cases. This study is limited by the small sample size and few reports of cancer and by the incomplete verification of the diagnosis with medical records or examination. A potential confounder of stress as a risk factor, exposure to chemical-warfare agents, was the target of the researchers’ investigation: although this exposure is subject to great uncertainty, the primary result for proximity to Khamisiyah (OR = 0.4) argues against its importance in the development of cancer. Macfarlane et al. (2003) assessed all first diagnoses of malignant cancer in a cohort of UK military personnel. The deployed group consisted of all military personnel who served in the Persian Gulf during September 1990-June 1991 (n = 51,721). The comparison group was randomly selected from members of the armed services who were in service on January 1, 1991, but not deployed in the Persian Gulf and was stratified to match the Gulf War cohort on age, sex, service branch, rank, and level of fitness for active service (n = 50,755). Followup was from April 1, 1991, until diagnosis of cancer, emigration, death, or July 31, 2002, whichever was earlier. Cancers were identified through the National Health Service Central Register. During followup, 270 incident cases of cancer were identified among the Gulf War veterans and 269 cases among the nondeployed group; the RR—after adjustment for sex, age group, service branch, and rank—was 0.99 (95% CI 0.83-1.17). Thus, there was no evidence of an association of Gulf War service with site-specific cancers. In subgroups of cohort members who participated in morbidity surveys that yielded more information on potential risk factors (28,518 deployed veterans and 20,829 nondeployed veterans), the RR was 1.11 (95% CI 0.86-1.44). That result did not change after adjustment for smoking or alcohol use, and there was no evidence of associations with exposure to pesticides; multiple vaccinations against anthrax, plague, and pertussis; or reported exposure to depleted uranium. Two studies by Gray et al. (1996, 2000) attempted to determine whether Gulf War veterans were at increased risk for hospitalization after the war compared with nondeployed veterans. DoD hospital records on 547,076 active-duty Gulf War veterans and 618,335 nondeployed active-duty veterans in all service branches were examined with demographic information from military records. The multiple logistic-regression models were adjusted for sex, age, race or ethnic group, marital status, branch of service, rank, salary, occupation, and prewar
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress hospitalizations. Using August 1991 as the end of the war, Gray et al. (1996) found a slightly increased risk of hospitalization for any neoplasm in the last 5 months of 1991 in deployed vs nondeployed veterans (standardized rate ratio about 1.10, 95% CI 1.0-1.2), but this dropped to about 0.92 (95% CI about 0.87-1.0) in 1992 and about 0.94 (95% CI about 0.87-1.1) in 1993. Most of the neoplasms diagnosed in 1991 were benign (for example, benign neoplasms of bone, articular cartilage, connective tissue and other soft tissue, skin, breast, and digestive system). In 1991, hospitalizations for malignant neoplasm of the testis were slightly higher in deployed men (rate ratio 2.12, 95% CI 1.11-4.02), but no difference was seen in 1992 or 1993. Expanding this study to include National Guard and reserve veterans, Gray et al. (2000) examined hospital records from the DoD, VA, and California Office of Statewide Health Planning and Development hospital systems for 1991-1994. The authors could not directly compare rates of hospitalization in the three hospital systems, so they compared proportional morbidity ratios (PMRs) of hospital-discharge diagnoses (14 diagnostic categories from ICD-9) in Gulf War-deployed and nondeployed veterans. PMRs for neoplasms were not higher in deployed veterans in any of the hospital systems. Several other large secondary studies looked at cancer in large populations of Gulf War veterans and found that there was no significant increase in any cancer in deployed veterans compared with nondeployed veterans. Although the studies below used self-reports of medical conditions, they used structured telephone interviews by trained interviewers or in-person interviews of the veterans. The Iowa Persian Gulf Study Group (1997) used a cross-sectional telephone-interview survey of Gulf War-deployed and nondeployed veterans who claimed Iowa as their place of residence in their military records. Randomly selected subjects were stratified on age, sex, rank, race, and branch of military service. Of the 4886 eligible subjects, 3695 (76%) completed the interview (1896 deployed and 1799 nondeployed). Deployed and nondeployed veterans had a similar prevalence of any cancer (prevalence 1.0% and 1.9% in deployed regular military and reserves, respectively, vs 1.0% and 0.6% in nondeployed regular military and reserves; Cochran-Mantel-Haenszel rate difference 0.8, 95% CI 0.2-1.4, p ≤ 0.05) and aplastic anemia (prevalence 0.1% and 0.0%, respectively, vs 0.0% for all nondeployed veterans; rate difference 0.1, 95% CI -0.1-0.2). Although deployed veterans were asked about exposure to unspecified psychologic stressors, similar data on nondeployed veterans are not provided. This study was limited by restriction of participants to Iowans, a sample size that may not be sufficient to detect cancers, lack of specificity as to reported cancers, and the use of self-reports of health effects. Kang et al. (2000b) used a nationally representative stratified random sample of Gulf War veterans and nondeployed veterans to assess the health of veterans with telephone interviews. On the basis of responses from 11,441 deployed veterans and 9476 nondeployed veterans, the authors estimated the population prevalence of self-reported cancers other than skin cancer during the preceding 12 months to be 0.7% in deployed and 0.6% in nondeployed for a statistically significant increased rate difference of 0.18 (95% CI 0.15-0.21, p ≤ 0.05). Prevalence was controlled for sex, age, race, marital status, rank, branch, unit component, active-duty status, and exposures. This study was limited by the use of self-reports and the lack of information on the number of cancer cases reported in the surveyed veterans. In 1998, Steele (2000) assessed the prevalence of cancer and other medical conditions in a stratified random sample of Kansas Gulf War veterans (n = 1545) and veterans who were not deployed to the gulf (n = 435), using names supplied by the DMDC. The study was conducted to identify cases of Gulf War illness. In telephone interviews, participants were asked whether they
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress had ever had a diagnosis or treatment by a physician for any of 16 specific medical conditions or for any medical conditions in five general categories and, if so, when the conditions had developed. Deployed veterans were also asked whether they had been notified by DoD about being in the area of the Khamisiyah munitions demolition. Cancers, other than skin cancer, were diagnosed after 1990 in 1% each of deployed and nondeployed veterans for a nonsignificant risk of 1.21 (95% CI 0.40-3.69), adjusted for sex, age, income, and education level. Kang and Bullman (2001) studied causes of postwar mortality in Gulf War veterans through 1997. They ascertained vital status of a stratified random sample of Gulf War-deployed veterans and nondeployed veterans from VA and Social Security Administration databases, and death certificates were obtained from VA and the National Death Index database. From 1990 to 1997, there were 4506 deaths among 621,902 Gulf War veterans, and causes of death were obtained for 94.7% of them. The OR for mortality from any cancer during this period was 0.90 (95% CI 0.81-1.01) in men and 1.11 (95% CI 0.78-1.57) in women adjusted for age, race, branch of service, unit component, and marital status. The main strength of this study was the large sample. As in previous studies of Gulf War veterans, the latent period for most cancers is too long for their manifestation during the study period, and there was also a lack of information on risk factors. Several secondary studies also looked at the prevalence of any cancer in Gulf War veterans. Eisen et al. (1991) and Proctor et al. (2001) examined U.S. veterans, Simmons et al. (2004) surveyed a large cohort of UK veterans, Goss Gilroy Inc. (1998) surveyed all Canadian Gulf War veterans, and O’Toole et al. (1996b) surveyed the entire Australian cohort of Gulf War veterans. Each of those studies found no significant increases in any cancer, on the basis of self-reports, in veterans deployed to the gulf compared with nondeployed veterans. Testicular Cancer Two studies have focused specifically on testicular cancer. Testicular cancer is relatively uncommon in the United States. The annual age-adjusted incidence is 5.3 cases per 100,000 men. However, it is one of the few cancers whose usual age of onset is in the same range as the age of the Gulf War veterans, about 20-44 (Ries et al. 2005). Knoke et al. (1998) examined testicular cancer in 517,223 deployed and 1,291,323 nondeployed male veterans on active duty during the time of the Gulf War. The authors identified cases of all first hospital admissions, in U.S. military hospitals worldwide, for a principal diagnosis of testicular cancer. Cases were identified by examining the DoD hospitalization database through April 1, 1997. A total of 505 cases were ascertained: 134 in the deployed and 371 in the nondeployed. In Cox proportional-hazards models adjusted for race and ethnicity, age, and occupation, no association with deployment status was observed (RR 1.05, 95% CI 0.86-1.29). The deployed did have an increased risk in the early months after the end of the deployment period. The initial increase in risk was originally reported in a study of all hospitalizations in the cohort by Gray et al. (1996) discussed above. However, by the end of 1996, the cumulative probability of hospitalization of the two groups was the same (0.034% for deployed and 0.035% for nondeployed). There was no interaction between covariates and deployment status. The authors also assessed the association of testicular cancer with specific occupations for both deployed and nondeployed veterans. The highest RRs were observed for men engaged in electronic-equipment repair (RR 1.56, 95% CI 1.23-2.00), construction-related trades (RR 1.42, 95% CI 0.93-2.17), and electric or mechanical repair (RR 1.26, 95% CI 1.01-1.58). The followup period was short for a cancer assessment, but it did include the age range
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress (22-31 years) when the disease might appear. No specific Gulf War exposures were assessed, although risk by occupational group was calculated. There was some evidence of an association of testicular cancer with Gulf War deployment in a pilot cancer-registry-based study. Levine et al. (2005) matched a stratified random sample of 621,902 Gulf War deployed active-duty, reserve, and National Guard veterans and 746,248 nondeployed veterans with the central cancer registries of New Jersey and the District of Columbia. From 1991 to 1999, 17 deployed and 11 nondeployed veterans were identified with testicular cancer for a proportional incidence rate of 2.33 (95% CI 0.95-5.70) adjusted for state of residence, deployment status, race, and age. The greatest proportions of testicular cancer were in deployed men in the age groups of 25-29 and 30-34 years (standardized incidence ratio 1.42) and in nondeployed men in age groups of 30-34 and 35-39 years (standardized incidence ratio 0.94). The number of excess cases peaked 4-5 years after deployment, as opposed to the findings in the Knoke et al. study, which found the excess in the first few months after the soldiers returned home. Gray et al. (1996) analyzed hospital records from DoD facilities for the last 5 months of 1991 and all of 1992 and 1993. In 1991, hospitalizations for malignant neoplasm of the testis were slightly higher in deployed men (rate ratio 2.12, 95% CI 1.11-4.02), but no difference was seen in 1992 or 1993. Skin Cancer There are two types of skin cancer: melanoma, which forms in the skin cells that make pigment and is less common, and the more common nonmelanoma skin cancer, which typically begins in cells that do not make pigments—basal cells (small round cells in the base of the outer layer of skin) or squamous cells (flat cells that form the surface of the skin). The annual age-adjusted incidence of melanoma of the skin is about 18.5 per 100,000 people. Skin cancer was assessed separately by the committee because of the potential for military personnel to be exposed to ultraviolet radiation and environmental toxicants and because several of the studies considered by the committee provided an analysis of skin cancer as distinct from other cancers. The committee identified only one primary study that assessed the prevalence of skin cancer in Vietnam veterans: CDC (1988b) looked for skin cancer as part of the VES. The prevalence of skin cancer on dermatologic examination was 0.6% in Vietnam-theater veterans and 0.7% in Vietnam-era veterans for a nonsignificant OR of 0.8 (95% CI 0.4-1.7) adjusted for age at enlistment, race, year of enlistment, enlistment status, score on general technical test, and primary military occupation. One primary study that assessed the risk of skin cancer in Gulf War veterans was identified. As of 2002, when Australian Gulf War veterans were compared with their nondeployed counterparts, they had no increase in prevalence of probable or possible skin cancers diagnosed after 1991 (Kelsall et al. 2004a). The entire Australian cohort of 1871 veterans who were deployed to Southeast Asia was compared with nondeployed veterans frequency matched for service type, sex, and age. Participants completed a self-report questionnaire about medical conditions that had been diagnosed or treated by a medical doctor and about when the conditions had been diagnosed. Participants also underwent a comprehensive health assessment by specially trained health professionals who were blinded to the deployment status of the participants and asked further questions about the diagnoses and determined whether the self-reports were unlikely, possible, or probable according to pre-established criteria. The participation rate was 80.5% for Gulf War veterans and 50.5% for the control group. This study
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress has the advantage of a good participation rate for the deployed veterans and use of criteria for assessing self-reports of health but is limited in that self-reports were not verified by a physical examination and the participation rate for the control group was poor. Although the veterans were asked about psychologic stressors experienced during their deployment, the results of this questionnaire were not correlated with specific health outcomes. Three secondary studies also estimated the risk of skin cancer in Gulf War veterans on the basis of self-reports. As discussed above, the Iowa Persian Gulf Study Group (1997) also surveyed deployed and nondeployed Gulf War veterans from a restricted geographic area to ascertain the prevalence of skin cancer. Compared with nondeployed veterans, Gulf War veterans had a significantly increased prevalence rate difference for skin cancer (Cochran-Mantel-Haenszel rate difference 0.8, 95% CI 0.4-1.3, p ≤ 0.05). In the Kang et al. (2000b) study, the population prevalence of self-reported skin cancer was estimated to be 1.5% in Gulf War veterans and 1.4% in Gulf War-era veterans for a statistically significant increased rate difference of 0.15 (95% CI 0.11-0.19, p ≤ 0.05). Steele (2000) looked at skin cancer in Gulf War-deployed and nondeployed Kansas veterans in 1998. On the basis of a structured telephone interview in which veterans were asked whether they had ever received a physician’s diagnosis of or treatment for a medical condition and when it had developed, the OR for skin cancer occurring after 1990 in deployed veterans was 1.17 (95% CI 0.47-2.90). As noted in the discussion of this study above, its limitations include a restricted geographic area, lack of verification of medical conditions by medical record or examination, and poor exposure data. PTSD and Cancer Few studies have assessed cancer in Vietnam War and Gulf War veterans who have PTSD. The committee identified only one primary study: Boscarino (2005) examined excess postservice mortality from cancer in Vietnam veterans by using data from the VES 16 years after the war. Mortality was assessed in Vietnam veterans who were known to be alive in 1983 and who completed a telephone interview at that time on PTSD symptoms and health status; 7924 Vietnam-theater and 7364 Vietnam-era veterans completed the telephone interview. Vital status was assessed for the period January 1985-December 2000 with the VA Beneficiary Identification Record Locator Subsystem (BIRLS) Death File, the Social Security Administration Death Master File, and the National Death Index Plus. Cause of death was coded according to ICD. During the telephone interview, veterans were asked about 15 PTSD-related symptoms and their frequency; in 1985-1986, PTSD was diagnosed in a subsample of the veterans (2490 theater veterans and 1972 era veterans) on the basis of personal interviews with the Diagnostic Interview Schedule Version III (DIS-III). With DIS-III, 377 veterans were diagnosed with lifetime PTSD on the basis of combat exposure, which was assessed with the Combat Exposure Scale. Boscarino reported that in the telephone interview there was a clear dose-response relationship between low, moderate, high, and very high combat exposure and whether the criteria for PTSD were met. The Cox proportional-hazards ratio for cancer mortality (188 total deaths) was 1.9 for PTSD-positive Vietnam-theater veterans (95% CI 1.1-3.3, p = 0.018) and 0.9 (95% CI 0.3-3.1) for Vietnam era veterans with the model adjusted for race, Army volunteer status, Army entry age, Army discharge status, Army illicit drug use, age at interview, intelligence, and pack-years of cigarette-smoking. Strengths of this study include a large sample, a sufficient latent period (17 years) for death from cancer, the use of an in-person structured interview to diagnose PTSD, and an assessment of combat exposure; limitations include lack of specification as to cancer type.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Kulka RA, Schlenger WE, Fairbank JA, Hough RL, Jordan BK, Marmar CR, Weiss DS. 1990. Trauma and the Vietnam War Generation: Report of Findings from the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel Publishers. Kuzma JM, Black DW. 2006. Chronic widespread pain and psychiatric disorders in veterans of the first Gulf War. Current Pain and Headache Reports 10(2):85-89. Lambert MT, Fowler DR. 1997. Suicide risk factors among veterans: Risk management in the changing culture of the Department of Veterans Affairs. Journal of Mental Health Administration 24(3):350-358. Lauterbach D, Vora R, Rakow M. 2005. The relationship between posttraumatic stress disorder and self-reported health problems. Psychosomatic Medicine 67(6):939-947. Lavie P, Hefez A, Halperin G, Enoch D. 1979. Long-term effects of traumatic war-related events on sleep. American Journal of Psychiatry 136(2):175-178. Lavie P, Katz N, Pillar G, Zinger, Y. 1998. Elevated awaking thresholds during sleep: Characteristics of chronic war-related posttraumatic stress disorder patients. Biological Psychiatry 44(10):1060-1065. Lee KA, Vaillant GE, Torrey WC, Elder GH. 1995. A 50-year prospective study of the psychological sequelae of World War II combat. American Journal of Psychiatry 152(4):516-522. Leung DY. 2000. Atopic dermatitis: New insights and opportunities for therapeutic intervention. Journal of Allergy and Clinical Immunology 105(5):860-876. Leung DY, Soter NA. 2001. Cellular and immunologic mechanisms in atopic dermatitis. Journal of the American Academy of Dermatology 44(1 Suppl):S1-S12. Levine PH, Young HA, Simmens SJ, Rentz D, Kofie VE, Mahan CM, Kang HK. 2005. Is testicular cancer related to Gulf War deployment? Evidence from a pilot population-based study of Gulf War era veterans and cancer registries. Military Medicine 170(2):149-153. Levy RL, Whitehead WE, Von Korff MR, Feld AD. 2000. Intergenerational transmission of gastrointestinal illness behavior. American Journal of Gastroenterology 95(2):451-456. Levy RL, Olden KW, Naliboff BD, Bradley LA, Francisconi C, Drossman DA, Creed F. 2006. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology 130(5):1447-1458. Lieberman HR, Bathalon GP, Falco CM, Kramer FM, Morgan CA, 3rd, Niro P. 2005a. Severe decrements in cognition function and mood induced by sleep loss, heat, dehydration, and undernutrition during simulated combat. Biological Psychiatry 57(4):422-429. Lieberman HR, Bathalon GP, Falco CM, Morgan CA, 3rd, Niro PJ, Tharion WJ. 2005b. The fog of war: Decrements in cognitive performance and mood associated with combat-like stress. Aviation Space and Environmental Medicine 76(7 Suppl):C7-C14. Lindauer RT, van Meijel EP, Jalink M, Olff M, Carlier IV, Gersons BP. 2006. Heart rate responsivity to script-driven imagery in posttraumatic stress disorder: Specificity of response and effects of psychotherapy. Psychosomatic Medicine 68(1):33-40. Lindem K, White RF, Heeren T, Proctor SP, Krengel M, Vasterling J, Wolfe J, Sutker PB, Kirkley S, Keane TM. 2003. Neuropsychological performance in Gulf War era veterans: Motivational factors and effort. Journal of Psychopathology and Behavioral Assessment 25(2):129-138.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 2006a. Functional bowel disorders. Gastroenterology 130(5):1480-1491. Longstreth G, Thompson W, Chey W, Houghton L, Mearin F, Spiller R. 2006b. Functional bowel disorders. In: Drossman D, Corazziari E, Delvaux M, Spiller R, Talley N, Thompson W, editors. Rome III: The Functional Gastrointestinal Disorders. 3rd Ed. McLean, VA: Degnon Associates, Inc. Macfarlane GJ, Thomas E, Cherry N. 2000. Mortality among UK Gulf War veterans. Lancet 356(9223):17-21. Macfarlane GJ, Biggs AM, Maconochie N, Hotopf M, Doyle P, Lunt M. 2003. Incidence of cancer among UK Gulf war veterans: Cohort study. British Medical Journal 327(7428):1373. Macfarlane GJ, Hotopf M, Maconochie N, Blatchley N, Richards A, Lunt M. 2005. Long-term mortality amongst Gulf War Veterans: Is there a relationship with experiences during deployment and subsequent morbidity? International Journal of Epidemiology 34(6):1403-1408. Maconochie N, Doyle P, Davies G, Lewis S, Pelerin M, Prior S, Sampson P. 2003. The study of reproductive outcome and the health of offspring of UK veterans of the Gulf war: Methods and description of the study population. BMC Public Health 3(1):4. Maconochie N, Doyle P, Carson C. 2004. Infertility among male UK veterans of the 1990-1 Gulf war: Reproductive cohort study. British Medical Journal 329(7459):196-201. Mason J, Southwick S, Yehuda R, Wang S, Riney S, Bremner D, Johnson D, Lubin H, Blake D, Zhou G, Gusman F, Charney D. 1994. Elevation of serum free triiodothyronine, total triiodothyronine, thyroxine-binding globulin, and total thyroxine levels in combat-related posttraumatic stress disorder. Archives of General Psychiatry 51(8):629-641. Mayer EA. 2006. Commentary on peripheral and central contributions to hyperalgesia in irritable bowel syndrome. Journal of Pain 7(8):539-543. McCauley LA, Joos SK, Barkhuizen A, Shuell T, Tyree WA, Bourdette DN. 2002a. Chronic fatigue in a population-based study of Gulf War veterans. Archives of Environmental Health 57(4):340-348. McCauley LA, Lasarev M, Sticker D, Rischitelli DG, Spencer PS. 2002b. Illness experience of Gulf War veterans possibly exposed to chemical warfare agents. American Journal of Preventive Medicine 23(3):200-206. McEwen BS. 2002. Protective and damaging effects of stress mediators: The good and bad sides of the response to stress. Metabolism 51(6 Suppl 1):2-4. McEwen BS. 2004. Protection and damage from acute and chronic stress: Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of the New York Academy of Sciences 1032:1-7. McFarlane AC. 1997. The prevalence and longitudinal course of PTSD. Implications for the neurobiological models of PTSD. Annals of the New York Academy of Sciences 821:10-23. McFarlane AC, Atchison M, Rafalowicz E, Papay P. 1994. Physical symptoms in post-traumatic stress disorder. Journal of Psychosomatic Research 38(7):715-726. McKeown ES, Parry SD, Stansfield R, Barton JR, Welfare MR. 2006. Postinfectious irritable bowel syndrome may occur after non-gastrointestinal and intestinal infection. Neurogastroenterology and Motility 18(9):839-843.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress McLeod D, Koenen KC, Meyer JM, Lyons MJ, Eisen S, True W, Goldberg J. 2001. Genetic and environmental influences on the relationship among combat exposure, posttraumatic stress disorder symptoms, and alcohol use. Journal of Traumatic Stress 14(2):259-275. Mellman TA, Randolph CA, Brawman-Mintzer O, Flores LP, Milanes FJ. 1992. Phenomenology and course of psychiatric disorders associated with combat-related posttraumatic stress disorder. American Journal of Psychiatry 149(11):1568-1574. Mellman TA, Kulick-Bell R, Ashlock LE, Nolan B. 1995a. Sleep events among veterans with combat-related posttraumatic stress disorder. American Journal of Psychiatry 152(1):110-115. Mellman TA, Kumar A, Kulick-Bell R, Kumar M, Nolan B. 1995b. Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biological Psychiatry 38(3):174-179. Mellman TA, Nolan B, Hebding J, Kulick-Bell R, Dominguez R. 1997. A polysomnographic comparison of veterans with combat-related PTSD, depressed men, and non-ill controls. Sleep 20(1):46-51. MHAT (Mental Health Advisory Team). 2006a. Mental Health Advisory Team (MHAT) III Operation Iraqi Freedom 04-06: Final Report. [Washington, DC]: Office of the Surgeon Multinational Force-Iraq and Office of the Surgeon General United States Army Medical Command. 29 May 2006. [Online]. Available: http://www.armymedicine.army.mil/news/mhat/mhat_iii/mhat-iii.cfm. MHAT. 2006b. Mental Health Advisory Team (MHAT) IV Operation Iraqi Freedom 05-07: Final Report. [Washington, DC]: Office of the Surgeon Multinational Force-Iraq and Office of the Surgeon General United States Army Medical Command. 17 November 2006. [Online]. Available: http://www.armymedicine.army.mil/news/mhat/mhat_iv/MHAT_IV_Report_17NOV06.pdf. Mizokami T, Wu Li A, El-Kaissi S, Wall JR. 2004. Stress and thyroid autoimmunity. Thyroid 14(12):1047-1055. Mooy JM, de Vries H, Grootenhuis PA, Bouter LM, Heine RJ. 2000. Major stressful life events in relation to prevalence of undetected type 2 diabetes: The Hoorn Study. Diabetes Care 23(2):197-201. Morgan CA, 3rd, Wang S, Mason J, Southwick SM, Fox P, Hazlett G, Charney DS, Greenfield G. 2000. Hormone profiles in humans experiencing military survival training. Biological Psychiatry 47(10):891-901. Muraoka MY, Carlson JG, Chemtob CM. 1998. Twenty-four-hour ambulatory blood pressure and heart rate monitoring in combat-related posttraumatic stress disorder. Journal of Traumatic Stress 11(3):473-484. Murburg MM, McFall ME, Lewis N, Veith RC. 1995. Plasma norepinephrine kinetics in patients with posttraumatic stress disorder. Biological Psychiatry 38(12):819-825. Murphy FM, Kang H, Dalager NA, Lee KY, Allen RE, Mather SH, Kizer KW. 1999. The health status of Gulf War veterans: Lessons learned from the Department of Veterans Affairs Health Registry. Military Medicine 164(5):327-331. Murray CD, Flynn J, Ratcliffe L, Jacyna MR, Kamm MA, Emmanuel AV. 2004. Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome. Gastroenterology 127(6):1695-1703.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress National Heart Lung and Blood Institute. 2007. Sleep Disorders Information. [Online]. Available: http://www.nhlbi.nih.gov/health/prof/sleep/ [accessed July 26, 2007]. Neylan TC, Marmar CR, Metzler TJ, Weiss DS, Zatzick DF, Delucchi KL, Wu RM, Schoenfeld FB. 1998. Sleep disturbances in the Vietnam generation: Findings from a nationally representative sample of male Vietnam veterans. American Journal of Psychiatry 155(7):929-933. Nisenbaum R, Barrett DH, Reyes M, Reeves WC. 2000. Deployment stressors and a chronic multisymptom illness among Gulf War veterans. Journal of Nervous and Mental Disease 188(5):259-266. Office of the Surgeon Multinational Force-Iraq, Office of the Surgeon General United States Army Medical Command. 2006. Mental Health Advisory Team (MHAT) IV Operation Iraqi Freedom 05-07. Final Report. Orr SP, Meyerhoff JL, Edwards JV, Pitman RK. 1998. Heart rate and blood pressure resting levels and responses to generic stressors in Vietnam veterans with posttraumatic stress disorder. Journal of Traumatic Stress 11(1):155-164. Orr SP, Metzger LJ, Lasko NB, Macklin ML, Hu FB, Shalev AY, Pitman RK. 2003. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: Association with posttraumatic stress disorder. Archives of General Psychiatry 60(3):283-288. Otis JD, Keane TM, Kerns RD. 2003. An examination of the relationship between chronic pain and post-traumatic stress disorder. Journal of Rehabilitation Research and Development 40(5):397-405. O’Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, French M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996a. The Australian Vietnam Veterans Health Study: III. Psychological health of Australian Vietnam veterans and its relationship to combat. International Journal of Epidemiology 25(2):331-340. O’Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, French M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996b. The Australian Vietnam Veterans Health Study: II. Self-reported health of veterans compared with the Australian population. International Journal of Epidemiology 25(2):319-330. O’Toole BI, Marshall RP, Schureck RJ, Dobson M. 1998. Posttraumatic stress disorder and comorbidity in Australian Vietnam veterans: Risk factors, chronicity and combat. Australian and New Zealand Journal of Psychiatry 32(1):32-42. Ouimette PC, Wolfe J, Chrestman KR. 1996. Characteristics of posttraumatic stress disorder-alcohol abuse comorbidity in women. Journal of Substance Abuse 8(3):335-346. Ozakinci G, Hallman WK, Kipen HM. 2006. Persistence of symptoms in veterans of the First Gulf War: 5-year follow-up. Environmental Health Perspectives 114(10):1553-1557. Palatini P, Julius S. 1997. Heart rate and the cardiovascular risk. Journal of Hypertension 15(1):3-17. Pallmeyer TP, Blanchard EB, Kolb LC. 1986. The psychophysiology of combat-induced posttraumatic stress disorder in Vietnam veterans. Behaviour Research and Therapy 24(6):645-652.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Papageorgiou AC, Silman, AJ, Macfarlane GJ. 2002. Chronic widespread pain in the population: A seven year follow up study. Annals of the Rheumatic Diseases 61:1071-1074. Pierce PF. 1997. Physical and emotional health of Gulf War veteran women. Aviation Space and Environmental Medicine 68(4):317-321. Pizarro J, Silver RC, Prause J. 2006. Physical and mental health costs of traumatic war experiences among Civil War veterans. Archives of General Psychiatry 63(2):193-200. Price RK, Risk NK, Haden AH, Lewis CE, Spitznagel EL. 2004. Post-traumatic stress disorder, drug dependence, and suicidality among male Vietnam veterans with a history of heavy drug use. Drug and Alcohol Dependence 76(Suppl):S31-S43. Prigerson HG, Maciejewski PK, Rosenheck RA. 2002. Population attributable fractions of psychiatric disorders and behavioral outcomes associated with combat exposure among U.S. men. American Journal of Public Health 92(1):59-63. Proctor SP, Heeren T, White RF, Wolfe J, Borgos MS, Davis JD, Pepper L, Clapp R, Sutker PB, Vasterling JJ, Ozonoff D. 1998. Health status of Persian Gulf War veterans: Self-reported symptoms, environmental exposures and the effect of stress. International Journal of Epidemiology 27(6):1000-1010. Proctor SP, White RF, Heeren T, Debes F, Gloerfelt-Tarp B, Appleyard M, Ishoy T, Guldager B, Suadicani P, Gyntelberg F, Ozonoff DM. 2003. Neuropsychological functioning in Danish Gulf War veterans. Journal of Psychopathology and Behavioral Assessment 25(2):85-93. Proctor SP, Harley R, Wolfe J, Heeren T, White RF. 2001. Health-related quality of life in Persian Gulf War veterans. Military Medicine 166(6):510-519. Putnam SD, Sanders JW, Frenck RW, Monteville M, Riddle MS, Rockabrand DM, Sharp TW, Frankart C, Tribble DR. 2006. Self-reported description of diarrhea among military populations in operations Iraqi Freedom and Enduring Freedom. Journal of Travel Medicine 13(2):92-99. Reid S, Hotopf M, Hull L, Ismail K, Unwin C, Wessely S. 2001. Multiple chemical sensitivity and chronic fatigue syndrome in British Gulf War veterans. American Journal of Epidemiology 153(6):604-609. Reifman A, Windle M. 1996. Vietnam combat exposure and recent drug use: A national study. Journal of Traumatic Stress 9(3):557-568. Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, Mariotto A, Feuer E, Edwards B. 2005. SEER Cancer Statistics Review, 1975-2002. [Online]. Available: http://caonline.amcancersoc.org/cgi/reprint/56/1/9.pdfseer.cancer.gov/csr/1975_2002/ [accessed June 2006]. Ro BI, Dawson TL. 2005. The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff. Journal of Investigative Dermatology Symposium Proceedings 10(3):194-197. Robins LN, Davis DH, Nurco DN. 1974. How permanent was Vietnam drug addiction? American Journal of Public Health 64(Suppl 12):38-43. Ryan MA, Ness RB, Wells TS, O’Donnell FL. 2004. Birth defects among infants of Gulf War veterans, 1989-1993. Birth Defects Research 70(1):47. Schnurr PP, Jankowski MK. 1999. Physical health and post-traumatic stress disorder: Review and synthesis. Seminars in Clinical Neuropsychiatry 4(4):295-304.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Schnurr PP, Spiro A. 1999. Combat exposure, posttraumatic stress disorder symptoms, and health behaviors as predictors of self-reported physical health in older veterans. Journal of Nervous and Mental Disease 187(6):353-359. Schnurr PP, Spiro A, 3rd, Paris AH. 2000. Physician-diagnosed medical disorders in relation to PTSD symptoms in older male military veterans. Health Psychology 19(1):91-97. Selected Cancers Cooperative Study Group. 1990a. The association of selected cancers with service in the U.S. military in Vietnam. I. Non-Hodgkin’s lymphoma. Archives of Internal Medicine 150(12):2473-2483. Selected Cancers Cooperative Study Group. 1990b. The association of selected cancers with service in the U.S. military in Vietnam. II. Soft-tissue and other sarcomas. Archives of Internal Medicine 150(12):2485-2492. Selected Cancers Cooperative Study Group. 1990c. The association of selected cancers with service in the U.S. military in Vietnam. III. Hodgkin’s disease, nasal cancer, nasopharyngeal cancer, and primary liver cancer. Archives of Internal Medicine 150(12):2495-2505. Shalev AY, Sahar T, Freedman S, Peri T, Glick N, Brandes D, Orr SP, Pitman RK. 1998. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Archives of General Psychiatry 55(6):553-539. Sharafkhaneh A, Giray N, Richardson P, Young T, Hirshkowitz M. 2005. Association of psychiatric disorders and sleep apnea in a large cohort. Sleep 28(11):1405-1411. Shipherd JC, Stafford J, Tanner LR. 2005. Predicting alcohol and drug abuse in Persian Gulf War veterans: What role do PTSD symptoms play? Addictive Behaviors 30(3):595-599. Simmons R, Maconochie N, Doyle P. 2004. Self-reported ill health in male UK Gulf War veterans: A retrospective cohort study. BMC Public Health 4(1):27. Sloan P, Arsenault L, Hilsenroth MJ. 2005. Impact of Event Scale prediction of DSM-IV PTSD and physical symptoms in Gulf War veterans. Stress, Trauma and Crisis: An International Journal 8(4):215-228. Smith TC, Gray GC, Knoke JD. 2000. Is systemic lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia associated with Persian Gulf War service? An examination of Department of Defense hospitalization data. American Journal of Epidemiology 151(11):1053-1059. Snow BR, Stellman JM, Stellman SD, Sommer JF Jr. 1988. Post-traumatic stress disorder among American Legionnaires in relation to combat experience in Vietnam: Associated and contributing factors. Environmental Research 47(2):175-192. Solter V, Thaller V, Karlovic D, Crnkovic D. 2002. Elevated serum lipids in veterans with combat-related chronic posttraumatic stress disorder. Croatian Medical Journal 43(6):685-689. Sostek MB, Jackson S, Linevsky JK, Schimmel EM, Fincke BG. 1996. High prevalence of chronic gastrointestinal symptoms in a National Guard Unit of Persian Gulf veterans. American Journal of Gastroenterology 91(12):2494-2497. Spiller R, Campbell E. 2006. Post-infectious irritable bowel syndrome. Current Opinions in Gastroenterology 22(1):13-17. Spiro A, 3rd, Hankin CS, Mansell D, Kazis LE. 2006. Posttraumatic stress disorder and health status: The veterans health study. Journal of Ambulatory Care Management 29(1):71-86.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Steele L. 2000. Prevalence and patterns of Gulf War illness in Kansas veterans: Association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology 152(10):992-1002. Stermer E, Bar H, Levy N. 1991. Chronic functional gastrointestinal symptoms in Holocaust survivors. American Journal of Gastroenterology 86(4):417-422. Stimpson NJ, Unwin C, Hull L, David T, Wessely S, Lewis G. 2006. Prevalence of reported pain, widespread pain, and pain symmetry in veterans of the Persian Gulf War (1990-1991): The use of pain manikins in Persian Gulf War health research. Military Medicine 171(12):1181-1186. Straus SE. 1991. History of chronic fatigue syndrome. Reviews of Infectious Diseases 13(Suppl 1):S2-S7. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. 1995. Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Military Medicine 160(3):131-136. Sutker PB, Allain AN Jr, Winstead DK. 1993a. Psychopathology and psychiatric diagnoses of World War II Pacific theater prisoner of war survivors and combat veterans. American Journal of Psychiatry 150(2):240-245. Sutker PB, Uddo M, Brailey K, Allain AN. 1993b. War-zone trauma and stress-related symptoms in Operation Desert Shield/Storm (ODS) returnees. Journal of Social Issues 49(4):33-50. Taft CT, Stern AS, King LA, King DW. 1999. Modeling physical health and functional health status: The role of combat exposure, posttraumatic stress disorder, and personal resource attributes. Journal of Traumatic Stress 12(1):3-23. Thomas HV, Stimpson NJ, Weightman A, Dunstan F, Lewis G. 2006. Pain in veterans of the Gulf War of 1991: A systematic review. BMC Musculoskeletal Disorders 7:74. Thomas TL, Kang HK, Dalager NA. 1991. Mortality among women Vietnam veterans, 1973-1987. American Journal of Epidemiology 134(9):973-980. Thompson R, Kane VR, Sayers SL, Brown GK, Coyne JC, Katz IR. 2002. An assessment of suicide in an urban VA Medical Center. Psychiatry 65(4):327-337. Toomey R, Kang HK, Karlinsky J, Baker DG, Vasterling JJ, Alpern R, Reda DJ, Henderson WG, Murphy FM, Eisen SA. 2007. Mental health of U.S. Gulf War veterans 10 years after the war. British Journal of Psychiatry 190:385-393. Uddo M, Vasterling JJ, Brailey K, Sutker PB. 1993. Memory and attention in combat-related post-traumatic stress disorder (PTSD). Journal of Psychopathology and Behavioral Assessment 15(1):43-52. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169-178. Vasterling JJ, Rogers C, Kaplan E. 2000. Qualitative block design analysis in posttraumatic stress disorder. Assessment 7(3):217-226. Vasterling JJ, Duke LM, Brailey K, Constans JI, Allain AN Jr, Sutker PB. 2002. Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology 16(1):5-14.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Vasterling JJ, Brailey K, Constans JI, Sutker PB. 1998. Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology 12(1):125-133. Vasterling JJ, Proctor SP, Amoroso P, Kane R, Gackstetter G, Ryan MA, Friedman MJ. 2006. The Neurocognition Deployment Health Study: A prospective cohort study of Army Soldiers. Military Medicine 171(3):253-260. Vasterling JJ, Brailey K, Tomlin H, Rice J, Sutker PB. 2003. Olfactory functioning in Gulf War-era veterans: Relationships to war-zone duty, self-reported hazards exposures, and psychological distress. Journal of the International Neuropsychological Society 9(3):407-418. Vieweg WV, Julius DA, Benesek J, Satterwhite L, Fernandez A, Feuer SJ, Pandurangi AK. 2006. Posttraumatic stress disorder and body mass index in military veterans. Preliminary findings. Progress in Neuro-Psychopharmacology and Biological Psychiatry 30(6):1150-1154. Villa VM, Harada ND, Washington D, Damron-Rodriquez J. 2002. Health and functioning among four war ears of U.S. veterans: Examining the impact of war cohort membership, socioeconomic status, mental health, and disease prevalence. Military Medicine 167(9):783-789. Wang S, Mason J. 1999. Elevations of serum T3 levels and their association with symptoms in World War II veterans with combat-related posttraumatic stress disorder: Replication of findings in Vietnam combat veterans. Psychosomatic Medicine 61(2):131-138. Wang S, Mason J, Southwick S, Johnson D, Lubin H, Charney D. 1995. Relationships between thyroid hormones and symptoms in combat-related posttraumatic stress disorder. Psychosomatic Medicine 57(4):398-402. Watanabe KK, Kang HK. 1995. Military service in Vietnam and the risk of death from trauma and selected cancers. Annals of Epidemiology 5(5):407-412. Weiss DS, Marmar CR, Schlenger WE, Fairbank JA, Jordan BK, Hough RL, Kulka RA. 1992. The prevalence of lifetime and partial post-traumatic stress disorder in Vietnam theater veterans. Journal of Traumatic Stress 5(2):365-376. Wells TS, Wang LZ, Spooner CN, Smith TC, Hiliopoulos KM, Kamens DR, Gray GC, Sato PA. 2006. Self-reported reproductive outcomes among male and female 1991 Gulf War era U.S. military veterans. Maternal and Child Health Journal 10(6):501-510. Werler MM, Sheehan JE, Mitchell AA. 2005. Gulf War veterans and hemifacial microsomia. Birth Defects Research 73(1):50-52. Wessely S. 2005. Risk, psychiatry and the military. British Journal of Psychiatry 186:459-466. White RF, Proctor SP, Heeren T, Wolfe J, Krengel M, Vasterling J, Lindem K, Heaton KJ, Sutker P, Ozonoff DM. 2001. Neuropsychological function in Gulf War veterans: Relationships to self-reported toxicant exposures. American Journal of Industrial Medicine 40(1):42-54. Whitehead WE, Palsson O, Jones KR. 2002. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 122(4):1140-1156. Wills TA, Yaeger AM, Sandy JM. 2003. Buffering effect of religiosity for adolescent substance use. Psychology of Addictive Behaviors 17(1):24-31.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Wolfe F. 1989. Fibromyalgia: The clinical syndrome. Rheumatic Diseases Clinics of North America 15(1):1-18. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin MC, Gatter RA, Hamaty D, Lesserd J, Lichtbroun AS, Masi AT, McCain GA, Reynolds WJ, Romano TJ, Russel IJ, Sheon RP. 1990. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism 33(2):160-172. Wolfe J, Schnurr PP, Brown PJ, Furey J. 1994. Posttraumatic stress disorder and war-zone exposure as correlates of perceived health in female Vietnam War veterans. Journal of Consulting and Clinical Psychology 62(6):1235-1240. Wolfe J, Proctor SP, Davis JD, Borgos MS, Friedman MJ. 1998. Health symptoms reported by Persian Gulf War veterans two years after return. American Journal of Industrial Medicine 33(2):104-113. Wolfe J, Proctor SP, Erickson DJ, Heeren T, Friedman MJ, Huang MT, Sutker PB, Vasterling JJ, White RF. 1999. Relationship of psychiatric status to Gulf War veterans’ health problems. Psychosomatic Medicine 61(4):532-540. Wolfe J, Proctor SP, Erickson DJ, Hu H. 2002. Risk factors for multisymptom illness in U.S. Army veterans of the Gulf War. Journal of Occupational and Environmental Medicine 44(3):271-281. Woodward SH, Murburg MM, Bliwise DL. 2000. PTSD-related hyperarousal assessed during sleep. Physiology and Behavior 70(1-2):197-203. Writer JV, DeFraites RF, Brundage JF. 1996. Comparative mortality among U.S. military personnel in the Persian Gulf region and worldwide during Operations Desert Shield and Desert Storm. Journal of the American Medical Association 275(2):118-121. Yarvis JS, Bordnick PS, Spivey CA, Pedlar D. 2005. Subthreshold PTSD: A comparison of alcohol, depression, and health problems in Canadian peacekeepers with different levels of traumatic stress. Stress, Trauma and Crisis: An International Journal 8(2-3):195-213. Yehuda R, Southwick SM, Giller EL, Ma X, Mason JW. 1992. Urinary catecholamine excretion and severity of PTSD symptoms in Vietnam combat veterans. Journal of Nervous and Mental Disease 180(5):321-325. Yehuda R, Keefe RS, Harvey PD, Levengood RA, Gerber DK, Geni J, Siever LJ. 1995. Learning and memory in combat veterans with posttraumatic stress disorder. American Journal of Psychiatry 152(1):137-139. Yehuda R, Siever LJ, Teicher MH, Levengood RA, Gerber DK, Schmeidler J, Yang RK. 1998. Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder. Biological Psychiatry 44(1):56-63. Zalewski C, Thompson W, Gottesman I. 1994. Comparison of neuropsychological test performance in PTSD, generalized anxiety disorder, and control Vietnam veterans. Assessment 1(2):133-142.
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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Zatzick DF, Marmar CR, Weiss DS, Browner WS, Metzler TJ, Golding JM, Stewart A, Schlenger WE, Wells KB. 1997a. Posttraumatic stress disorder and functioning and quality of life outcomes in a nationally representative sample of male Vietnam veterans. American Journal of Psychiatry 154(12):1690-1695. Zatzick DF, Weiss DS, Marmar CR, Metzler TJ, Wells K, Golding JM, Stewart A, Schlenger WE, Browner WS. 1997b. Post-traumatic stress disorder and functioning and quality of life outcomes in female Vietnam veterans. Military Medicine 162(10):661-665. Zhang Q, Zhou XD, Denny T, Ottenweller JE, Lange G, LaManca JJ, Lavietes MH, Pollet C, Gause WC, Natelson BH. 1999. Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology 6(1):6-13.
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