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An increasing number of immunocompromised individuals are pursuing international travel, and a better understanding of their international travel patterns and pretravel health care is needed. We evaluated the clinical features, itineraries, and pretravel h

A system designed to rapidly identify an infectious disease outbreak or bioterrorism attack and provide important demographic and geographic information is lacking in most health departments nationwide. The Department of Defense Global Emerging Infections System sponsored a meeting and workshop in May 2000 in which participants discussed prototype systems and developed recommendations for new surveillance systems. The authors provide a summary of the group's findings, including expectations and recommendations for new surveillance systems. The consensus of the group was that a nationally led effort in developing health indicator surveillance methods is needed to promote effective, innovative systems. [ABSTRACT FROM AUTHOR]

Abstract Background The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. Here we investigated functions of c-Myc during mouse mammary gland development using a conditional knockout approach. Results Generation of c-mycfl/fl mice carrying the mammary gland-specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients. Conclusion We have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival. See related minireview by Evan et al: http://jbiol.com/content/8/8/77

Background: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib., Objective: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile., Design: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579)., Setting: Sixty-seven trial sites in 8 countries., Participants: Adults hospitalized with COVID-19 ( n = 999; 85% U.S. participants)., Intervention: Baricitinib+remdesivir versus placebo+remdesivir., Measurements: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories., Results: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile., Limitation: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants., Conclusion: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19., Primary Funding Source: National Institute of Allergy and Infectious Diseases., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2593.

Healthcare workers (HCWs) at community hospitals, also known as frontline hospitals (FLHs), may encounter patients with possible infectious diseases, including those caused by high-consequence pathogens such as Zaire ebolavirus. We created and piloted a 1-day, in-person, didactic and skills training program to determine the feasibility and acceptability of implementing an educational program to enhance the knowledge and skills needed to respond when a patient with a potential high-consequence pathogen presents to an FLH. The Maryland Department of Health queried all 104 state FLHs to identify their interest in participating in the pilot training program. HCWs from 12 (75%) of the 16 interested FLHs participated in the program before it was interrupted by the COVID-19 pandemic. In addition to pathogen-specific training based on the Identify, Isolate, and Inform framework, we provided skills training in the proper use of personal protective equipment, spill cleanup, and removal of an incapacitated HCW from an isolation area. We conducted a paired pretraining and posttraining knowledge assessment and measured a significant learning gain among 135 participants (2-tailed t test, P <.05). Over 95% of the participants reported that the training was relevant to their daily work and the clinical simulations and reference material were useful and appropriate for their learning level. Findings from this pilot program demonstrated the feasibility and acceptability of a 1-day combined didactic and skills training program focused on high-consequence pathogens. We plan to reengage the original FLHs and add regional FLHs in an updated training effort based on our findings.

Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined., Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots., Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets., Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease., Competing Interests: Potential conflicts of interest. N. J. reports salary support to his institution by Sagent Pharmaceuticals. D. I. has received clinical trial funding paid to her institution from Gilead Sciences. M. K. J. has received grant funding paid to her institution from Gilead Sciences. R. A. M. has received grants and research funding to his institution from Gilead Sciences, Pfizer, Sanofi, and GlaxoSmithKline (GSK). A. R. B. has received grant funding to her institution from Pfizer, Merck, and Cynavac, and has consulted for Janssen and GSK. A. L. has received research grant support to her institution from Gilead. R. G. has received research funding from Gilead Sciences and GSK. W. R. S. has received clinical trial funding paid to his institution from Gilead Sciences. C. A. B. has received contracts and grants to her institution from Gilead Sciences. All other authors report no potential conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Introduction: Over the past decade, there have been outbreaks associated with high consequence infectious diseases such as Ebola virus disease, Lassa fever, and Monkeypox. The proper handling of clinical waste from patients infected with such pathogens is critical to ensure healthcare personnel and community safety., Methods: Mock clinical waste bags were created to simulate four distinct waste streams: personal protective equipment (PPE), dry linens, wet linens, and solidified liquids. Pressure and temperature data loggers were buried in the middle of simulated waste loads to record time at a sterilization temperature of 132°C (270°F) to reduce sterilization time. We also validated super rapid biological indicators (BIs) by embedding standard BIs (48 h), rapid BIs (3 h), and super rapid BIs (24 min) within each load. Cycles were validated over a 2-day period, using a total of 36 simulated waste bags (6 bags each for PPE, dry linen, and wet linen, and 18 bags for solidified liquids)., Results: All waste bags achieved the target sterilization temperature, all BIs passed and cycle times were substantially decreased. For PPE waste processing, an estimated 15 h was saved for a 24-h period., Discussion: Default factory settings are inadequate to disinfect Category A clinical waste. Reliance on autoclave temperature readings may overestimate time at goal sterilization temperature for actual waste loads., Conclusions: The data provided by within bag data loggers and BIs allow for the optimization of autoclave parameters to increase throughput and enhance staff safety., Competing Interests: The authors have no conflicts of interest to report., (Copyright 2022, ABSA International 2022.)

This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

In response to the Ebola outbreak of 2014-2016, the US Office of the Assistant Secretary for Preparedness and Response (ASPR) established 10 regional treatment centers, called biocontainment units (BCUs), to prepare and provide care for patients infected with high-consequence pathogens. Many of these BCUs were among the first units to activate for coronavirus disease 2019 (COVID-19) patient care. The activities of the Johns Hopkins BCU helped prepare the Johns Hopkins Health System for COVID-19 in the 3 domains of containment care: (1) preparedness planning, education and training, (2) patient care and unit operations, and (3) research and innovation. Here, we describe the role of the JH BCU in the Hopkins COVID-19 response to illustrate the value of BCUs in the current pandemic and their potential role in preparing healthcare facilities and health systems for future infectious disease threats.

Introduction: International travellers contribute to the rapid spread of Zika virus (ZIKV) and its sentinel identification globally. We describe ZIKV infections among international travellers seen at GeoSentinel sites with a focus on ZIKV acquired in the Americas and the Caribbean, describe countries of exposure and traveller characteristics, and assess ZIKV diagnostic testing by site., Methods: Records with an international travel-related diagnosis of confirmed or probable ZIKV from January 2012 through December 2019 reported to GeoSentinel with a recorded illness onset date were included to show reported cases over time. Records from March 2016 through December 2019 with an exposure region of the Americas or the Caribbean were included in the descriptive analysis. A survey was conducted to assess the availability, accessibility and utilization of ZIKV diagnostic tests at GeoSentinel sites., Results: GeoSentinel sites reported 525 ZIKV cases from 2012 through 2019. Between 2012 and 2014, eight cases were reported, and all were acquired in Asia or Oceania. After 2014, most cases were acquired in the Americas or the Caribbean, a large decline in ZIKV cases occurred in 2018-19.Between March 2016 and December 2019, 423 patients acquired ZIKV in the Americas or the Caribbean, peak reporting to these regions occurred in 2016 [330 cases (78%)]. The median age was 36 years (range: 3-92); 63% were female. The most frequent region of exposure was the Caribbean (60%). Thirteen travellers were pregnant during or after travel; one had a sexually acquired ZIKV infection. There was one case of fetal anomaly and two travellers with Guillain-Barré syndrome. GeoSentinel sites reported various challenges to diagnose ZIKV effectively., Conclusion: ZIKV should remain a consideration for travellers returning from areas with risk of ZIKV transmission. Travellers should discuss their travel plans with their healthcare providers to ensure ZIKV prevention measures are taken., (Published by Oxford University Press 2020.)

The biocontainment unit at Johns Hopkins Hospital is a specially designed, inactive high-level isolation unit designated to care for patients infected with high-consequence pathogens. The unit team designed a facility-specific readiness scale and checklist that focus on infrastructure, consumable supplies, and staffing to assess activation readiness of the biocontainment unit. Over a period of 50 days and 14 days, these tools were used as part of a routine risk assessment to first identify barriers and then tier the impact of these barriers into activation categories of "Ready," "Ready with Considerations," and "Not Ready." The assessment identified the greatest risks to activation readiness were staffing and waste management capabilities. Assessing threats to activation readiness and the risk of not being ready should be a priority for maintaining facility, regional, and national capacity to safely isolate and care for patients infected with high-consequence pathogens while maintaining healthcare worker safety.

Background: Cutaneous leishmaniasis (CL) may be emerging among international travellers and migrants. Limited data exist on mucocutaneous leishmaniasis (MCL) in travellers. We describe the epidemiology of travel-associated CL and MCL among international travellers and immigrants over a 20-year period through descriptive analysis of GeoSentinel data., Methods: Demographic and travel-related data on returned international travellers diagnosed with CL or MCL at a GeoSentinel Surveillance Network site between 1 September 1997 and 31 August 2017 were analysed., Results: A total of 955 returned travellers or migrants were diagnosed with travel-acquired CL (n = 916) or MCL during the study period, of whom 10% (n = 97) were migrants. For the 858 non-migrant travellers, common source countries were Bolivia (n = 156, 18.2%) and Costa Rica (n = 97, 11.3%), while for migrants, they were Syria (n = 34, 35%) and Afghanistan (n = 22, 22.7%). A total of 99 travellers (10%) acquired their disease on trips of ≤ 2 weeks. Of 274 cases for which species identification was available, Leishmania Viannia braziliensis was the most well-represented strain (n = 117, 42.7%), followed by L. major (n = 40, 14.6%) and L. V. panamensis (n = 38, 13.9%). Forty cases of MCL occurred, most commonly in tourists (n = 29, 72.5%) and from Bolivia (n = 18, 45%). A total of 10% of MCL cases were acquired in the Old World., Conclusions: Among GeoSentinel reporting sites, CL is predominantly a disease of tourists travelling mostly to countries in Central and South America such as Bolivia where risk of acquiring L. V. braziliensis and subsequent MCL is high. The finding that some travellers acquired leishmaniasis on trips of short duration challenges the common notion that CL is a disease of prolonged travel. Migrants from areas of conflict and political instability, such as Afghanistan and Syria, were well represented, suggesting that as mass migration of refugees continues, CL will be increasingly encountered in intake countries., (© International Society of Travel Medicine 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Infectious diseases (ID) physicians play a crucial role in public health in a variety of settings. Unfortunately, much of this work is undercompensated despite the proven efficacy of public health interventions such as hospital acquired infection prevention, antimicrobial stewardship, disease surveillance, and outbreak response. The lack of compensation makes it difficult to attract the best and the brightest to the field of ID, threatening the future of the ID workforce. Here, we examine compensation data for ID physicians compared to their value in population and public health settings and suggest policy recommendations to address the pay disparities that exist between cognitive and procedural specialties that prevent more medical students and residents from entering the field. All ID physicians should take an active role in promoting the value of the subspecialty to policymakers and influencers as well as trainees., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand ( N = 52), Costa Rica ( N = 13), Indonesia, and Laos ( N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases.

Background: The number of US students studying abroad more than tripled during the past 20 years. As study abroad programmes' destinations diversify, students increasingly travel to resource-limited countries, placing them at risk for infectious diseases. Data describing infections acquired by US students while travelling internationally are limited. We describe illnesses among students who returned from international travel and suggest how to prevent illness among these travellers., Methods: GeoSentinel is a global surveillance network of travel and tropical medicine providers that monitors travel-related morbidity. This study included the records of US resident student international travellers, 17-24 years old, who returned to the USA, had a confirmed travel-related illness at one of 15 US GeoSentinel sites during 2007-17 and had a documented exposure region. Records were analysed to describe demographic and travel characteristics and diagnoses., Results: The study included 432 students. The median age was 21 years; 69% were female. More than 70% had a pre-travel consultation with a healthcare provider. The most common exposure region was sub-Saharan Africa (112; 26%). Students were most commonly exposed in India (44; 11%), Ecuador (28; 7%), Ghana (25; 6%) and China (24; 6%). The median duration of travel abroad was 40 days (range: 1-469) and presented to a GeoSentinel site a median of 8 days (range: 0-181) after travel; 98% were outpatients. Of 581 confirmed diagnoses, the most common diagnosis category was gastrointestinal (45%). Acute diarrhoea was the most common gastrointestinal diagnosis (113 of 261; 43%). Thirty-one (7%) students had vector-borne diseases [14 (41%) malaria and 11 (32%) dengue]. Three had vaccine-preventable diseases (two typhoid; one hepatitis A); two had acute human immunodeficiency virus infection., Conclusions: Students experienced travel-related infections, despite the majority having a pre-travel consultation. US students should receive pre-travel advice, vaccinations and chemoprophylaxis to prevent gastrointestinal, vector-borne, sexually transmitted and vaccine-preventable infections.

Infection caused by the four serotypes of dengue virus (DENV-1-4) is a leading cause of mosquito-borne disease. Clinically-severe dengue disease is more common when secondary dengue infection occurs following prior infection with a heterologous dengue serotype. Other flaviviruses such as yellow fever virus, Japanese encephalitis virus, and Zika virus, can also elicit antibodies which are cross-reactive to DENV. As candidate dengue vaccines become available in endemic settings and for individuals who have received other flavivirus vaccines, it is important to examine vaccine safety and immunogenicity in these flavivirus-experienced populations. We performed a randomized, controlled trial of the National Institutes of Health live attenuated tetravalent dengue vaccine candidate (TV003) in fifty-eight individuals with prior exposure to flavivirus infection or vaccine. As in prior studies of this vaccine in flavivirus-naive volunteers, flavivirus-experienced subjects received two doses of vaccine six months apart and were followed closely for clinical events, laboratory changes, viremia, and neutralizing antibody titers. TV003 was well tolerated with few adverse events other than rash, which was predominately mild. Following one dose, 87% of vaccinees had an antibody response to all four serotypes (tetravalent response), suggesting a robust immune response. In addition, 76% of vaccinees were viremic; mean peak titers ranged from 0.68–1.1 log10 PFU/mL and did not differ by serotype. The second dose of TV003 was not associated with viremia, rash, or a sustained boost in antibody titers indicating that a single dose of the vaccine is likely sufficient to prevent viral replication and thus protect against disease. In comparison to the viremia and neutralizing antibody response elicited by TV003 in flavivirus-naïve subjects from prior studies, we found that subjects who were flavivirus-exposed prior to vaccination exhibited slightly higher DENV-3 viremia, higher neutralizing antibody titers to DENV-2, -3, and -4, and a higher tetravalent response frequency after TV003 administration. In summary, we demonstrate that the NIH tetravalent dengue vaccine TV003 is well-tolerated in flavivirus-experienced individuals and elicits robust post-vaccination neutralizing antibody titers., Trial Registration: ClinicalTrials.gov NCT01506570.

Background: There is increasing recognition of the contribution of community-acquired cases to the global burden of Clostridium difficile infection (CDI). The epidemiology of CDI among international travellers is poorly understood, and factors associated with international travel, such as antibiotic use and changes in gut microbiota, could potentially put travellers at higher risk., Methods: We summarized demographic, travel-associated and geographic characteristics of travellers with CDI in the GeoSentinel database from 1997 to 2015. We also surveyed GeoSentinel sites to compare various testing indications, approaches, and diagnostic modalities., Results: We identified 260 GeoSentinel records, including 187 that satisfied criteria for analysis (confirmed cases in non-immigrant travellers aged >2 years, seen <12 weeks post-travel). CDI was reported in all age groups and in travellers to all world regions; the largest proportions of cases having destinations in Asia (31%), Central/South America or the Caribbean (30%) and Africa (24%). Our site survey revealed substantial heterogeneity of testing approaches between sites; the most commonly used test was the C. difficile toxin gene PCR., Conclusions: CDI is encountered in returning international travellers, although there is considerable variability in testing practices. These data underscore the importance of awareness of C. difficile as a potential cause of travel-associated diarrhoea., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: Zika virus has spread rapidly in the Americas and has been imported into many nonendemic countries by travelers., Objective: To describe clinical manifestations and epidemiology of Zika virus disease in travelers exposed in the Americas., Design: Descriptive, using GeoSentinel records., Setting: 63 travel and tropical medicine clinics in 30 countries., Patients: Ill returned travelers with a confirmed, probable, or clinically suspected diagnosis of Zika virus disease seen between January 2013 and 29 February 2016., Measurements: Frequencies of demographic, trip, and clinical characteristics and complications., Results: Starting in May 2015, 93 cases of Zika virus disease were reported. Common symptoms included exanthema (88%), fever (76%), and arthralgia (72%). Fifty-nine percent of patients were exposed in South America; 71% were diagnosed in Europe. Case status was established most commonly by polymerase chain reaction (PCR) testing of blood and less often by PCR testing of other body fluids or serology and plaque-reduction neutralization testing. Two patients developed Guillain-Barré syndrome, and 3 of 4 pregnancies had adverse outcomes (microcephaly, major fetal neurologic abnormalities, and intrauterine fetal death)., Limitation: Surveillance data collected by specialized clinics may not be representative of all ill returned travelers, and denominator data are unavailable., Conclusion: These surveillance data help characterize the clinical manifestations and adverse outcomes of Zika virus disease among travelers infected in the Americas and show a need for global standardization of diagnostic testing. The serious fetal complications observed in this study highlight the importance of travel advisories and prevention measures for pregnant women and their partners. Travelers are sentinels for global Zika virus circulation and may facilitate further transmission., Primary Funding Source: Centers for Disease Control and Prevention, International Society of Travel Medicine, and Public Health Agency of Canada.

Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population., Competing Interests: The authors have declared that no competing interests exist.

A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials., (Copyright © 2016, American Association for the Advancement of Science.)

An increasing number of immunocompromised individuals are pursuing international travel, and a better understanding of their international travel patterns and pretravel health care is needed. We evaluated the clinical features, itineraries, and pretravel health care of 486 immunocompromised international travelers seen at Global TravEpiNet sites from January 2009 to June 2012. We used bivariate analyses and logistic regressions using random intercept models to compare demographic and travel characteristics, vaccines administered, and medications prescribed for immunocompromised travelers versus 30,702 immunocompetent travelers. Immunocompromised travelers pursued itineraries that were largely similar to those of immunocompetent travelers, with nearly one-third of such travelers visiting countries with low human development indices. Biological agents, including tumor necrosis factor blockers, were commonly used immunosuppressive medications among immunocompromised travelers. A strong collaboration between travel-medicine specialists, primary care doctors, and specialist physicians is needed to prepare immunocompromised people for international travel. Incorporating routine questioning and planning regarding travel into the primary care visits of immunocompromised people may be useful., (© The American Society of Tropical Medicine and Hygiene.)

Background: The largest-ever outbreak of Ebola virus disease (EVD), ongoing in West Africa since late 2013, has led to export of cases to Europe and North America. Clinicians encountering ill travelers arriving from countries with widespread Ebola virus transmission must be aware of alternate diagnoses associated with fever and other nonspecific symptoms., Objective: To define the spectrum of illness observed in persons returning from areas of West Africa where EVD transmission has been widespread., Design: Descriptive, using GeoSentinel records., Setting: 57 travel or tropical medicine clinics in 25 countries., Patients: 805 ill returned travelers and new immigrants from Sierra Leone, Liberia, or Guinea seen between September 2009 and August 2014., Measurements: Frequencies of demographic and travel-related characteristics and illnesses reported., Results: The most common specific diagnosis among 770 nonimmigrant travelers was malaria (n = 310 [40.3%]), with Plasmodium falciparum or severe malaria in 267 (86%) and non-P. falciparum malaria in 43 (14%). Acute diarrhea was the second most common diagnosis among nonimmigrant travelers (n = 95 [12.3%]). Such common diagnoses as upper respiratory tract infection, urinary tract infection, and influenza-like illness occurred in only 26, 9, and 7 returning travelers, respectively. Few instances of typhoid fever (n = 8), acute HIV infection (n = 5), and dengue (n = 2) were encountered., Limitation: Surveillance data collected by specialist clinics may not be representative of all ill returned travelers., Conclusion: Although EVD may currently drive clinical evaluation of ill travelers arriving from Sierra Leone, Liberia, and Guinea, clinicians must be aware of other more common, potentially fatal diseases. Malaria remains a common diagnosis among travelers seen at GeoSentinel sites. Prompt exclusion of malaria and other life-threatening conditions is critical to limiting morbidity and mortality., Primary Funding Source: Centers for Disease Control and Prevention.

Background: People who travel to areas with high rabies endemicity and have animal contact are at increased risk for rabies exposure. We examined characteristics of international travelers queried regarding rabies vaccination during pretravel consultations at Global TravEpiNet (GTEN) practices during 2009-2010., Material and Methods: We performed bivariate and multivariable analyses of data collected from 18 GTEN clinics. Travel destinations were classified by strength level of rabies vaccination recommendation., Results: Of 13,235 travelers, 226 (2%) reported previous rabies vaccination, and 406 (3%) received rabies vaccine at the consultation. Common travel purposes for these 406 travelers were leisure (26%), research/education (17%), and nonmedical service work (14%). Excluding the 226 who were previously vaccinated, 8070 (62%) of 13,009 travelers intended to visit one or more countries with a strong recommendation for rabies vaccination; 1675 (21%) of these 8070 intended to travel for 1 month or more. Among these 1675 travelers, 145 (9%) were vaccinated, 498 (30%) declined vaccination, 832 (50%) had itineraries that clinicians determined did not indicate vaccination, and 200 (12%) remained unvaccinated for other reasons. In both bivariate and multivariate analyses, travelers with trip durations >6 months versus 1-3 months (adjusted odds ratio [OR]=4.9 [95% confidence interval [CI] 2.1, 11.4]) and those traveling for "research/education" or to "provide medical care" (adjusted OR=5.1 [95% CI 1.9, 13.7] and 9.5 [95% CI 2.2, 40.8], respectively), compared with leisure travelers, were more likely to receive rabies vaccination., Conclusions: Few travelers at GTEN clinics received rabies vaccine, although many planned trips 1 month long or more to a strong-recommendation country. Clinicians often determined that vaccine was not indicated, and travelers often declined vaccine when it was offered. The decision to vaccinate should take into account the strength of the vaccine recommendation at the destination country, duration of stay, availability of postexposure prophylaxis, potential for exposure to animals, and likelihood of recurrent travel to high-risk destinations.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates., (Copyright © 2013 The British Pharmacological Society.)

Background: Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection., Methods: In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180., Results: A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%-90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia., Conclusions: TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection.

Dengue, a neglected tropical disease that is reemerging around the world, became a nationally notifiable disease in the United States in 2009. Travel to tropical and subtropical areas in the developing world poses the greatest risk of infection for US residents, and an increase in travel to these areas makes this infection more likely to be seen by primary care physicians in their practices.

Conditions that facilitate sustained dengue transmission exist in the United States, and outbreaks have occurred during the past decade in Texas, Hawaii, and Florida. More outbreaks can also be expected in years to come. To combat dengue, medical and public health practitioners in areas with mosquito vectors that are competent to transmit the virus must be aware of the threat of reemergent dengue, and the need for early reporting and control to reduce the impact of dengue outbreaks. Comprehensive dengue control includes human and vector surveillance, vector management programs, and community engagement efforts. Public health, medical, and vector-control communities must collaborate to prevent and control disease spread. Policy makers should understand the role of mosquito abatement and community engagement in the prevention and control of the disease.

Background:  International travel poses a risk of destination-specific illness and may contribute to the global spread of infectious diseases. Despite this, little is known about the health characteristics and pretravel healthcare of US international travelers, particularly those at higher risk of travel-associated illness., Methods:  We formed a national consortium (Global TravEpiNet) of 18 US clinics registered to administer yellow fever vaccination. We collected data regarding demographic and health characteristics, destinations, purpose of travel, and pretravel healthcare from 13235 international travelers who sought pretravel consultation at these sites from January 2009 through January 2011., Results:  The destinations and itineraries of Global TravEpiNet travelers differed from those of the overall population of US international travelers. The majority of Global TravEpiNet travelers were visiting low- or lower-middle-income countries, and Africa was the most frequently visited region. Seventy-five percent of travelers were visiting malaria-endemic countries, and 38% were visiting countries endemic for yellow fever. Fifty-nine percent of travelers reported ≥1 medical condition. Atovaquone/proguanil was the most commonly prescribed antimalarial drug, and most travelers received an antibiotic for self-treatment of travelers' diarrhea. Hepatitis A and typhoid were the most frequently administered vaccines., Conclusions:  Data from Global TravEpiNet provide insight into the characteristics and pretravel healthcare of US international travelers who are at increased risk of travel-associated illness due to itinerary, purpose of travel, or existing medical conditions. Improved understanding of this epidemiologically significant population may help target risk-reduction strategies and interventions to limit the spread of infections related to global travel.

Many viral vaccines used in aquaculture are unable to stimulate an appropriate level of immunity to withstand infection. By targeting specific components of the immune system it may be possible to trigger stronger, more effective responses to antigens. Flagellin has the ability to stimulate both the soluble and membrane-bound forms of toll-like receptor 5 (TLR5) in salmon leading to a proinflammatory response and activation of both the innate and adaptive immune system. In this study flagellin (FlaD from Vibrio anguillarum) was recombinantly produced in two forms, full-length (FDL) and a truncated form (FDS) with portions of the N- and C-termini removed to prevent polymerization. FDS was used to produce an antibody that was able to bind both forms of flagellin in immunoblot analysis. In cell culture using COS-7 cells, FDL was shown to stimulate the NF-κB pathway more effectively than FDS. Both forms of flagellin were used as an adjuvant with the antigen LPH (Hemocyanin from Limulus polyphemus hemolymph) in an immunization dose-response study. FDS and FDL stimulated the innate immune system of salmon inducing proinflammatory effects on days 2, 4 and 7 and the gene expression of important cytokines such as TNFα, IL-6, IL-8, and IL-1β were significantly up-regulated (p<0.05) in the spleen. TLR5S was more highly up-regulated than TLR5M indicating that the soluble form of TLR5 may play an important role in the innate immune response in salmon. ELISA analysis showed that the use of flagellin as an adjuvant with LPH was not able to significantly induce flagellin or LPH antibodies. This study shows that flagellin has the potential to be a highly effective adjuvant for salmon immunization, but further research is needed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Over the past 3 decades, dengue has spread rapidly and has emerged as one of the world's most common mosquitoborne viral diseases. Although often found in tropical and semitropical areas, dengue is capable of being transmitted in temperate climates as well. Dengue is currently endemic to Mexico, most other Latin American countries, and parts of the Caribbean, and it has the potential to become reestablished as an endemic disease in the United States. In fact, sustained transmission of dengue has occurred in Florida within the past year. Conditions exist in the U.S. that could facilitate sustained dengue transmission, including environmental factors, competent mosquito vectors, limited vector and dengue surveillance, increased domestic outdoor daytime activities in warmer months, and low public awareness of the disease. If dengue were to be reestablished in the U.S., it could have significant medical, public health, and economic consequences for the country. The impact of dengue as a public health threat could be lessened through enhanced awareness and reporting of cases, increased support for vector surveillance and control programs, and a greater focus on vaccine development.

Background: Despite a decreasing incidence of listeriosis in the United States, molecular subtyping has increased the number of recognized outbreaks. In September 2000, the New York City Department of Health identified a cluster of infections caused by Listeria monocytogenes isolates with identical molecular subtypes by pulsed-field gel electrophoresis (PFGE) and ribotyping., Methods: To determine the magnitude of the outbreak and identify risk factors for infection, we notified state health departments and conducted a case-control study. A case was defined as a patient or mother-infant pair infected with Listeria monocytogenes whose isolate yielded the outbreak PFGE pattern. Controls were patients infected with Listeria monocytogenes whose isolate yielded a different PFGE pattern. Patients were asked about food and drink consumed during the 30 days before the onset of illness., Results: Between May and December 2000, there were 30 clinical isolates of Listeria monocytogenes with identical PFGE patterns identified in 11 US states. Cases of infection caused by these isolates were associated with 4 deaths and 3 miscarriages. A case-control study implicated sliced processed turkey from a delicatessen (Mantel-Haenszel odds ratio, 8.0; 95% confidence interval, 1.2-43.3). A traceback investigation identified a single processing plant as the likely source of the outbreak, and the company voluntarily recalled 16 million pounds of processed meat. The same plant had been identified in a Listeria contamination event that had occurred more than a decade previously., Conclusions: Prevention of persistent L. monocytogenes contamination in food processing plants presents a critical challenge to food safety professionals.

International travelers engaging in casual sex are at risk for acquiring sexually transmitted diseases (STDs), including HIV. The frequency of international travel emphasizes the need for a travel sexual activity history to be included in the clinical assessment of any returned traveler. When formulating a differential diagnosis, the STD prevalence rates at the travel destination and the risk profile of the traveler and the sexual partner need to be considered. Casual sex with host country nationals residing in tropical and subtropical areas of the developing world increases the traveler's risk for acquiring STDs rarely seen in industrialized countries, particularly bacterial genital ulcer diseases. Pretravel counseling needs to include education on STD prevention. A post-travel STD diagnostic evaluation is indicated when casual sexual activity has occurred during travel, regardless of whether symptoms are present.

A system designed to rapidly identify an infectious disease outbreak or bioterrorism attack and provide important demographic and geographic information is lacking in most health departments nationwide. The Department of Defense Global Emerging Infections System sponsored a meeting and workshop in May 2000 in which participants discussed prototype systems and developed recommendations for new surveillance systems. The authors provide a summary of the group's findings, including expectations and recommendations for new surveillance systems. The consensus of the group was that a nationally led effort in developing health indicator surveillance methods is needed to promote effective, innovative systems.

Simian immunodeficiency virus (SIV) infection of macaques is a useful and relevant model for evaluating candidate human immunodeficiency virus (HIV) vaccines. One important feature of this model is that SIV vaccines can be evaluated for their ability to prevent infection as well as to prevent or delay the onset of AIDS. In the present study, a group of macaques was vaccinated with whole inactivated SIV and challenged with peripheral blood mononuclear cells from an SIV-infected macaque. This challenge represented a rigorous and realistic test of the immunization protocol. All macaques became infected after challenge; however, immunized animals survived significantly longer (P < .03) than naive controls. These data suggest that similar vaccines administered to humans at risk for HIV-1 infection might delay or prevent AIDS even if the vaccine failed to prevent infection.

Sulfur mustard (SM) (di-2-chlorethyl sulfide), used for chemical warfare in World War I, is a highly reactive radiomimetic alkylating agent. When applied to the skin of rabbits and guinea pigs, it produced vascular leakage, leukocyte infiltration, and slow death of basal epidermal cells. Thirty to sixty minutes after exposure to SM, injury to the superficial microvasculature (beneath the SM application site) was detected by measuring vascular leakage with Evans blue dye and also with horseradish peroxidase. At this same time, injury to the superficial fibroblasts was observed ultrastructurally; and an unexpectedly high percentage of basophils was found among the early infiltrating granulocytes. At 2 to 4 hr, the vascular leakage ceased, and had resumed by 8 hr in a more diffuse form. At this time, the basal epidermal cells showed pyknotic nuclei, an increase in their lysosomal enzymes (observed histochemically), and autophagic vacuoles (observed ultrastructurally). Leukocyte infiltration was marked, consisting mostly of heterophils (PMN) with a reduced percentage of basophils. During the next 24 to 72 hr, the entire inflammatory reaction reached its peak; and a superficial, crust-covered ulcer developed. Then, over the next 10 days, the lesion gradually subsided with concomitant repair and healing. Glucocorticosteroids decreased the early edematous phase, but did not affect the rate of healing. These findings suggest that the skin response to sulfur mustard has an immediate and a delayed phase. The immediate phase, i.e., within the first hour, was characterized by injury to the superficial fibroblasts and to the endothelium of superficial capillaries and venules, possibly because of direct damage to their cell membranes. At this time, a restricted vascular leakage and a selective granulocyte infiltration containing many basophils occurred. The delayed phase, which became evident after 8 hr, was characterized by the death of basal epidermal cells, probably because of DNA damage. This phase was accompanied by generalized vascular leakage, by massive heterophil immigration, and eventually by ulceration.

Between June 1 and July 15, 1984, twenty persons with glandular tularemia were identified on the Lower Brule and Crow Creek Indian reservations in South Dakota. The median age of the patients was 6 years (range, 2 to 20 years). The clinical illness was mild, consisting of fever, headache, and lymphadenopathy. All lymphadenopathy was in the head and neck area. Dermacentor variabilis ticks were identified as the vector. Although the mild clinical illness suggested Francisella tularensis, type B, was the agent, both type A and type B strains of F tularensis were isolated from ticks collected from dogs in the area. Tularemia is generally thought to be a severe systemic illness in North America. This outbreak illustrates that it can be a mild disease and that both type A and type B strains can be tick-borne and coexist in the same ecosystem.

Improved techniques were developed for processing inflammatory skin lesions in glycol methacrylate (JB-4, Polysciences, Inc.) and for quantitating their leukocyte infiltrates by light microscopy: (1) fixation of entire pelts from rabbits, guinea pigs, rats and mice bearing multiple lesions eliminated artifacts due to biopsy and produced uniformly oriented skin sections; (2) adding dimethylsulfoxide and hydrogen peroxide to the Karnovsky-type fixative increased the rate and effectiveness of fixation; (3) the presence of glycerol in the infiltrating methacrylate and the polymerized plastic block improved the sectionability of skin and other tissues; (4) coating slides with JB-4 Solution A prevented detachment of specimens; (5) Giemsa staining at a carefully selected pH provided optimal differentiation of leukocytes from the several species examined, including man. These techniques, which allowed an accurate histologic assessment of inflammatory skin lesions, were especially valuable for quantitating basophils.