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BACKGROUND: Current evidence suggests an important role of the interleukin-6 (IL-6) pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cytokine release storm in severely ill coronavirus disease 2019 (COVID-19) patients. Inhibition of the IL-6 pathway with tocilizumab has been employed successfully in some of these patients but the data is mostly consistent of case reports and series. METHODS: We performed a systematic search of PubMed, Embase, and Medline from 22nd April 2020 and again on 27th April 2020 using the following search terms alone or in combination: "COVID-19," "coronavirus," "SARS-CoV-2," "COVID," "anti-interleukin-6 receptor antibodies," "anti-IL-6," "tocilizumab," "sarilumab," "siltuximab." We included studies that reported individual patient data. We extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes. The primary endpoint was in-hospital mortality. Secondary endpoints included in-hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers. RESULTS: Three hundred fifty-two records were identified through a systematic search, of which 10 studies met the inclusion criteria. A single study currently under review was also added. Eleven observational studies encompassing 29 patients were included in the present review. There were more males (24 [82.8%]), and hypertension was the most common comorbidity (16 [48.3%]). Over an average of 5.4 hospital days, the primary endpoint occurred in 6 (20.7%) patients. Among surviving patients, about 10% had worsened disease and 17% recovered. The most common complication was acute respiratory distress syndrome (8 [27.6%]). The IL-6 level was significantly higher after the initiation of tocilizumab with median (interquartile range) of 376.6 (148-900.6) pg/mL compared to the baseline of 71.1 (31.9-122.8) pg/mL (P = .002). Mean (standard deviation) levels of C-reactive protein (CRP) were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (P < .0001). Baseline demographics were not significantly different among survivors and nonsurvivors by Fisher's exact test. CONCLUSION: In COVID-19 patients treated with tocilizumab, IL-6 levels are significantly elevated, which are supportive of cytokine storm. Following initiation of tocilizumab, there is elevation in the IL-6 levels and CRP levels dramatically decrease, suggesting an improvement in this hyperinflammatory state. Ongoing randomized control trials will allow for further evaluation of this promising therapy. IMPORTANCE: Recent data indicate that severe COVID-19 causes a cytokine release storm and is associated with worse clinical outcomes and IL-6 plays an important role. It is suggestive that anti-IL-6 results in the improvement of this hyperinflammatory state. However, to our knowledge, there is no individual patient data systematic review performed to summarize baseline characteristics and clinical outcomes of COVID-19 patients who received tocilizumab.

The Deployment and Travel Medicine Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS) examines the integrated relationship between provider and patient inputs and health outcomes associated with travel and deployments. This study describes malaria chemoprophylaxis prescribing patterns by medical providers within the U.S. Department of Defense’s Military Health System and its network of civilian healthcare providers during a 5-year period. Chemoprophylaxis varied by practice setting, beneficiary status, and providers’ travel medicine expertise. Whereas both civilian and military facilities prescribe an increasing proportion of atovaquone–proguanil, doxycycline remains the most prevalent antimalarial at military facility based practices. Civilian providers dispense higher rates of mefloquine than their military counterparts. Within military treatment facilities, travel medicine specialists vary their prescribing pattern based on service member versus beneficiary status of the patient, both in regards to primary prophylaxis, and use of presumptive anti-relapse therapy (PQ-PART). By contrast, nonspecialists appear to carry over practice patterns developed under force health protection (FHP) policy for service members, into the care of beneficiaries, particularly in high rates of prescribing doxycycline and PQ-PART compared with both military travel medicine specialists and civilian comparators. Force health protection policy plays an important role in standardizing and improving the quality of care for deployed service members, but this may not be the perfect solution outside of the deployment context. Solutions that broaden both utilization of decision support tools and travel medicine specialty care are necessary.

Background Post-infectious Irritable Bowel Syndrome (PI-IBS) is a functional bowel disorder which has significant impacts to a patient’s quality of life. No IBS-specific biomarker or treatment regimen for PI-IBS currently exists, therefore understanding practice patterns and variance is of interest. Methods This online survey of primary care physicians and general practitioners in the USA aimed to understand the knowledge and treatment of PI-IBS within the physician’s current practice. Summary statistics are provided with a commentary on implications for practices and treatment of PI-IBS. Results Most physician survey respondents (n = 50) were aware of PI-IBS, but less than half discussed this condition as a possible outcome in their patients with a recent gastrointestinal infection. Most physicians indicated that they would treat the patients themselves with a focus on managing IBS through different treatment modalities based on severity. Treatment for PI-IBS followed IBS recommendations, but most physicians also prescribed a probiotic for therapy. Physicians estimated that 4 out of 10 patients who develop PI-IBS will have life-long symptoms and described significant impacts to their patient’s quality of life. Additionally, physicians estimated a significant financial burden for PI-IBS patients, ranging from $100–1000 (USD) over the course of their illness. Most physicians agreed that they would use a risk score to predict the probability of their patients developing PI-IBS, if available. Conclusions While this survey is limited due to sample size, physician knowledge and treatment of PI-IBS was consistent across respondents. Overall, the physicians identified significant impacts to patient’s quality of life due to PI-IBS.

Background Youth with chronic irritability and excessive reactivity, diagnosed as disruptive mood dysregulation disorder (DMDD), have social impairment in multiple settings (i.e., peers, school, and home). This paper presents a pilot randomized trial assessing the feasibility, acceptability, and preliminary efficacy of interpersonal psychotherapy (IPT) for mood and behavior dysregulation (IPT-MBD), an adapted version of IPT for depressed adolescents. IPT-MBD focuses on decreasing outbursts and irritability and improving interpersonal interactions. Methods Nineteen adolescents (aged 12-17) with DMDD or its research precursor, severe mood dysregulation, were randomly assigned to IPT-MBD (n = 10) or treatment-as-usual (TAU, n = 9) in a 24-week psychosocial intervention study. Assessments of mood symptoms and overall functioning were conducted by an independent evaluator, blinded to treatment, every 4 weeks. Parent and self-report irritability measures were collected every 4 weeks. Results Eighty percent of participants randomized to the IPT-MBD arm completed the study. Also, participants enrolled in the IPT-MBD arm attended >80% of therapy sessions. Parents and teens agreed that the frequency and duration of therapy were appropriate and were satisfied with IPT-MBD treatment. Clinical global impression scales for severity and improvement showed statistically greater improvement in the IPT-MBD group compared to TAU. Conclusions In this small pilot randomized trial, IPT-MBD was feasible and acceptable to parents and teens. There was significantly more improvement in the IPT-MBD group compared to TAU. IPT-MBD holds promise as a potentially effective psychosocial intervention for clinically impaired youth with DMDD and warrants further investigation in a larger randomized trial.

Background: Hoarding behavior may distinguish a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Little is known about the relationship between executive dysfunction and hoarding in individuals with OCD. Methods: The study sample included 431 adults diagnosed with DSM-IV OCD. Participants were assessed by clinicians for Axis I disorders, personality disorders, indecision, and hoarding. Executive functioning domains were evaluated using a self-report instrument, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). We compared scores on these domains in the 143 hoarding and 288 non-hoarding participants, separately in men and women. We used logistic regression to evaluate relationships between executive function scores and hoarding, and correlation and linear regression analyses to evaluate relationships between executive function scores and hoarding severity, in women. Results: In men, the hoarding group had a significantly higher mean score than the non-hoarding group only on the shift dimension. In contrast, in women, the hoarding group had higher mean scores on the shift scale and all metacognition dimensions, i.e., those that assess the ability to systematically solve problems via planning and organization. The relationships in women between hoarding and scores on initiating tasks, planning/organizing, organization of materials, and the metacognition index were independent of other clinical features. Furthermore, the severity of hoarding in women correlated most strongly with metacognition dimensions. Conclusions: Self-reported deficits in planning and organization are associated with the occurrence and severity of hoarding in women, but not men, with OCD. This may have implications for elucidating the etiology of, and developing effective treatments for, hoarding in OCD. Keywords: Obsessive-compulsive disorder, OCD, Hoarding, Executive function

Background Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Methods Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 × 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. Results There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Conclusions Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. Clinical trials registration NCT02280044.

Background Clinicians have long considered doubt to be a fundamental characteristic of obsessive–compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. Methods Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. Results The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive–compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. Conclusions Doubt is associated with important clinical features of OCD, including impairment and cognitive–behavioral treatment response.

IntroductionOperational stress describes individual behavior in response to the occupational demands and tempo of a mission. The stress response of military personnel involved in combat and peace-keeping missions has been well-described. The spectrum of effect on medical professionals and support staff providing humanitarian assistance, however, is less well delineated. Research to date concentrates mainly on shore-based humanitarian missions.ProblemThe goal of the current study was to document the pattern of operational stress, describe factors responsible for it, and the extent to which these factors impact job performance in military and civilian participants of Continuing Promise 2011 (CP11), a ship-based humanitarian medical mission.MethodsThis was a retrospective study of Disease Non-Battle Injury (DNBI) data from the medical sick-call clinic and from weekly self-report questionnaires for approximately 900 US military and civilian mission participants aboard the USNS COMFORT (T-AH 20). The incidence rates and job performance impact of reported Operational Stress/Mental Health (OS/MH) issues and predictors (age, rank, occupation, service branch) of OS/MH issues (depression, anxiety) were analyzed over a 22-week deployment period.ResultsIncidence rates of OS/MH complaints from the sick-call clinic were 3.7% (4.5/1,000 persons) and 12.0% (53/1,000 persons) from the self-report questionnaire. The rate of operational stress increased as the mission progressed and fluctuated during the mission according to ship movement. Approximately 57% of the responders reported no impact on job performance. Younger individuals (enlisted ranks E4-6, officer ranks O1-3), especially Air Force service members, those who had spent only one day off ship, and those who were members of specific directorates, reported the highest rates of operational stress.ConclusionThe overall incidence of OS/MH complaints was low in participants of CP11 but was under-estimated by clinic-based reporting. The OS/MH complaints increased as the mission progressed, were more prevalent in certain groups, and appeared to be related to ship’s movement. These findings document the pattern of operational stress in a ship-based medical humanitarian mission and confirm unique ship-based stressors. This information may be used by planners of similar missions to develop mitigation strategies for known stressors and by preventive medicine, behavioral health specialists, and mission leaders to develop sensitive surveillance tools to better detect and manage operational stress while on mission.ScoutenWT, MehalickML, YoderE, McCoyA, BrannockT, RiddleMS. The epidemiology of operation stress during Continuing Promise 2011: a humanitarian response and disaster relief mission aboard a US Navy hospital ship. Prehosp Disaster Med. 2017;32(4):393–402.

General personality dimensions are associated with clinical severity and treatment response in individuals with depression and many anxiety disorders, but little is known about these relationships in individuals with obsessive-compulsive disorder (OCD). Individuals in the current study included 705 adults with OCD who had participated in family and genetic studies of the disorder. Participants self-completed the Neuroticism, Extraversion, Openness Personality Inventory or Neuroticism, Extraversion, Openness Five-Factor Inventory-3. Relationships between personality scores, and subjective impairment and OCD treatment response, were evaluated. The odds of subjective impairment increased with (unit increase in) the neuroticism score (odds ratio, OR = 1.03; 95% CI = 1.01-1.04; p < 0.01) and decreased with extraversion scores (OR = 0.98; 95% CI = 0.96-0.99; p < 0.01). The odds of reporting a good response to serotonin/selective serotonin reuptake inhibitors (OR = 1.02; 95% CI = 1.01-1.04; p < 0.01) or cognitive behavioural therapy (OR = 1.03; 95% CI = 1.01-1.05; p < 0.01) increased with the extraversion score. The magnitude of these relationships did not change appreciably after adjusting for other clinical features related to one or more of the personality dimensions. The findings suggest that neuroticism and extraversion are associated with subjective impairment, and that extraversion is associated with self-reported treatment response, in individuals with OCD. © 2019 John Wiley & Sons, Ltd.

Background: This study addresses the strength of associations between trichotillomania (TTM) and other DSM-IV Axis I conditions in a large sample (n = 2606) enriched for familial obsessive-compulsive disorder (OCD), to inform TTM classification. Methods: We identified participants with TTM in the Johns Hopkins OCD Family Study (153 families) and the OCD Collaborative Genetics Study, a six-site genetic linkage study of OCD (487 families). We used logistic regression (with generalized estimating equations) to assess the strength of associations between TTM and other DSM-IV disorders. Results: TTM had excess comorbidity with a number of conditions from different DSM-IV chapters, including tic disorders, alcohol dependence, mood disorders, anxiety disorders, impulse-control disorders, and bulimia nervosa. However, association strengths (odds ratios) were highest for kleptomania (6.6), pyromania (5.8), OCD (5.6), skin picking disorder (4.4), bulimia nervosa (3.5), and pathological nail biting (3.4). Conclusions: TTM is comorbid with a number of psychiatric conditions besides OCD, and it is strongly associated with other conditions involving impaired impulse control. Though DSM-5 includes TTM as an OCD-related disorder, its comorbidity pattern also emphasizes the impulsive, appetitive aspects of this condition that may be relevant to classification. Keywords: Comorbidity, classification, Impulse-control disorder, Obsessive-compulsive disorder, Trichotillomania

OBJECTIVES: Functional gastrointestinal disorders occur more frequently among deployed veterans, although studies evaluating the relative impact of risk factors, including stress and antecedent infectious gastroenteritis (IGE), are limited. We examined risk factors for new-onset irritable bowel syndrome (IBS) among active duty participants in the military's Millennium Cohort Study. METHODS: Medical encounter data from 2001 to 2009, limited to Cohort members on active duty, were used to identify incident IBS cases (any and highly probable). IGE was identified using medical encounter or self-report. Covariate data were obtained from the Millennium Cohort Study surveys and analyzed using Cox proportional hazards methods. RESULTS: Overall, 41,175 Cohort members met the eligibility criteria for inclusion and 314 new-onset cases of IBS were identified among these. Significant risk factors (adjusted hazard ratio, 95% confidence interval) included antecedent IGE (2.05, 1.53–2.75), female gender (1.96, 1.53–2.52), number of life stressors (1: 1.82, 1.37–2.41; 2: 2.86, 2.01–4.06; 3+: 6.69, 4.59–9.77), and anxiety syndrome (1.74, 1.17–2.58). Limited to highly probable IBS, a stronger association with antecedent IGE was observed, particularly when based on medical encounter records (any IGE: 2.20, 1.10–4.43; medical encounter IGE only: 2.84, 1.33–6.09). Precedent anxiety or depression and IGE interacted with increased IBS risk compared with IGE alone. CONCLUSIONS: These results confirm previous studies on the association between sociodemographic or life stressors and IBS. IGE was significantly associated with IBS risk. Whether deployed or not, US service members often encounter repeated exposure to high levels of stress, which, combined with other environmental factors such as IGE, may result in long-term debilitating functional gastrointestinal disorders.

Background Human challenge models for enterotoxigenic Escherichia coli (ETEC) facilitate vaccine down-selection. The B7A (O148:H28 CS6+LT+ST+) strain is important for vaccine development. We sought to refine the B7A model by identifying a dose and fasting regimen consistently inducing moderate-severe diarrhea. Methods An initial cohort of 28 subjects was randomized (1:1:1:1) to receive B7A following an overnight fast at doses of 108 or 109 colony forming units (cfu) or a 90-minute fast at doses of 109 or 1010 cfu. A second cohort included naïve and rechallenged subjects who had moderate-severe diarrhea and were given the target regimen. Immune responses to important ETEC antigens were assessed. Results Among subjects receiving 108 cfu of B7A, overnight fast, or 109 cfu, 90-minute fast, 42.9% (3/7) had moderate-severe diarrhea. Higher attack rates (71.4%; 5/7) occurred in subjects receiving 109 cfu, overnight fast, or 1010 cfu, 90-minute fast. Upon rechallenge with 109 cfu of B7A, overnight fast, 5/11 (45.5%) had moderate-severe diarrhea; the attack rate among concurrently challenge naïve subjects was 57.9% (11/19). Anti-CS6, O148 LPS and LT responses were modest across all groups. Conclusions An overnight fast enabled a reduction in the B7A inoculum dose; however, the attack rate was inconsistent and protection upon rechallenge was minimal.

Travelers’ diarrhea (TD) is the most prevalent illness encountered by deployed military personnel and has a major impact on military operations, from reduced job performance to lost duty days. Frequently, the etiology of TD is unknown and, with underreporting of cases, it is difficult to accurately assess its impact. An increasing number of ailments include an altered or aberrant gut microbiome. To better understand the relationships between long-term deployments and TD, we studied military personnel during two nine-month deployment cycles in 2015–2016 to Honduras. To collect data on the prevalence of diarrhea and impact on duty, a total of 1173 personnel completed questionnaires at the end of their deployment. 56.7% reported reduced performance and 21.1% reported lost duty days. We conducted a passive surveillance study of all cases of diarrhea reporting to the medical unit with 152 total cases and a similar pattern of etiology. Enteroaggregative E. coli (EAEC, 52/152), enterotoxigenic E. coli (ETEC, 50/152), and enteropathogenic E. coli (EPEC, 35/152) were the most prevalent pathogens detected. An active longitudinal surveillance of 67 subjects also identified diarrheagenic E. coli as the primary etiology (7/16 EPEC, 7/16 EAEC, and 6/16 ETEC). Eleven subjects were recruited into a nested longitudinal substudy to examine gut microbiome changes associated with deployment. A 16S rRNA amplicon survey of fecal samples showed differentially abundant baseline taxa for subjects who contracted TD versus those who did not, as well as detection of taxa positively associated with self-reported gastrointestinal distress. Disrupted microbiota was also qualitatively observable for weeks preceding and following the incidents of TD. These findings illustrate the complex etiology of diarrhea amongst military personnel in deployed settings and its impacts on job performance. Potential factors of resistance or susceptibility can provide a foundation for future clinical trials to evaluate prevention and treatment strategies.

Background . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. Methods . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). Results . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. Conclusions . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Enterotoxigenic

Rotavirus infection is the global leading cause of diarrhea-associated morbidity and mortality among children younger than 5 years.To examine the extent of rotavirus infection among children younger than 5 years by country and the number of deaths averted because of the rotavirus vaccine.This report builds on findings from the Global Burden of Disease Study 2016, a cross-sectional study that measured diarrheal diseases and their etiologic agents. Models were used to estimate burden in data-sparse locations.Diarrhea due to rotavirus infection.Rotavirus-associated mortality and morbidity by country and year and averted deaths attributable to the rotavirus vaccine by country.Rotavirus infection was responsible for an estimated 128 500 deaths (95% uncertainty interval [UI], 104 500-155 600) among children younger than 5 years throughout the world in 2016, with 104 733 deaths occurring in sub-Saharan Africa (95% UI, 83 406-128 842). Rotavirus infection was responsible for more than 258 million episodes of diarrhea among children younger than 5 years in 2016 (95% UI, 193 million to 341 million), an incidence of 0.42 cases per child-year (95% UI, 0.30-0.53). Vaccine use is estimated to have averted more than 28 000 deaths (95% UI, 14 600-46 700) among children younger than 5 years, and expanded use of the rotavirus vaccine, particularly in sub-Saharan Africa, could have prevented approximately 20% of all deaths attributable to diarrhea among children younger than 5 years.Rotavirus-associated mortality has decreased markedly over time in part because of the introduction of the rotavirus vaccine. This study suggests that prioritizing vaccine introduction and interventions to reduce diarrhea-associated morbidity and mortality is necessary in the continued global reduction of rotavirus infection.

The authors examined the efficacy of a family-based intervention to prevent the onset of anxiety disorders in offspring of anxious parents.Participants were 136 families with a parent meeting DSM-IV criteria for an anxiety disorder and one child 6-13 years of age without an anxiety disorder. Families were randomly assigned to the family-based intervention (N=70) or to an information-monitoring control condition (N=66). All families were expected to complete assessments, administered by blind interviewers, at baseline, at the end of the intervention (or 8 weeks after randomization) and at 6- and 12-month follow-ups. Onset of any anxiety disorder and anxiety symptom severity (assessed using the Anxiety Disorders Interview Schedule for Children) at 12 months were the primary and secondary outcome measures, respectively.The incidence of child anxiety disorders was 31% in the control group and 5% in the intervention group (odds ratio=8.54, 95% CI=2.27, 32.06). At the 1-year follow-up, youths in the control group also had higher anxiety symptoms ratings than those in the intervention group. Effect sizes were medium to large (0.81 at 6 months and 0.57 at 12 months for anxiety symptoms), and the number needed to treat was 3.9 at 12 months. Significant moderators included baseline levels of child anxiety; significant mediators were parental distress and modeling of anxiety. Child maladaptive cognitions and parental anxiety did not mediate outcomes.A brief psychosocial prevention program holds promise for reducing the 1-year incidence of anxiety disorders among offspring of anxious parents.

Background & Aims Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. Methods We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998 to 2010 and 3231 matched subjects who had not been exposed to C difficile . Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. Results C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9–12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4–2.6), dyspepsia (RR, 3.3; 95%, 1.4–7.7), and constipation (RR, 2.2; 95% CI, 1.3–3.7). Approximately 14.1% of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care–associated C difficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a C difficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile . Conclusions The incidence of community- and health care–associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population.

Background There is a recognized need for biological markers to facilitate diagnoses of irritable bowel syndrome (IBS) and to distinguish it from other functional and organic disorders. As postinfectious IBS (PI-IBS) is believed to account for as many as one third of all IBS cases, here we sought to identify differences in specific cytokines and serologic responses across patients with idiopathic IBS and PI-IBS and healthy controls. Methods At total of 120 US military personnel were identified from the Defense Medical Surveillance System-based International Classification of Diseases, 9th Revision, Clinical Modification (ICD9-CM) codes recorded during medical encounters and were grouped based on infectious gastroenteritis (IGE) episode (Shigella, Campylobacter, Salmonella, or an unspecified pathogen) followed by IBS, IBS without antecedent IGE, or IGE without subsequent IBS within 2 years of the IGE exposure. Sera from subjects were assayed for cytokine levels and antibodies against a panel of microbiome antigens. Results In total, 10 of 118 markers considered were shown to differ between IBS patients and healthy controls, including cytokines interleukin-6 (IL-6), IL-8, IL-1β, and macrophage inflammatory protein-1β (MIP-1β), as well as antibody responses to microbial antigens. Antimicrobial antibody response profiles also differed between PI-IBS cases compared with IBS cases without an antecedent episode of acute IGE. Comparisons also suggest that immunoglobulin A (IgA) and IgG profiles may point to pathogen-specific origins among PI-IBS cases. Conclusion Taken together, these results provide further evidence as to the molecular distinctness of classes of IBS cases and that serum biomarkers may prove useful in elucidating their pathobiological pathways.

Introduction Knowledge of disease burden attributable to functional gastrointestinal disorders (FGD) in travelers is lacking, despite the high incidence of travelers' diarrhea (TD) associated with increased FGD risk. One tool for assessing the impact of disease on health-related quality of life is the health utility index (HUI), which values health states based on preferential health outcomes. Health utilities can be used as preference weights in the estimation of quality-adjusted life-years (QALYs). Methods Six months following travel to Egypt or Turkey, 120 US military personnel completed a survey on TD during deployment, health-related quality of life (SF-36), and the onset of functional bowel disorders (Rome II). Elements from the SF-36 were used to develop SF-6D values, which were combined with health state valuations to enable calculation of HUI scores for each subject. Mean index scores were compared across functional outcomes, specific symptoms, and demographic profiles. Results The presence of FGD significantly reduced index scores, with irritable bowel syndrome (IBS) and dyspepsia showing the greatest impact (−0.17 and −0.19, respectively) compared with those with no FGD (p < 0.05). Importantly, however, several individuals met multiple FGD outcome definitions. Additionally, a number of symptoms associated with abnormal bowel habits and abdominal pain were associated with reduced index scores regardless of outcome. Conclusion FGD are associated with significant morbidity as assessed by HUIs. Given the strong link between TD and FGD as well as the large number of travelers from the developed to the developing world, additional study is needed to further understand this association and efforts aimed at primary disease prevention are warranted.

Background Infectious diarrhea is a common problem among travelers. Expert guidelines recommend the prompt use of antibiotics for self-treatment of moderate or severe travelers' diarrhea (TD). There is limited data on whether travelers follow these self-treatment guidelines. We evaluated the risk factors associated with TD, the use of TD self-treatment, and the risk of irritable bowel syndrome (IBS) during travel. Methods Department of Defense beneficiaries traveling outside the United States for ≤6.5 months were enrolled in a prospective cohort study. Participants received pre- and post-travel surveys, and could opt into a travel illness diary and follow-up surveys for symptoms of IBS. Standard definitions were used to assess for TD and IBS. Suboptimal self-treatment was defined as the use of antibiotics (with or without antidiarrheal agents) for mild TD, or the use of antidiarrheals alone or no self-treatment in cases of moderate or severe TD. Results Twenty-four percent of participants (270/1,120) met the criteria for TD. The highest incidence was recorded in Africa [8.6 cases/100 person-weeks, 95% confidence interval (CI): 6.7–10.5]. Two hundred and twelve participants with TD provided information regarding severity and self-treatment: 89 (42%) had mild TD and 123 (58%) had moderate or severe TD. Moderate or severe TD was independently associated with suboptimal self-treatment [OR 10.4 (95% CI: 4.92–22.0)]. Time to last unformed stool did not differ between optimal and suboptimal self-treatment. IBS occurred in 4.5% (7/154) of TD cases and in 3.1% (16/516) of cases without TD (p = 0.39). Among TD cases, a lower incidence of IBS was noted in participants who took antibiotics [4.8% (5/105) vs 2.2% (1/46)] in those who did not, but the difference did not reach statistical significance (p = 0.60). Conclusions Our results suggest the underutilization of antibiotics in travelers with moderate or severe TD. Further studies are needed to systematically evaluate pre-travel instruction and traveler adherence to self-treatment guidelines, and the impact of suboptimal self-treatment on outcomes.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P

Enterotoxigenic Escherichia coli (ETEC) infections are highly prevalent in developing countries, where clinical presentations range from asymptomatic colonization to severe cholera-like illness. The molecular basis for these varied presentations, which may involve strain-specific virulence features as well as host factors, has not been elucidated. We demonstrate that, when challenged with ETEC strain H10407, originally isolated from a case of cholera-like illness, blood group A human volunteers developed severe diarrhea more frequently than individuals from other blood groups. Interestingly, a diverse population of ETEC strains, including H10407, secrete the EtpA adhesin molecule. As many bacterial adhesins also agglutinate red blood cells, we combined the use of glycan arrays, biolayer inferometry, and noncanonical amino acid labeling with hemagglutination studies to demonstrate that EtpA is a dominant ETEC blood group A-specific lectin/hemagglutinin. Importantly, we have also shown that EtpA interacts specifically with glycans expressed on intestinal epithelial cells from blood group A individuals and that EtpA-mediated bacterial-host interactions accelerate bacterial adhesion and effective delivery of both the heat-labile and heat-stable toxins of ETEC. Collectively, these data provide additional insight into the complex molecular basis of severe ETEC diarrheal illness that may inform rational design of vaccines to protect those at highest risk.

Background Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. Methods A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. Results Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. Conclusions Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. Clinical trial registration NCT01618591.

Shigellosis is a clinical syndrome caused by invasion of the epithelium lining the terminal ileum, colon, and rectum by Shigella species. Although infections occur globally, and in people of all ages, endemic infections among children aged 1-4 years living in low-income and middle-income settings constitute most of the disease burden. The versatile manifestations of these highly contagious organisms range from acute watery diarrhoea to fulminant dysentery characterised by frequent scant bloody stools with fever, prostration, and abdominal cramps. A broad array of uncommon, but often severe, intestinal and extraintestinal complications can occur. Despite marked reductions in mortality during the past three decades, there are roughly 164 000 annual deaths attributable to shigellosis. Intercontinental dissemination of multiresistant shigella strains, facilitated by travellers and men who have sex with men, has prompted new recommendations for antibiotic therapy. Awareness of disease burden and the emerging threats posed by shigella have accelerated interest in development of shigella vaccines, many of which are being tested in clinical trials.

Crisis hotlines have been central to suicide prevention efforts; however, utilization among youth remains low. A sample of at-risk youth was surveyed about their awareness, utilization, and attitudes toward local and national crisis hotlines. Youth reported low rates of awareness and utilization, yet expressed a strong interest in phone hotlines (41% vs. 59% for new media categories combined). Youth reported stigma, but that help-seeking could be positively influenced by peers and adults in their support system. Implications include making crisis services available across several mediums and the importance of engaging trusted others in youth suicide awareness campaigns and prevention efforts.

Summary Objective This study assessed the efficacy of education and self-treatment with loperamide on diarrhea morbidity and healthcare utilization in a deployed military setting. Method In this prospective, controlled study, volunteers from military personnel deployed to Incirlik Air Base received either travelers' diarrhea education (non-loperamide group) or education plus a supply of loperamide (loperamide group). Volunteers were surveyed to determine frequency and outcomes of diarrheal illness. Results 109 deployed personnel were enrolled with 48 assigned to the loperamide group, and 61 to the non-loperamide group. Overall, 41 (38%) service members had at least one diarrheal episode. Only 10 (9%) service members sought treatment from a healthcare provider and the distribution was similar in both groups. Loperamide use for self-treatment was more common in the loperamide group (85%) vs. (57%), [ p = 0.02]) but use of antibiotics was similar in both groups (loperamide (30%) vs. non-loperamide (20%). Conclusions Provision of loperamide and education did not significantly affect healthcare utilization or antibiotic use to manage diarrheal episodes, when compared to education alone. Further prospective studies will either need a very large patient population to power them or should use other primary end points such a functional assessment in addition to seeking care.

Some individuals with obsessive-compulsive disorder (OCD) have autistic-like traits, including deficits in social and communication behaviors (pragmatics). The objective of this study was to determine if pragmatic impairment aggregates in OCD families and discriminates a clinically and genetically distinct subtype of OCD. We conducted clinical examinations on, and collected DNA samples from, 706 individuals with OCD in 221 multiply affected OCD families. Using the Pragmatic Rating Scale (PRS), we compared the prevalence of pragmatic impairment in OCD-affected relatives of probands with and without pragmatic impairment. We also compared clinical features of OCD-affected individuals in families having at least one, versus no, individual with pragmatic impairment, and assessed for linkage to OCD in the two groups of families. The odds of pragmatic impairment were substantially greater in OCD-affected relatives of probands with pragmatic impairment. Individuals in high-PRS families had greater odds of separation anxiety disorder and social phobia, and a greater number of schizotypal personality traits. In high-PRS families, there was suggestive linkage to OCD on chromosome 12 at marker D12S1064 and on chromosome X at marker DXS7132 whereas, in low-PRS families, there was suggestive linkage to chromosome 3 at marker D3S2398. Pragmatic impairment aggregates in OCD families. Separation anxiety disorder, social phobia, and schizotypal personality traits are part of a clinical spectrum associated with pragmatic impairment in these families. Specific regions of chromosomes 12 and X are linked to OCD in high-PRS families. Thus, pragmatic impairment may distinguish a clinically and genetically homogeneous subtype of OCD.

The objective of this systematic review and meta-analysis was to estimate the risk of developing functional dyspepsia (FD) following acute infectious gastroenteritis (IGE).Eligible studies were identified through PubMed and EMBASE searches. Data and quality indicators were extracted by two authors from nine studies examining the risk of FD following IGE in 5,755 exposed individuals.Estimates of FD risk following IGE based on a random effects model yielded a pooled odds ratio (OR) of 2.18 (95% confidence interval (CI): 1.70-2.81). Subanalyses revealed differences in the odds of FD following self-reported IGE (OR: 2.83, 95% CI: 2.10-3.81) compared with documented IGE medical encounters (OR: 1.81, 95% CI: 1.26-2.58), and a decreasing FD risk with time from IGE (≤12 months: OR: 4.76, 95% CI: 2.47-9.20 and12 months: OR: 1.97, 95% CI: 1.51-2.56).Taken together, these data suggest that the risk of developing FD is significantly increased following IGE.

Introduction: We aimed to identify potential risk factors for intussusception (ISS) among children presenting to two pediatric hospitals in Egypt. Methodology: In this case-control study, enrolled children < 3 years old with ISS (confirmed radiologically and/or surgically) were matched by age and gender to controls admitted with acute non-abdominal surgical illnesses. Stool samples were collected and tested for various enteric bacteria, rotavirus, enteric adenoviruses (EA, 40 and 41) and astroviruses using commercially available ELISA diagnostic kits. Results: From December 2004 to May 2009, 158 cases and 425 matched controls were enrolled. A history of diarrhoea and cough over the preceding four weeks of interview were more common in cases than controls, respectively. Children with mothers who had secondary education and above were 2.2 times more likely to have ISS than those whose mothers had a lower level of education. In spite of the low detection rate of EA infection (regardless of diarrhoea history) and asymptomatic rotavirus infection, they were detected in higher frequencies in cases than controls; however, infection with astrovirus and bacterial pathogens did not appear to be associated with increased risk of ISS. Conclusions: History of diarrhoea and cough over the four weeks preceding the study and maternal education above secondary level were potential risk factors for ISS. EA and asymptomatic rotavirus infection were detected in higher frequencies among cases than controls; however, association with ISS cannot be confirmed. Additional research is needed to confirm these findings and evaluate the pathogenesis which may link such infections with ISS.

Introduction Vaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines. Methods Data were obtained from the Defense Medical Surveillance System and vaccination identified between 1998 and 2011 from vaccination codes. Clinical outcomes were assessed for four weeks post vaccination. Adverse event rates and odds ratios were estimated across the two vaccine types. Results A total of 1.9 million predominately male military personnel received 3.6 million S. Typhi vaccinations with 94.3% of vaccinees receiving the Vi capsule vaccine though variability in the vaccine administered was observed. Receipt of other vaccinations in the 6 months surrounding the S. Typhi vaccine was common. Rates of nausea (195 per 100,000 vaccinations), headache (13 per 100,000 vaccinations) and fever (40 per 100,000 vaccinations) were significantly higher following Vi capsule vaccination compared to receipt of Vivotif (130, 2, 10 per 100,000 vaccinations, respectively). In contrast the rates of rash and non-infectious diarrhea (186 and 426 per 100,000 vaccinations, respectively) were increased in those receiving Vivotif compared to the Vi capsule vaccine. Discussion The US military is a major consumer of S. Typhi vaccines. The parenterally administered vaccine appears to be more amenable, though we were limited in our ability to assess the reasons for its higher usage. While we observed a higher rate of several adverse events in subjects receiving the intramuscular vaccination, the overall rate of these events was low. Future studies assessing more long-term health outcomes are warranted.

Background: Hoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive–compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD. Method: The study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PBI) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PBI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding. Results: In men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p

Several candidate vaccines against Shigella spp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hampered Shigella vaccine development over the past several decades. Bioconjugation technology, exploited here for an Shigella flexneri 2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novel S. flexneri 2a bioconjugate vaccine made of the polysaccharide component of the S. flexneri 2a O-antigen, conjugated to the exotoxin protein A of Pseudomonas aeruginosa (EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significant S. flexneri 2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity against S. flexneri 2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response to S. flexneri 2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.)

Background. There is limited information on compliance rates with anti-vectorial protective measures (AVPMs) during travel to countries with risk of dengue and chikungunya. We evaluated differences in mosquito exposures, and factors associated with AVPM compliance in travellers going to countries where the principal mosquito-borne infectious disease threat is falciparum malaria and those where risk of dengue or chikungunya predominates. Methods. Department of Defence beneficiaries with planned travel to regions where the predominant mosquito-borne infection is falciparum malaria, and those with predominantly dengue or chikungunya risk, were included. Regions were divided into three groups: ‘high-risk falciparum malaria’, ‘low-risk falciparum malaria’ and ‘chikungunya/dengue risk’. Demographics, trip characteristics, arthropod exposure and AVPM compliance were captured using pre- and post-travel surveys. Skin repellent compliance was defined as self-reported use, categorized as ‘often/every day’. A logistic regression model was used to estimate factors associated with AVPM compliance. Results. 183 (9%), 185 (9%) and 149 (7%) travelled to high and low falciparum malaria risk regions, and chikungunya/dengue risk regions, respectively. Overall, 53% (95% CI: 48–57%) and 16% (95% CI: 12–19%) were compliant with repellent use on skin and clothing, respectively. Daytime bites were reported more frequently in chikungunya/dengue risk regions than high malaria risk regions (37% vs. 10%), while night time bites were frequently in high malaria risk regions (53% vs 20%; P < 0.001). Compliance with skin repellents was associated with female gender [RR: 1.54 (95% CI: 1.05–2.28)], observing mosquitoes during travel [RR: 2.77 (95% CI: 1.76–4.36)] and travel during the rainy season [RR: 2.45 (95% CI: 1.66–3.71)]). Conclusions. Poor AVPM compliance was observed in the overall cohort. Compliance with skin repellent use was associated with female gender, observing mosquitoes and travelling during the rainy season, and was not associated with the risk of malaria or chikungunya/dengue at the travel destination.

Travelers' diarrhea (TD) is the most common ailment affecting travelers, including deployed U.S. military. Continuing Promise 2011 was a 5-month humanitarian assistance/disaster response (HA/DR) military and non-governmental organization training mission aboard the hospital ship USNS Comfort, which deployed to Central and South America and the Caribbean between April and September 2011. Enhanced TD surveillance was undertaken during this mission for public health purposes. Passive surveillance (clinic visits), active surveillance (self-reported questionnaires), and stool samples were collected weekly from shipboard personnel. Descriptive statistics and multivariate-logistic regression methods were used to estimate disease burden and risk factor identification. Two polymerase chain reaction methods on frozen stool were used for microbiological identification. TD was the primary complaint for all clinic visits (20%) and the leading cause of lost duties days due to bed rest confinement (62%), though underreported, as the active self-reported incidence was 3.5 times higher than the passive clinic-reported incidence. Vomiting (p = 0.002), feeling lightheaded or weak (p = 0.005), and being a food handler (p = 0.017) were associated with increased odds of lost duty days. Thirty-eight percent of self-reported cases reported some amount of performance impact. Based on the epidemiological curve, country of exercise and liberty appeared to be temporally associated with increased risk. From the weekly self-reported questionnaire risk factor analysis, eating off ship in the prior week was strongly associated (adjusted odds ratio [OR] 2.4, p

Objective Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome. Method TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naive patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome. Results Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI=1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI=0.8-2.2) to 10.5 (95% CI=1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI=1.6-3.3) for nonobese patients, but 1.1 (95% CI=0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS. Conclusions Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information—Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681.

OBJECTIVE. We evaluated outcomes of patients 65 years old and older who underwent CT colonography (CTC) between 2004 and 2009. CONCLUSION. The frequency of referral to colonoscopy based on a polyp size threshold of 6 mm was 14.5%. Colorectal neoplasia was found in 9.3% of patients, with advanced neoplasia in 3.3%. Potentially important extracolonic findings were observed in 2.9% of patients. The low rates of referral to colonoscopy, prevalence of advanced neoplasia, and prevalence of extracolonic findings make CTC a viable option for Medicare-aged patients.

Background. The US Centers for Disease Control and Prevention estimates 20.9 million norovirus infections annually in the United States. Although the acute disease burden is sizeable, emerging data suggest norovirus may be associated with chronic gastrointestinal problems. We identified known outbreaks in US military recruits and used the Defense Medical Encounter Database (DMED) to identify the risk of new onset functional gastrointestinal disorders (FGD) and gastroesophageal reflux disease (GERD). Methods. Subjects reporting for care of acute gastroenteritis (AGE) at a military treatment clinic during 3 known norovirus outbreaks were identified. Each AGE subject was matched with up to 4 subjects with unrelated medical encounters. Medical encounter data were analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident FGD or GERD. Relative risks were calculated using regression models. Results. We identified 1718 subjects from 3 outbreaks. After controlling for important demographic covariates, the incidence of constipation, dyspepsia, and GERD was approximately 1.5-old higher (P< .01) in AGEexposed subjects than matched subjects. We also noted variability in outcome incidence across outbreaks. Conclusions. It appears that the risk of dyspepsia, constipation, and GERD are higher among those who have AGE during a confirmed norovirus outbreak. Although these findings need confirmation, they suggest that dysmotility may result subsequent to these infections. If confirmed, the costs and morbidity associated with the chronic consequences of norovirus should be considered.

The Current Topics in Military Tropical Medicine series provides focused reviews addressing specific questions faced by operational military medical personnel. This issue in the series explores the diagnosis and management of persistent diarrhea in deployed service members.

The aim of this study is to determine whether neurocognitive performance distinguishes individuals with compulsive hoarding (CH) from those with obsessive-compulsive disorder (OCD). Compared to control subjects, OCD patients and CHs scored significantly worse on the Serial Reaction Time Task suggesting disturbed implicit memory in both patient groups. On the Iowa Gambling Task, an overall learning progression difference over time was found between the CHs, OCD group, and control subjects, suggesting differences in decision-making between the groups. The groups did not differ in performance on the Stop Signal Reaction Time Task (motor inhibition). This study found evidence for impaired implicit memory in CHs, but also in OCD patients, albeit less severe. There was evidence that OCD patients learned more slowly on a decision-making task than CHs and control subjects. This latter finding provides some evidence to suggest that CH and OCD have, at least on this one measure, differing cognitive substrates.

Background Shigella flexneri 2a lipopolysaccharide 50 is a nasally delivered subunit vaccine consisting of a macromolecular complex composed of LPS, IpaB, IpaC and IpaD. The current study examined vaccine safety and immunogenicity across a dose range and the clinical performance of a new intranasal delivery device. Methods Volunteers ( N = 36) were randomized to receive vaccine via the Dolphin™ (Valois of America, Congers, New York) intranasal spray device at one of three doses (240, 480, and 690 μg) on days 0, 14, and 28. Another group ( N = 8) received the 240 μg dose via pipette. Vaccine safety was actively monitored and antigen-specific humoral and mucosal immune responses were determined. Results There were no serious adverse events and the majority of adverse events (98%) were mild. Antibody secreting cells (ASC), plasma, and mucosal immune responses to Shigella antigens were detected at all three dose levels with the 690 μg dose inducing the highest magnitude and frequency of responses. Vaccination with comparable doses of Invaplex 50 via the Dolphin™ resulted in higher plasma and ASC immune responses as compared to pipette delivery. Conclusion In this trial the S. flexneri 2a Invaplex 50 vaccine was safe, well-tolerated and induced robust levels of antigen-specific intestinal IgA and ASC responses. The spray device performed well and offered an advantage over pipette intranasal delivery.

Vaccination programs have significantly reduced the incidence of numerous infectious diseases; however, public attitudes toward immunization oftentimes remain contentious. Concerns over vaccine safety and effectiveness, compounded with reduced perceived risk of disease, influence decision making and frequently override public health recommendations. Although vaccinations are compulsory for US military personnel, their concerns mirror the general population, resulting in sub-optimal coverage.Demographics of the 1,757 respondents: 83.3% male, 71.1% Army, 87.5% enlisted, mean age of 29.2 years (standard deviation: 8.3). The majority (89.3%) reported receiving all pre-deployment vaccines; 17.1% stated they would decline if given the opportunity. Factors associated with an increased likelihood of declining vaccines included a perception that the vaccines were not safe (odds ratio [OR]: 3.7; p0.001) and rarely/never believing information from the military command (OR: 2.2; p0.001). Those with a perceived risk for the diseases targeted by the vaccines were less likely to decline (OR: 0.6; p0.001).In US military personnel, negative perceptions of pre-deployment vaccines exist. These attitudes appear to be associated with negative perceptions of vaccine safety and low perceived disease risk. Targeted interventions, focusing on the drivers of negative perceptions toward vaccines, and accounting for the source of the educational material, may influence attitudes and improve vaccination perceptions.A self-administered questionnaire was completed by a convenience sample of US military personnel deployed to Iraq, Afghanistan and surrounding regions. Questions solicited demographic information and assessed agreement with statements in an attempt to identify factors associated with declining pre-deployment vaccines.

Military personnel are frequently deployed to regions of the world with high travelers’ diarrhea (TD) rates. Pathogens associated with TD have been linked to several post-infectious sequelae, including functional gastrointestinal disorders (FGD), such as irritable bowel syndrome (IBS) and functional dyspepsia. Furthermore, stress associated with deployment may potentiate the increased FGD risk. We sought to assess whether self-reported diarrhea, vomiting, and stressors during deployment were associated with increased FGD risk. Using active duty military medical encounter data from the Defense Medical Surveillance System (DMSS), we conducted a matched case–control study to assess the odds of FGD (IBS, functional constipation, functional diarrhea, dyspepsia) following self-reported diarrhea or vomiting during deployment. Only first-time deployers with detailed self-reporting of deployment-related exposures from 2008 and 2009 were included. Univariate and multivariate analyses were performed. A total of 129 cases of FGD were identified, with the following distribution: constipation (n = 67), dyspepsia (n = 15), IBS (n = 22), and overlapping disorders (n = 25). Diarrhea and/or vomiting during deployment were significantly associated with the development of FGD. Other demographic factors were also associated with variable risk. We found no consistent effect of war-related stressors or non-combat-related correlates of stress. Deployment-related TD is common in deployed military personnel and is associated with an increased risk of several FGD. When considering effective countermeasures and mitigation strategies, both the acute effects and chronic sequelae of enteric infections should be considered. Increased emphasis on existing and novel primary prevention strategies are needed, as well as outcome studies among those developing these conditions.

BackgroundExperts have proposed removing obsessive–compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues.MethodCase family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives).ResultsAnxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive–compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously.ConclusionsOn the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5 kb downstream of the gene [Shugart et al. (2009); Am J Med Genet Part B 150B:886–892]. The aims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9 kb upstream to 84 kb downstream of the gene at average spacing of 1.7 kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families.We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8 kb upstream of the gene, was associated with OCD in all families (P = 0.003) and in families with male affecteds (P = 0.002). A three-SNP haplotype (rs4740788–rs10491734–rs10491733) was associated with OCD in the total sample (P = 0.00015) and in families with male affecteds (P = 0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD.

Background: A history of separation anxiety disorder (SAD) is frequently reported by patients with obsessive–compulsive disorder (OCD). The purpose of this study was to determine if there are clinical differences between OCD-affected individuals with, versus without, a history of SAD. Methods: Using data collected during the OCD Collaborative Genetic Study, we studied 470 adult OCD participants; 80 had a history of SAD, whereas 390 did not. These two groups were compared as to onset and severity of OCD, lifetime prevalence of Axis I disorders, and number of personality disorder traits. Results: OCD participants with a history of SAD were significantly younger than the non-SAD group (mean, 34.2 versus 42.2 years; P

To better understand the epidemiology of diarrhea in deployed personnel to the Middle East, a prospective cohort study of travelers' diarrhea (TD) was conducted between May 2004 and January 2005 at the Multinational Force and Observers (MFO) camp in the southern Sinai. A baseline entry questionnaire and stool specimen was provided on study entry, and volunteers were followed every 6 weeks. Of 211 volunteers, 145 (68.7%) completed one or more follow-up visits. In total, 416 follow-up surveys were completed, which described an overall incidence of 25.2 episodes per 100 person months (95% confidence interval = 21.2-30.0). Additionally, stools were collected in 72 of 77 diarrhea-associated clinic visits, with bacterial pathogens most commonly isolated (enterotoxigenic Escherichia coli in 30 [42%] samples and Campylobacter jejuni in 7 [10%] samples) Despite modern preventive methods, diarrhea is still a common problem for deployed US military personnel in Egypt, frequently resulting in diminished ability to work.

Functional gastrointestinal disorders (FGDs) are recognized sequelae of infectious gastroenteritis (IGE). Within the active duty military population, a group with known high IGE rates, the population-based incidence, risk factors, and attributable burden of care referable to FGD after IGE are poorly defined.Using electronic medical encounter data (1999-2007) on active duty US military, a matched, case-control study describing the epidemiology and risk determinants of FGD (irritable bowel syndrome (IBS), functional constipation (FC), functional diarrhea (FD), dyspepsia (D)) was conducted. Incidence rates and duration of FGD-related medical care were estimated, and conditional logistic regression was utilized to evaluate FGD risk after IGE.A total of 31,866 cases of FGD identified were distributed as follows: FC 55% (n=17,538), D 21.2% (n=6,750), FD 2.1% (n=674), IBS 28.5% (n=9,091). Previous IGE episodes were distributed as follows: specific bacterial pathogen (n=65, 1.2%), bacterial, with no pathogen specified (n=2155, 38.9%), protozoal (n=38, 0.7%), viral (n=3431, 61.9%). A significant association between IGE and all FGD (odds ratio (OR) 2.64; P0.001) was seen, with highest risk for FD (OR 6.28, P0.001) and IBS (OR 3.72, P0.001), and moderate risk for FC (2.15, P0.001) and D (OR 2.39, P0.001). Risk generally increased with temporal proximity to, and bacterial etiology of, exposure. Duration of FGD-related care was prolonged with 22.7% having FGD-associated medical encounters 5 years after diagnosis.FGD are common in this population at high risk for IGE. When considering effective countermeasures and mitigation strategies, attention directed toward prevention as well as the acute and chronic sequelae of these infections is needed.

In this edition of The Journal of Travel Medicine , Nair and colleagues report that a significant percentage of patients experience persistent gastrointestinal (GI) symptoms, specifically abdominal pain and change in bowel habits, following an episode of travelers' diarrhea (TD).1 What makes the Nair study unique is the pathogen‐specific survey identifying the first direct evidence suggesting enterotoxigenic Escherichia coli (ETEC) as a trigger of post‐TD functional abdominal symptoms. Equally important is the evaluation of a multitude of GI symptoms post‐TD, rather than the more circumscribed syndrome of postinfectious irritable bowel syndrome (PI‐IBS). The accumulation of such specific data on many and varied GI symptoms resists a common and limiting tendency to focus on a single disease diagnosis, such as that of PI‐IBS. Instead, it allows us to look at a panoply of symptoms which may be directly related to a pathogenic microorganism, or which may be indirectly related, or even, perhaps, not related at all. The study also frames the challenges inherent in the attribution of disease causation for a subjectively defined illness with an often unidentified exposure. One of the major challenges of such studies is accounting for the large number of individuals who have preexisting GI disease prior to their travels. For example, IBS affects up to 15% of individuals in industrialized countries,2 many of which may not have been previously diagnosed. Thus, in any evaluation of subjects with post‐TD GI symptoms, a clear and accurate determination of the status of each subject's GI tract prior to travel and after the episode of TD is imperative. Was the subject … Corresponding Author: Bradley A. Connor, MD, Division of Gastroenterology and Hepatology, Weill Medical College of Cornell University, 50 East 69th Street, New York, NY 10021, USA. E‐mail: bconnor1{at}gmail.com

Background. Transmission of tuberculosis (TB) during travel is a significant potential infectious disease threat to travelers. However, there is uncertainty in the travel medicine community regarding the evidence base for both estimates of risk for latent TB infection (LTBI) in long-term travelers and for information regarding which travelers may benefit from pre- or post-travel TB screening. The purpose of this study was to determine the risk for tuberculin skin test (TST) conversion, used as a surrogate for L TBI, in long-term travelers from low- to high-risk countries. 1W.etbods. We performed a systematic review to acquire all published and unpublished data on TST conversion in long-term civilian and military travelers from 1990 to J nne 2008. Point estimates and confidence intervals (Cis) of the incidence of TST conversion were combined in a random effects model and assessed for heterogeneity. Results. The cumulative risk with CI for L TBI as measured by TST conversion was 2.0% (99% CI: 1.6%-2.4%). There was a marked heterogeneity (x2 heterog·eneity statistic, p < ().()001) which could not be explained by evaluable study characteristics. When stratifying by military and civilian studies, the cumulative risk estimate was 2.0% (99% CI: 1.6-2.4) for military and 2.3% (99% CI: 2.1-2.5) for civilian smdies. Conclusion. The overall cumulative incidence of 2.0% is what could be expected to occur among the local population in many developing-country settings, though TST conversion likely overestimates the risk of TB infection because of the low positive predictive value (PPV) of the TST in low-prevalence populations such as travelers. To maximize the PPV of a screening test for LTBI, a targeted testing strategy for long-term military and civilian travelers is recommended, based on exposures known to increase the risk ofTB. Studies to better define higher risk groups, activities, and locations are needed.