Epidemiological and Clinical Characteristics of International Travelers with Enteric Fever and Antibiotic Resistance Profiles of Their Isolates: a GeoSentinel Analysis.

Enteric fever, caused by Salmonella enterica serovar Typhi (S Typhi) and S. enterica serovar Paratyphi (S Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site's national guidelines. A total of 889 travelers (S Typhi infections, n = 474; S Paratyphi infections, n = 414; coinfection, n = 1) were included; 114 (13%) were children of <18 years old. Most individuals (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S Typhi and 75 S Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children.

Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways.

To better understand the innate immune response to Vibrio cholerae infection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor gene TLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling in vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in DUOX2 and TLR8 expression were also modeled in vitro when Caco-2 or THP-1 cells, respectively, were stimulated with live V. cholerae but not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to V. cholerae extend our understanding of the mucosal immune signaling pathways and effectors activated in vivo following cholera.

Improving Clinician Awareness of and Screening for Chagas Disease with an Educational Intervention.

Chagas disease is an underrecognized, chronic, and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. We aimed to improve awareness and screening for Chagas disease among patients from endemic areas using a large safety-net academic hospital system in the United States. We developed an educational intervention consisting of a case-based didactic session presented to physicians, trainees, and other healthcare providers at conferences across different departments. Performance on a knowledge assessment administered before and after the presentation was analyzed with paired Student's t-test for within-subject difference testing. Institutional testing rates for T. cruzi were evaluated for an equal time period (29 months) before and after the start of the intervention. Testing rates were compared by a Welch's unequal variances t-test and by interrupted time series based on multivariate linear regression. Eleven educational sessions were held over the intervention period, and 103 participants completed the pre- and post-presentation surveys. The mean survey scores were 59.2% before the presentation and 96.6% after presentation (P <0.001). Trypanosoma cruzi testing during the postintervention period was significantly higher than testing during the pre-intervention period (171 patients pre-intervention versus 378 patients postintervention [P = 0.015]). Notable increases in testing from the pre-intervention to postintervention periods occurred among midwives (1-68 patients tested) and trainees (57-133 patients tested). Overall, 56/537 (10.4%) nonduplicate T. cruzi commercial screening tests were positive. Testing increased over time, both at an institutional level and within targeted departments. In addition to the educational program, other factors likely influenced expanded testing.

Chagas cardiomyopathy in Boston, Massachusetts: Identifying disease and improving management after community and hospital-based screening.

BACKGROUND: Limited data exist regarding cardiac manifestations of Chagas disease in migrants living in non-endemic regions. METHODS: A retrospective cohort analysis of 109 patients with Chagas disease seen at Boston Medical Center (BMC) between January 2016 and January 2023 was performed. Patients were identified by screening and testing migrants from endemic regions at a community health center and BMC. Demographic, laboratory, and cardiac evaluation data were collected. RESULTS: Mean age of the 109 patients was 43 years (range 19-76); 61% were female. 79% (86/109) were diagnosed with Chagas disease via screening and 21% (23/109) were tested given symptoms or electrocardiogram abnormalities. Common symptoms included palpitations (25%, 27/109) and chest pain (17%, 18/109); 52% (57/109) were asymptomatic. Right bundle branch block (19%, 19/102), T-wave changes (18%, 18/102), and left anterior fascicular block (11%, 11/102) were the most common electrocardiogram abnormalities; 51% (52/102) had normal electrocardiograms. Cardiomyopathy stage was ascertained in 94 of 109 patients: 51% (48/94) were indeterminate stage A and 49% (46/94) had cardiac structural disease (stages B1-D). Clinical findings that required clinical intervention or change in management were found in 23% (25/109), and included cardiomyopathy, apical hypokinesis/aneurysm, stroke, atrial or ventricular arrhythmias, and apical thrombus. CONCLUSIONS: These data show high rates of cardiac complications in a cohort of migrants living with Chagas disease in a non-endemic setting. We demonstrate that Chagas disease diagnosis prompts cardiac evaluation which often identifies actionable cardiac disease and provides opportunities for prevention and treatment.

Epidemiology of travel-associated dengue from 2007 to 2022: A GeoSentinel analysis.

BACKGROUND: Dengue is a leading cause of febrile illness among international travellers. We aimed to describe the epidemiology and clinical characteristics of imported dengue in returning travellers evaluated at GeoSentinel sites from 2007 to 2022. METHODS: We retrieved GeoSentinel records of dengue among travellers residing in non-endemic countries. We considered dengue confirmed when diagnosed by a positive dengue virus (DENV)-specific reverse-transcriptase polymerase chain reaction, positive NS-1 antigen and/or anti-DENV IgG seroconversion, and probable when diagnosed by single anti-DENV IgM or high-titre anti-DENV IgG detection. Severe dengue was defined as evidence of clinically significant plasma leakage or bleeding, organ failure, or shock, according to the 2009 World Health Organization guidance. Complicated dengue was defined as either severe dengue or dengue with presence of any warning sign. Analyses were descriptive. RESULTS: This analysis included 5958 travellers with confirmed (n = 4859; 81.6%) or probable (n = 1099; 18.4%) dengue. The median age was 33 years (range: <1-91); 3007 (50.5%) travellers were female. The median travel duration was 21 days (interquartile range [IQR]: 15-32). The median time between illness onset and GeoSentinel site visit was 7 days (IQR: 4-15). The most frequent reasons for travel were tourism (67.3%), visiting friends or relatives (12.2%) and business (11.0%). The most frequent regions of acquisition were South East Asia (50.4%), South Central Asia (14.9%), the Caribbean (10.9%) and South America (9.2%). Ninety-five (1.6%) travellers had complicated dengue, of whom 27 (0.5%) had severe dengue and one died. Of 2710 travellers with data available, 724 (26.7%) were hospitalized. The largest number of cases (n = 835) was reported in 2019. CONCLUSIONS: A broad range of international travellers should be aware of the risk of acquiring dengue and receive appropriate pre-travel counselling regarding preventive measures. Prospective cohort studies are needed to further elucidate dengue risk by destination and over time, as well as severe outcomes and prolonged morbidity (long dengue) due to travel-related dengue.

Travel-Related Diagnoses Among U.S. Nonmigrant Travelers or Migrants Presenting to U.S. GeoSentinel Sites - GeoSentinel Network, 2012-2021.

Problem/Condition: During 2012-2021, the volume of international travel reached record highs and lows. This period also was marked by the emergence or large outbreaks of multiple infectious diseases (e.g., Zika virus, yellow fever, and COVID-19). Over time, the growing ease and increased frequency of travel has resulted in the unprecedented global spread of infectious diseases. Detecting infectious diseases and other diagnoses among travelers can serve as sentinel surveillance for new or emerging pathogens and provide information to improve case identification, clinical management, and public health prevention and response. Reporting Period: 2012-2021. Description of System: Established in 1995, the GeoSentinel Network (GeoSentinel), a collaboration between CDC and the International Society of Travel Medicine, is a global, clinical-care-based surveillance and research network of travel and tropical medicine sites that monitors infectious diseases and other adverse health events that affect international travelers. GeoSentinel comprises 71 sites in 29 countries where clinicians diagnose illnesses and collect demographic, clinical, and travel-related information about diseases and illnesses acquired during travel using a standardized report form. Data are collected electronically via a secure CDC database, and daily reports are generated for assistance in detecting sentinel events (i.e., unusual patterns or clusters of disease). GeoSentinel sites collaborate to report disease or population-specific findings through retrospective database analyses and the collection of supplemental data to fill specific knowledge gaps. GeoSentinel also serves as a communications network by using internal notifications, ProMed alerts, and peer-reviewed publications to alert clinicians and public health professionals about global outbreaks and events that might affect travelers. This report summarizes data from 20 U.S. GeoSentinel sites and reports on the detection of three worldwide events that demonstrate GeoSentinel's notification capability. Results: During 2012-2021, data were collected by all GeoSentinel sites on approximately 200,000 patients who had approximately 244,000 confirmed or probable travel-related diagnoses. Twenty GeoSentinel sites from the United States contributed records during the 10-year surveillance period, submitting data on 18,336 patients, of which 17,389 lived in the United States and were evaluated by a clinician at a U.S. site after travel. Of those patients, 7,530 (43.3%) were recent migrants to the United States, and 9,859 (56.7%) were returning nonmigrant travelers.Among the recent migrants to the United States, the median age was 28.5 years (range = <19 years to 93 years); 47.3% were female, and 6.0% were U.S. citizens. A majority (89.8%) were seen as outpatients, and among 4,672 migrants with information available, 4,148 (88.8%) did not receive pretravel health information. Of 13,986 diagnoses among migrants, the most frequent were vitamin D deficiency (20.2%), Blastocystis (10.9%), and latent tuberculosis (10.3%). Malaria was diagnosed in 54 (<1%) migrants. Of the 26 migrants diagnosed with malaria for whom pretravel information was known, 88.5% did not receive pretravel health information. Before November 16, 2018, patients' reasons for travel, exposure country, and exposure region were not linked to an individual diagnosis. Thus, results of these data from January 1, 2012, to November 15, 2018 (early period), and from November 16, 2018, to December 31, 2021 (later period), are reported separately. During the early and later periods, the most frequent regions of exposure were Sub-Saharan Africa (22.7% and 26.2%, respectively), the Caribbean (21.3% and 8.4%, respectively), Central America (13.4% and 27.6%, respectively), and South East Asia (13.1% and 16.9%, respectively). Migrants with diagnosed malaria were most frequently exposed in Sub-Saharan Africa (89.3% and 100%, respectively).Among nonmigrant travelers returning to the United States, the median age was 37 years (range = <19 years to 96 years); 55.7% were female, 75.3% were born in the United States, and 89.4% were U.S. citizens. A majority (90.6%) were seen as outpatients, and of 8,967 nonmigrant travelers with available information, 5,878 (65.6%) did not receive pretravel health information. Of 11,987 diagnoses, the most frequent were related to the gastrointestinal system (5,173; 43.2%). The most frequent diagnoses among nonmigrant travelers were acute diarrhea (16.9%), viral syndrome (4.9%), and irritable bowel syndrome (4.1%).Malaria was diagnosed in 421 (3.5%) nonmigrant travelers. During the early (January 1, 2012, to November 15, 2018) and later (November 16, 2018, to December 31, 2021) periods, the most frequent reasons for travel among nonmigrant travelers were tourism (44.8% and 53.6%, respectively), travelers visiting friends and relatives (VFRs) (22.0% and 21.4%, respectively), business (13.4% and 12.3%, respectively), and missionary or humanitarian aid (13.1% and 6.2%, respectively). The most frequent regions of exposure for any diagnosis among nonmigrant travelers during the early and later period were Central America (19.2% and 17.3%, respectively), Sub-Saharan Africa (17.7% and 25.5%, respectively), the Caribbean (13.0% and 10.9%, respectively), and South East Asia (10.4% and 11.2%, respectively).Nonmigrant travelers who had malaria diagnosed were most frequently exposed in Sub-Saharan Africa (88.6% and 95.9% during the early and later period, respectively) and VFRs (70.3% and 57.9%, respectively). Among VFRs with malaria, a majority did not receive pretravel health information (70.2% and 83.3%, respectively) or take malaria chemoprophylaxis (88.3% and 100%, respectively). Interpretation: Among ill U.S. travelers evaluated at U.S. GeoSentinel sites after travel, the majority were nonmigrant travelers who most frequently received a gastrointestinal disease diagnosis, implying that persons from the United States traveling internationally might be exposed to contaminated food and water. Migrants most frequently received diagnoses of conditions such as vitamin D deficiency and latent tuberculosis, which might result from adverse circumstances before and during migration (e.g., malnutrition and food insecurity, limited access to adequate sanitation and hygiene, and crowded housing,). Malaria was diagnosed in both migrants and nonmigrant travelers, and only a limited number reported taking malaria chemoprophylaxis, which might be attributed to both barriers to acquiring pretravel health care (especially for VFRs) and lack of prevention practices (e.g., insect repellant use) during travel. The number of ill travelers evaluated by U.S. GeoSentinel sites after travel decreased in 2020 and 2021 compared with previous years because of the COVID-19 pandemic and associated travel restrictions. GeoSentinel detected limited cases of COVID-19 and did not detect any sentinel cases early in the pandemic because of the lack of global diagnostic testing capacity. Public Health Action: The findings in this report describe the scope of health-related conditions that migrants and returning nonmigrant travelers to the United States acquired, illustrating risk for acquiring illnesses during travel. In addition, certain travelers do not seek pretravel health care, even when traveling to areas in which high-risk, preventable diseases are endemic. Health care professionals can aid international travelers by providing evaluations and destination-specific advice.Health care professionals should both foster trust and enhance pretravel prevention messaging for VFRs, a group known to have a higher incidence of serious diseases after travel (e.g., malaria and enteric fever). Health care professionals should continue to advocate for medical care in underserved populations (e.g., VFRs and migrants) to prevent disease progression, reactivation, and potential spread to and within vulnerable populations. Because both travel and infectious diseases evolve, public health professionals should explore ways to enhance the detection of emerging diseases that might not be captured by current surveillance systems that are not site based.

Impact, healthcare utilization and costs of travel-associated mosquito-borne diseases in international travellers: a prospective study.

BACKGROUND: International travellers frequently acquire infectious diseases whilst travelling, yet relatively little is known about the impact and economic burden of these illnesses on travellers. We conducted a prospective exploratory costing study on adult returning travellers with falciparum malaria, dengue, chikungunya or Zika virus. METHODS: Patients were recruited in eight Travel and Tropical Medicine clinics between June 2016 and March 2020 upon travellers' first contact with the health system in their country of residence. The patients were presented with a structured 52-question self-administered questionnaire after full recovery to collect information on patients' healthcare utilization and out-of-pocket costs both in the destination and home country, and about income and other financial losses due to the illness. RESULTS: A total of 134 patients participated in the study (malaria, 66; dengue, 51; chikungunya, 8; Zika virus, 9; all fully recovered; median age 40; range 18-72 years). Prior to travelling, 42% of patients reported procuring medical evacuation insurance. Across the four illnesses, only 7% of patients were hospitalized abroad compared with 61% at home. Similarly, 15% sought ambulatory services whilst abroad compared with 61% at home. The average direct out-of-pocket hospitalization cost in the destination country (USD $2236; range: $108-$5160) was higher than the direct out-of-pocket ambulatory cost in the destination country (USD $327; range: $0-$1560), the direct out-of-pocket hospitalization cost at home (USD $35; range: $0-$120) and the direct out-of-pocket ambulatory costs at home (US$45; range: $0-$192). Respondents with dengue or malaria lost a median of USD $570 (Interquartile range [IQR] 240-1140) and USD $240 (IQR 0-600), respectively, due to their illness, whilst those with chikungunya and Zika virus lost a median of USD $2400 (IQR 1200-3600) and USD $1500 (IQR 510-2625), respectively. CONCLUSION: Travellers often incur significant costs due to travel-acquired diseases. Further research into the economic impact of these diseases on travellers should be conducted.

Genomic Epidemiology of a Severe Acute Respiratory Syndrome Coronavirus 2 Outbreak in a US Major League Soccer Club: Was It Travel Related?

Background: Professional soccer athletes are at risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). United States Major League Soccer (MLS) uses protocol-based SARS-CoV-2 testing for identification of individuals with coronavirus disease 2019. Methods: Per MLS protocol, fully vaccinated players underwent SARS-CoV-2 real-time polymerase chain reaction testing weekly; unvaccinated players were tested every other day. Demographic and epidemiologic data were collected from individuals who tested positive, and contact tracing was performed. Whole genome sequencing (WGS) was performed on positive specimens, and phylogenetic analyses were used to identify potential transmission patterns. Results: In the fall of 2021, all 30 players from 1 MLS team underwent SARS-CoV-2 testing per protocol; 27 (90%) were vaccinated. One player who had recently traveled to Africa tested positive for SARS-CoV-2; within the following 2 weeks, 10 additional players and 1 staff member tested positive. WGS yielded full genome sequences for 10 samples, including 1 from the traveler. The traveler's sample was Delta sublineage AY.36 and was closely related to a sequence from Africa. Nine samples yielded other Delta sublineages including AY.4 (n = 7), AY.39 (n = 1), and B.1.617.2 (n = 1). The 7 AY.4 sequences clustered together; suggesting a common source of infection. Transmission from a family member visiting from England to an MLS player was identified as the potential index case. The other 2 AY.4 sequences differed from this group by 1-3 nucleotides, as did a partial genome sequence from an additional team member. Conclusions: WGS is a useful tool for understanding SARS-CoV-2 transmission dynamics in professional sports teams.

Treatment strategies for nitroimidazole-refractory giardiasis: a systematic review.

RATIONALE FOR REVIEW: Giardiasis is one of the most common human protozoal infections worldwide. First-line therapy of giardiasis includes nitroimidazole antibiotics. However, treatment failure with nitroimidazoles is increasingly reported, with up to 45% of patients not responding to initial treatment. There is no clear consensus on the approach to the management of nitroimidazole-refractory giardiasis. This systematic review aims to summarize the literature on pharmacotherapy for nitroimidazole-refractory giardiasis. METHODS: We conducted a systematic review of the literature to determine the optimal management strategies for nitroimidazole-refractory giardiasis. We searched Pubmed/MEDLINE, Embase and Cochrane library using the following search terms 'Giardia' AND 'treatment failure' OR 'refractory giardia' OR 'resistant giardia' with date limits of 1 January 1970 to 30 June 2021. We included all reports on humans, which described clinical outcomes of individuals with treatment refractory giardiasis, including case series and case reports. A descriptive synthesis of the data was conducted with pooling of data for interventions. KEY FINDINGS: Included in this review were five prospective studies, three retrospective studies, seven case series and nine case reports. Across these reports, a wide heterogeneity of treatment regimens was employed, including retreatment with an alternative nitroimidazole, combination therapy with a nitroimidazole and another agent and monotherapy with non-nitroimidazole regimens, including quinacrine, paromomycin and nitazoxanide. Retreatment with a nitroimidazole was not an effective therapy for refractory giardiasis. However, treatment with a nitroimidazole in combination with albendazole had a cure rate of 66.9%. In the included studies, quinacrine monotherapy was administered to a total of 179 patients, with a clinical cure rate of 88.8%. Overall, quinacrine was fairly well tolerated. CONCLUSIONS: Reports on the treatment of nitroimidazole-refractory giardiasis demonstrate a heterogeneous approach to treatment. Of these, quinacrine appeared to be highly effective, though more data on its safety are needed.

Acute transverse myelitis in West Nile Virus, a rare neurological presentation.

INTRODUCTION: West Nile Virus varies in presentation from asymptomatic to a febrile illness often associated with malaise, weakness and maculopapular rash. West Nile neuro-invasive disease often manifests as meningitis, encephalitis, and less commonly acute flaccid paralysis in a "polio-like" presentation. Acute transverse myelitis (ATM) is a rare manifestation. We present a case of neuro-invasive West Nile Virus infection with radiographic evidence of longitudinally extensive transverse myelitis (LETM), a subset of ATM. CASE NARRATION: A 42-year-old male from Massachusetts presented with progressive asymmetric paralysis of 4 days duration after developing a prodrome of fever, neck stiffness and urinary retention. Physical examination demonstrated asymmetric lower extremity weakness Lumbar puncture revealed lymphocytic pleocytosis with normal protein and glucose and a positive West Nile IgM in CSF (4.89, reference <0.90), and West Nile Virus detected by PCR in CSF. His West Nile serum IgM was 3.03 (reference range <0.90) and IgG was <1.30 (reference range <1.30). MRI of the lumbar spine showed findings consistent with the diagnosis of ATM. CONCLUSION: With our patient's presentation of acute onset asymmetrical weakness following a viral illness, we ruled out differentials including demyelinating syndrome such as GBS, inflammation of the meninges through meningitis or meningoencephalitis, or traumatic/ischemic involvement of the spinal cord directly. Due to the MRI findings, his motor weakness and urinary retention, supporting CSF findings and WNV positive serologies, ATM due to WNV infection was the main suspect for his presentation. Although ATM is an uncommon manifestation of WNV, it is imperative to consider this in the differential for patients presenting with acute onset flaccid paralysis in regions where WNV is endemic.

Health Considerations for HIV-Infected International Travelers.

PURPOSE OF THE REVIEW: International travel continues to steadily increase, including leisure travel, travel to one's country of origin to visit friends and relatives, travel for service work, and business travel. Travelers with HIV may have an increased risk for travel-associated infections. The pre-travel medical consultation is an important means of assessing one's risk for travel-related health issues. The aim of this review is to provide an update on key health considerations for the HIV-infected traveler. RECENT FINDINGS: Like all travelers, the HIV-infected traveler should adhere to behavioral precautions, including safety measures with food and water consumption, safe sexual practices, and arthropod bite avoidance. HIV is a risk factor for venous thromboembolism and patients should be educated regarding this risk. Most pre-travel vaccines are safe and immunogenic in HIV-infected individuals, though live vaccines should be avoided in patients with low CD4 counts. Malaria chemoprophylaxis is strongly recommended in patients with HIV traveling to endemic areas and no significant interactions exist between the commonly used prophylactic anti-malarial agents and anti-retroviral therapy (ART). Travelers with HIV, particularly those who are not on ART or who have low CD4 cell counts, may have increased risk for tuberculosis, malaria, enteric infections, visceral leishmaniasis, American trypanosomiasis, and endemic mycoses such as histoplasmosis, talaromycosis, and coccidioidomycosis. The immune status of the HIV-infected traveler should be assessed prior to travel along with the duration, itinerary, and activities planned during travel in order to carefully consider individual risk for travel-related health issues.

Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated Vibrio cholerae.

Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae infection from OCV, we stimulated differentiated, macrophage-like THP-1 cells with live versus heat-inactivated V. cholerae with and without endogenous or exogenous cholera holotoxin (CT). Interleukin 23A gene (IL23A) expression was higher in cells exposed to live V. cholerae than in cells exposed to inactivated organisms (mean change, 38-fold; 95% confidence interval [95% CI], 4.0 to 42; P < 0.01). IL-23 secretion was also higher in cells exposed to live V. cholerae than in cells exposed to inactivated V. cholerae (mean change, 5.6-fold; 95% CI, 4.4 to 11; P < 0.001). This increase in IL-23 secretion was more marked than for other key innate immune cytokines (e.g., IL-1ß and IL-6) and dependent on exposure to the combination of both live V. cholerae and CT. While IL-23 secretion was reduced following stimulation with either heat-inactivated wild-type V. cholerae or a live isogenic ctxAB mutant of V. cholerae, the addition of exogenous CT restored IL-23 secretion in combination with the live isogenic ctxAB mutant V. cholerae, but not when it was paired with stimulation by heat-inactivated V. cholerae The posttranslational regulation of IL-23 under these conditions was dependent on the activity of the cysteine protease cathepsin B. In humans, IL-23 promotes the differentiation of Th17 cells to T follicular helper cells, which maintain and support long-term memory B cell generation after infection. Based on these findings, the stimulation of IL-23 production may be a determinant of protective immunity following V. cholerae infection.IMPORTANCE An episode of cholera provides better protection against reinfection than oral cholera vaccines, and the reasons for this are still under study. To better understand this, we compared the immune responses of human cells exposed to live Vibrio cholerae with those of cells exposed to heat-killed V. cholerae (similar to the contents of oral cholera vaccines). We also compared the effects of active cholera toxin and the inactive cholera toxin B subunit (which is included in some cholera vaccines). One key immune signaling molecule, IL-23, was uniquely produced in response to the combination of live bacteria and active cholera holotoxin. Stimulation with V. cholerae that did not produce the active toxin or was killed did not produce an IL-23 response. The stimulation of IL-23 production by cholera toxin-producing V. cholerae may be important in conferring long-term immunity after cholera.

Illnesses Associated with Freshwater Recreation During International Travel.

PURPOSE OF REVIEW: International travel, adventure travel, and eco-tourism are increasing over the past few decades. This review aims to summarize the spectrum of infections associated with recreational freshwater activities and international travel. RECENT FINDINGS: Recreational water activities can be associated with a wide range of infections. Acute febrile illnesses due to leptospirosis and schistosomiasis are not uncommon in travelers following extensive freshwater exposure. Aeromonas and other water-associated pathogens are important to consider in a traveler presenting with a skin and soft tissue infection. Recreational water activities are often associated with diarrheal illnesses, especially in children, and the range of enteric pathogens includes bacterial pathogens such as Escherichia coli O157:H7 and Shigella species and the protozoan parasites Cryptosporidium and Giardia duodenalis. Infections due to free-living amebas though rare can lead to fulminant central nervous system infections. A diverse range of infections may be associated with freshwater exposure, and it is important that these entities are considered in a returning traveler presenting with an acute illness.

beta-Blockers for the treatment of cardiac arrest from ventricular fibrillation?

More than 160,000 people suffer sudden cardiac death each year in the US. It is estimated that ventricular fibrillation (VF) is the initial rhythm in approximately 30% of these cases. Ventricular fibrillation that does not respond to the first few defibrillation attempts is associated with mortality rates of up to 97%. Currently, no pharmacological intervention has been shown to increase long-term survival in patients with shock-refractory VF. The purpose of this review article is to evaluate whether beta-blocker administration during the resuscitation of cardiac arrest from VF or pulseless ventricular tachycardia (VT) improves outcome. We searched the MEDLINE and EMBASE databases for human clinical trials, animal experimental trials, review articles, case reports and abstracts published between 1966 and September 2006. No human prospective randomized controlled trial has studied the effects of beta-blocker administration during VF directly. Prospective trials of anti-arrhythmics with beta-blocking properties have been published, as well as several case reports/case series and experimental animal studies. The evidence thus far suggests that beta-blockade during resuscitation from VF may be associated with increasing rates of resuscitation, greater post-resuscitation survival, and improved post-resuscitation myocardial function. These positive effects on outcome may be mediated by a decrease in the oxygen requirements of the fibrillating heart, thus improving the overall balance between myocardial oxygen supply and demand during resuscitation. While no significant detrimental effects directly related to low dose beta-blockade during VF have been reported in the studies reviewed, concerns relating to possible loss of myocardial contractility and hypotension remain. To this day, high quality human trials are lacking. Preliminary human studies are needed to assess the effects of beta-blockers in the treatment of cardiac arrest from ventricular fibrillation or pulseless VT further.

Subacute Bacterial Endocarditis with Leptotrichia goodfellowii in a Patient with a Valvular Allograft: A Case Report and Review of the Literature.

Leptotrichia species are normal constituents of the oral cavity and the genitourinary tract microbiota that are known to provoke disease in immunocompromised patients and rarely in immunocompetent individuals. Following the description of Leptotrichia goodfellowii sp. nov., two cases of endocarditis by this species have been reported. Here, we report a case of Leptotrichia goodfellowii endocarditis in an immunocompetent patient with a valvular allograft. The isolation and identification of Leptotrichia can be challenging, and it is likely that infection with this pathogen is significantly underdiagnosed. A definitive identification, as in this case, most often requires 16S rRNA gene sequencing, highlighting the increasingly important role of this diagnostic modality among immunocompetent patients with undetermined anaerobic bacteremia.

Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin.

Gene therapy for Duchenne muscular dystrophy will require methods to deliver gene constructs encoding functional versions of dystrophin to the vast majority of a patient's musculature. Obstacles to achieving these goals include identifying which forms of dystrophin would be effective in a clinical setting and developing gene delivery shuttles capable of carrying and expressing dystrophin cassettes without toxic or adverse immunologic consequences. We review here recent work from our laboratory to identify sequences within dystrophin that are required to prevent development of dystrophic changes in muscle or which might be able to correct pre-existing damage. We also describe work aimed at developing viral shuttle vectors able to carry and express these dystrophin cassettes at high levels and in a muscle-specific fashion. While great challenges remain in developing methods for systemic gene delivery, we show that a variety of viral vectors are able to carry and express therapeutic levels of dystrophin when delivered directly to mouse skeletal muscle.

Clinical, virologic, and immunologic correlates of HIV-1 intraclade B dual infection among men who have sex with men.

OBJECTIVE: To investigate the susceptibilities to and consequences of HIV-1 dual infection. DESIGN: We compared clinical, virologic, and immunologic factors between participants who were dually infected with HIV-1 subtype B and monoinfected controls who were matched by ongoing HIV risk factor. METHODS: The viral load and CD4 progressions of dually and singly infected participant groups were compared with linear mixed-effects models, and individual dynamics before and after superinfection were assessed with a structural change test (Chow test). Recombination breakpoint analysis (GARD), HLA frequency analysis, and cytotoxic T-lymphocyte (CTL) epitope mapping were also performed (HIV LANL Database). RESULTS: The viral loads of dually infected participants increased more over 3 years of follow-up than the viral loads of monoinfected controls, whereas CD4 progressions of the two groups did not differ. Viral escape from CTL responses following superinfection was observed in two participants whose superinfecting strain completely replaced the initial strain. This pattern was not seen among participants whose superinfecting virus persisted in a recombinant form with the initial virus or was only detected transiently. Several HLA types were over-represented in dually infected participants as compared to monoinfected controls. CONCLUSIONS: These results identify potential factors for dual infection susceptibility and further define its clinical consequences.