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ObjectiveThe purpose of this study was to assess chiropractic interns' knowledge and adherence to radiographic clinical practice guidelines (CPGs) and compare their clinical decisions to previous surveys of established practitioners in Canada and Australia.MethodsA clinical decision-making survey was administered to 88 interns. The survey contained clinical scenarios and vignettes with inquiries regarding indications for radiographic referral, the likelihood of referral, and the application of CPGs.ResultsForty-four percent (43.75%) of the interns were aware of CPGs, 38.75% were unsure, and 17.5% were not aware. When asked specific questions about the appropriateness of diagnostic imaging, the interns' responses were similar to those of practitioners in Canada and Australia. When interns evaluated a clinical vignette, there was lower compliance with CPGs.ConclusionThe interns' clinical decisions regarding the use of diagnostic radiography did not significantly differ from those of practitioners who were surveyed in other related studies. Interns were inconsistent in applying their decision making in clinical cases. Notwithstanding the similarities with practitioners, some deviation from the guidelines indicates the need for further intern education to improve the implementation of CPGs for optimal cost-effective and clinically appropriate care.

Objective: To develop an evidence-based clinical practice guideline (CPG) through a broad-based consensus process on best practices for chiropractic management of patients with chronic musculoskeletal (MSK) pain. Design: CPG based on evidence-based recommendations of a panel of experts in chronic MSK pain management. Methods: Using systematic reviews identified in an initial literature search, a steering committee of experts in research and management of patients with chronic MSK pain drafted a set of recommendations. Additional supportive literature was identified to supplement gaps in the evidence base. A multidisciplinary panel of experienced practitioners and educators rated the recommendations through a formal Delphi consensus process using the RAND Corporation/University of California, Los Angeles, methodology. Results: The Delphi process was conducted January–February 2020. The 62-member Delphi panel reached consensus on chiropractic management of five common chronic MSK pain conditions: low-back pain (LBP), neck pain, tension headache, osteoarthritis (knee and hip), and fibromyalgia. Recommendations were made for nonpharmacological treatments, including acupuncture, spinal manipulation/mobilization, and other manual therapy; modalities such as low-level laser and interferential current; exercise, including yoga; mind–body interventions, including mindfulness meditation and cognitive behavior therapy; and lifestyle modifications such as diet and tobacco cessation. Recommendations covered many aspects of the clinical encounter, from informed consent through diagnosis, assessment, treatment planning and implementation, and concurrent management and referral. Appropriate referral and comanagement were emphasized. Conclusions: These evidence-based recommendations for a variety of conservative treatment approaches to the management of common chronic MSK pain conditions may advance consistency of care, foster collaboration between provider groups, and thereby improve patient outcomes.

Objective The purpose of this scoping review was to identify and synthesize literature on dosage variables on the efficacy of low-level laser therapy (LLLT) for neuromusculoskeletal conditions. Methods A scoping literature review was conducted by searching the following databases: the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, Medline, the Physiotherapy Evidence Database, the Index to Chiropractic Literature, manufacturer websites, and online guidelines. The search was modeled after STARLITE criteria. The reporting used Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews (PRISMA-ScR). Articles were included if LLLT was used in any treatment group for a neuromusculoskeletal complaint with dosage and effectiveness reported. This was tabulated by source, dosage variables, conditions, outcome measures, and conclusions. Data were charted in Excel format. Frequency counts were performed on ordinal data. Descriptive statistics were computed for the continuous data. Results A total of 86 articles were included in the review. They revealed a broad range of musculoskeletal conditions and diverse dosage parameters. Seven individual parameters were found that would alter the dosage. Although duration of application is an independent clinical factor, the negative-outcome studies were inconsistent in duration. There was lack of statistical difference between the studies with improved vs unimproved outcomes. No statistical differences were noted between the dosage parameters and efficacy. Conclusion Although many articles were found on LLLT for neuromusculoskeletal conditions, the studies had amorphous parameters. A heterogeneity of reported doses precluded the synthesis of sufficient evidence to correlate dosage variables with improved or unimproved outcomes. Therefore, based on the current literature, dosage variables for the efficacy of LLLT for neuromusculoskeletal conditions are uncertain at this time.

Background Human noroviruses (HuNoV) are the leading cause of gastroenteritis. No vaccine is currently available to prevent norovirus illness or infection. Safe, infectious challenge strains are needed to assess vaccine efficacy in the controlled human infection model (CHIM). Methods A stock of HuNoV strain Norwalk virus ([NV] GI.1) was prepared. Healthy, genetically susceptible adults were inoculated with NV Lot 001-09NV and monitored for infection, gastroenteritis symptoms, and immune responses. Results Lot 001-09NV induced gastroenteritis in 9 (56%) and infection in 11 (69%) of 16 genetically susceptible subjects. All infected subjects developed strong immune responses to GI.1 with a 30-fold (geometric mean titer) increase in blocking titers (BT50) and a 161-fold increase in GI.1-specific immunoglobulin (Ig)G titers when compared with baseline. GI.1-specific cellular responses in peripheral blood were observed 9 days postchallenge with an average of 3253 IgA and 1227 IgG antibody-secreting cells per million peripheral blood mononuclear cells. Conclusions GI.1 Lot 001-09NV appears to be similar in virulence to previous passages of NV strain 8fIIa. The safety profile, attack rate, and duration of illness make GI.1 Lot 001-09NV a useful challenge strain for future vaccine studies aimed at establishing immune correlates., A new robust platform for the purification of a novel GI.1 human norovirus stock, Lot 001-09NV, produced an infectious inoculum that can be used to compare and standardize immune response levels and efficacy of future norovirus vaccine candidates.

Objective: To develop evidence-based recommendations on best practices for delivery of clinical preventive services by chiropractors and to offer practical resources to empower provider applications in practice. Design: Clinical practice guideline based on evidence-based recommendations of a panel of practitioners and experts on clinical preventive services. Methods: Synthesizing the results of a literature search for relevant clinical practice guidelines and systematic reviews, a multidisciplinary steering committee with training and experience in health promotion, clinical prevention, and/or evidence-based chiropractic practice drafted a set of recommendations. A Delphi panel of experienced practitioners and faculty, primarily but not exclusively chiropractors, rated the recommendations by using the formal consensus methodology established by the RAND Corporation/University of California. Results: The Delphi consensus process was conducted during January-February 2021. The 65-member Delphi panel reached a high level of consensus on appropriate application of clinical preventive services for screening and health promotion counseling within the chiropractic scope of practice. Interprofessional collaboration for the successful delivery of clinical preventive services was emphasized. Recommendations were made on primary, secondary, tertiary, and quaternary prevention of musculoskeletal pain. Conclusions: Application of this guideline in chiropractic practice may facilitate consistent and appropriate use of screening and preventive services and foster interprofessional collaboration to promote clinical preventive services and contribute to improved public health.

Travel medicine has virtually stopped in light of the coronavirus pandemic. It is worth contemplating how travel medicine will be affected by the ongoing pandemic when international travel starts to become more possible. How will we advise patients and use the coming vaccines that may be available? Travel medicine practices are well-suited to play a major role in advising travellers in the pandemic era.

Background : Travelers' diarrhea causes significant morbidity including some sequelae, lost travel time and opportunity cost to both travelers and countries receiving travelers. Effective prevention and treatment are needed to reduce these negative impacts. Methods : This critical appraisal of the literature and expert consensus guideline development effort asked several key questions related to antibiotic and non-antibiotic prophylaxis and treatment, utility of available diagnostics, impact of multi-drug resistant (MDR) colonization associated with travel and travelers' diarrhea, and how our understanding of the gastrointestinal microbiome should influence current practice and future research. Studies related to these key clinical areas were assessed for relevance and quality. Based on this critical appraisal, guidelines were developed and voted on using current standards for clinical guideline development methodology. Results : New definitions for severity of travelers' diarrhea were developed. A total of 20 graded recommendations on the topics of prophylaxis, diagnosis, therapy and follow-up were developed. In addition, three non-graded consensus-based statements were adopted. Conclusions : Prevention and treatment of travelers' diarrhea requires action at the provider, traveler and research community levels. Strong evidence supports the effectiveness of antimicrobial therapy in most cases of moderate to severe travelers' diarrhea, while either increasing intake of fluids only or loperamide or bismuth subsalicylate may suffice for most cases of mild diarrhea. Further studies are needed to address knowledge gaps regarding optimal therapies, the individual, community and global health risks of MDR acquisition, manipulation of the microbiome in prevention and treatment and the utility of laboratory testing in returning travelers with persistent diarrhea.

Objective The purpose of this study was to assess the self-reported knowledge of concussion recognition and treatment with first-contact family medical and chiropractic practitioners by means of a pilot study of the need, construct validity, and feasibility for further investigation of mild traumatic brain injury (MTBI) knowledge base. Methods Two hundred forty-eight practicing chiropractic and 120 medical physicians in the south and northeastern sections of the United States were contacted by e-mail, telephone, and postal mail to answer an 18-item survey on knowledge, diagnosis, and common practice with respect to traumatic brain injury patients. Descriptive analysis was used to assess common trends. Results Twenty-three chiropractic and 11 medical primary care practitioners returned completed surveys, making this a low-power pilot study. The majority claimed confidence in diagnosis of MTBI, but a lack of knowledge of many of the assessment tools and the international guidelines. Chiropractic and medical clinicians revealed similar competencies and differing deficiencies. Both groups admitted infrequent diagnosis of MTBI in practice. There was recognition of major TBI signs, but lack of recognition or inquiry for subtle MTBI signs. Conclusions There is a need and feasibility for further study of the knowledge transfer to the chiropractic physician with a larger population. These findings correlate with similar medical practitioner studies, and may also support previous findings of underreporting of the prevalence of MTBI. The survey instrument appears to provide valid data on knowledge of MTBIs, with some modifications.

Objective The purpose of this study was to review the literature on current challenges and propose solutions for the optimal utilization of the electronic health records (EHRs) in chiropractic practice. Methods A search was performed in the PubMed, Index of Chiropractic Literature, and Current Index to Nursing and Allied Health Literature databases from November 2005 to February 2015. A combination of the following key words was used: electronic health records , electronic medical records , implementation , documentation , benefits , and challenges . Articles were categorized into common problems and solutions. These were filtered by application to chiropractic or educational institutions. Results The search resulted in 45 papers, which included case reports of EHR implementation, governmental insurance reports, commentaries, controlled studies, narrative reviews of past experiences with conversion from paper systems, and the implementation of EHRs in small offices and chiropractic offices. Minimal literature was found that directly related to chiropractic EHRs. Improper utilization, incorrect use of the software, faulty implementation, workflow burdens, financial considerations, and insufficient training were found to negatively affect the quality of the record. Conclusions Documentation errors are often innate in the EHR software. Improper utilization, insufficient training, or difficulty in integration of the EHR into the clinical office setting results in poor implementation of the electronic version of the clinical record. Solutions that may decrease documentation errors include EHR training, continued financial incentives, and appropriate implementation process and utilization of available software features.

Acute diarrhea is the most common medical complaint of international travelers to high-risk tropical and semitropical regions of the world. Enterotoxigenic Escherichia coli (ETEC) is the most common cause with strains of Campylobacter jejuni and other invasive bacterial enteropathogens also important causes especially in South Asia. Treatment can shorten the disease. Loperamide and other drugs acting symptomatically can decrease the number of watery stools passed and antimicrobial agents can shorten the overall illness. Because of the significance of acquiring fecal carriage of multidrug-resistant Enterobacteriaceae with antibiotics, most travel authorities only recommend treatment with these drugs when illness is moderate to severe. Mild illness, which allows people to function relatively normally, is best left untreated or treated symptomatically. A major health consequence of travelers' diarrhea (TD) is development of postinfectious functional bowel disease, which may occur in as many as 5% of those reporting TD.

Background Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. Methods Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. Results Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. Conclusion Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints.

Campylobacter jejuni or Campylobacter coli organisms may exist as commensals in the intestinal tracts of a wide variety of wild and domestic animals. Whether or not Campylobacters are pathogenic in their animal hosts. That some of the organisms associated with animals cause infection and disease in humans is known from data obtained in a few outbreaks in which an animal or animal product was ultimately identified as a source. The sources of Campylobacter organisms found in water are not known but may be due to fecal contamination by wild or domestic animals. Studies of mud from contaminated rivers in Southampton failed to show Campylobacters. However, isolations from both mud and sewage sludge have been made in the US Campylobacter enteritis has been reported in children and young adults who before their illnesses had close contact with infected puppies. Campylobacter enteritis is sometimes associated with bacteremia.

Background Norovirus (NoV) is a common cause of acute gastroenteritis, but no vaccines are currently licensed. Vaxart is developing an oral tableted NoV vaccine that induces both systemic and mucosal immune responses. Methods Two separate clinical studies were conducted to evaluate the safety and immunogenicity of an oral NoV vaccine and NoV infection. The first study investigated an oral tablet vaccine based on a recombinant adenovirus vector expressing NoV VP1 (rAd-VP1). In the second study, a controlled NoV infection (Norwalk virus) was performed using a strain isolated and purified from an infected subject. Serum and PBMCs were collected pre- and post-immunization/infection. Serum immune responses were assessed using IgG/IgA ELISAs and blocking titer (BT50) assays. Cellular immune responses were evaluated using antibody-secreting cell (ASC) assays to quantitate norovirus-specific B cells. Flow cytometry was used to analyze the phenotype of circulating B and T cells. Results The rAd-VP1 vaccine was well tolerated whereas most subjects (56%) in the controlled infection study had significant gastroenteritis 2–4 days post-inoculation. Subjects in cohorts vaccinated 28 days apart with 1 × 1010 or 1 × 1011 IUs showed the highest rises in serum IgG and IgA titers compared with those immunized 2 or 7 days apart with a 1 × 1010 IU vaccine dose. Subjects in the 1 × 1011 IU vaccine dose cohort had a 6-fold rise in serum IgA and 4-fold rise in BT50 titers, with mean IgA and IgG ASC values of 698 and 389 counts, respectively. In comparison, NoV-challenged subjects showed an average of 2,072 IgA and 886 IgG ASC counts. Remarkably, flow cytometry analysis revealed that activated B- and T-cell responses were similar post-vaccination and post-infection, with significant expansion of T follicular cells, plasmablasts, mucosal homing B cells, and preferential activation of IgA B cells. Conclusion The phenotype of activated B and T cells induced post-immunization was similar to that induced post-infection, suggesting that an oral vaccine can induce comparable adaptive immune responses without the substantial adverse clinical events that occur from natural infection. Future work in dose ranging will aide in the development of a safe and efficacious oral NoV vaccine. Disclosures All Authors: No reported Disclosures.

Background . Travellers' diarrhea (TD) remains one of the most common illnesses encountered by travellers to less developed areas of the world. Because bacterial pathogens such as enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli , Campylobacter spp. and Shigella spp. are the most frequent causes, antibiotics have been useful in both prevention and treatment of TD. Methods. Results of trials that assessed the use of medications for the prevention and treatment of TD were identified through PubMed and MEDLINE searches using search terms 'travellers' diarrhea', 'prevention' and 'treatment'. References of articles were also screened for additional relevant studies. Results. Prevention of TD with antibiotics has been recommended only under special circumstances. Doxycycline, trimethoprim-sulfamethoxazole, fluoroquinolones and rifaximin have been used for prevention, but at present the first three antibiotics may have limited use secondary to increasing resistance, leaving rifaximin as the only current option. Bismuth subsalicylate (BSS) (Pepto-Bismol tablets) is also an option for prophylaxis. Treatment with antibiotics has been recommended for moderate to severe TD. Azithromycin is the drug of choice, especially in Asia where Campylobacter is common. Fluoroquinolone antibiotics continue to be effectively used in Latin America and Africa where ETEC is predominant. BSS and loperamide (LOP) also are effective as standalone treatments. LOP may be used alone for treatment of mild TD or in conjunction with antibiotics for treatment of TD. Conclusions . Historically, antibiotic prophylaxis has not been routinely recommended and has been reserved for special circumstances such as when a traveller with an underlying illness cannot tolerate TD. Antibiotics with or without LOP have been useful in shortening the duration and severity of TD. Emerging antibiotic resistance, limited new antibiotic alternatives and faecal carriage of antibiotic-resistant bacteria by travellers may prompt a re-evaluation of classic recommendations for treatment and prevention of TD with antibiotics.

Background Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. Methods A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. Results In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. Conclusions Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. Clinical trials registration NCT01968733.

Background The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults. Methods Sixty subjects 18–49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration. Results Doses of 0.03–1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses ( p > 0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 μg), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release. Conclusions VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 μg doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation.

Background Enteropathogens cannot be identified in 40% to 50% of subjects with travelers’ diarrhea (TD). Methods We used polymerase chain reaction (PCR) methods to look for the presence of two bacterial causes of diarrhea in a large group of international travelers after failing to detect a pathogen by conventional tests. DNA was isolated from the diarrheal stool and subjected to PCR from 162 subjects from whom we earlier failed to identify a pathogen in a previous study and included 54 from Antigua, Guatemala, 39 from Guadalajara, Mexico, 29 from Kolkata, India, and 40 from Goa, India. Gene products for enterotoxigenic Escherichia coli (ETEC)—LT (heat‐labile enterotoxin) and ST (heat‐stable enterotoxin)—and diffusely adherent E coli (DAEC), afa/dr (Afa fimbrial and Dr nonfimbrial family of adhesins), were used. Results At least one gene product was identified in diarrhea stool samples of 47 of 162 (29%) subjects. ETEC virulence genes (LT, ST) were found in 34 (21%) samples studied, with rates of occurrence ranging from 8% in Goa to 39% for the samples from Guatemala ( p = 0.0006). A large number of ST‐only strains explained the high ETEC rate in Guatemala. DAEC afa / dr family of adhesions was identified in between 8 and 14% of the samples. Conclusions ETEC and DAEC were implicated in nearly one‐third of the subjects initially diagnosed as pathogen negative. Direct PCR results from stools are consistent with the previous assumption that most undiagnosed TD is bacterial in nature and also highlights the potential value that PCR can add to studies designed to evaluate treatment and preventive interventions for TD, including vaccines.

The seroconversion rates and geometric mean concentrations (GMC) of IgG anti-PA for stored sera from U.S. military personnel immunized 3, 4, and 6 times with the U.S. licensed anthrax vaccine adsorbed were studied. Anti-PA IgG concentrations were measured by ELISA. All 246 vaccinees had low but detectable pre-immunization anti-PA IgG (GMC 1.83 microg/mL). Three doses elicited a GMC of 59.92 microg/mL and a seroconversion rate of 85.3%, four doses elicited a GMC of 157.44 microg/mL and 67.9% and the sixth of 276.95 microg/mL and 45.5%, respectively. The forth dose elicited 100% seroconversion compared to the pre-immunization level. These results should facilitate comparison between different immunization schedules and new vaccines.

Background & Aims: Antimotility agents provide rapid temporary relief of acute diarrhea, whereas antibiotics slowly cure the illness. Thus, the combination of an antimotility agent and an antibiotic may provide greater therapeutic benefit than either drug alone. This study evaluated the efficacy and safety of rifaximin-loperamide in the treatment of travelers' diarrhea. Methods: Consenting adults with acute diarrhea (≥3 unformed stools in 24 hours with ≥1 symptom of enteric infection) were randomized to receive rifaximin 200 mg 3 times daily for 3 days; loperamide 4 mg initially followed by 2 mg after each unformed stool; or a combination of both drugs using the same dosing regimen. The primary end point was the median time from beginning therapy until passing the last unformed stool. Results: A total of 310 patients completed treatment with rifaximin (n = 102), loperamide (n = 104), or rifaximin-loperamide combination therapy (n = 104). The groups showed demographic similarity. Rifaximin and rifaximin-loperamide significantly reduced the median time until passage of the last unformed stool (32.5 ± 4.14 h and 27.3 ± 4.13 h, respectively) vs loperamide (69 ± 4.11 h; P = .0019). The mean number of unformed stools passed during illness was lower with rifaximin-loperamide (3.99 ± 4.28) compared with rifaximin (6.23 ± 6.90; P = .004) or loperamide alone (6.72 ± 6.93; P = .002). All treatments were well tolerated with a low incidence of adverse events. Conclusions: Rifaximin-loperamide therapy provided rapid symptomatic improvement and greater overall wellness compared with either agent alone.

Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea is recognized frequently in individuals who travel in developing countries around the world (4, 7, 8, 26, 29, 47) and is a major medical problem for military personnel deployed in these countries (26, 44, 45). Since strict personal hygiene and avoidance of local water and fresh and undercooked foods are recommendations with which travelers have difficulty complying, other means to reduce the ETEC attack rate must be considered. The use of short-term chemoprophylaxis and self-treatment for diarrhea are effective for travelers who are unwilling to accept even a short period of illness because of the serious impact it would have on their overall mission. However, the routine use of antimicrobial prophylaxis for the general traveler is not recommended because of the potential for associated adverse drug reactions and the potential to worsen the problem of antibiotic resistance of enteric bacteria (8, 25, 29, 43, 47). These factors make development of vaccines against ETEC a priority. ETEC strains produce a heat-labile toxin (LT) and/or a heat-stable toxin (ST) that are largely responsible for the symptoms of diarrhea. LT is immunogenic, but ST is a peptide and nonimmunogenic. ETEC strains also express antigenically distinct fimbriae collectively termed colonization factors (CF) (5). The most common CF include colonization factor antigen I (CFA/I), CFA/II, and CS6 (59). The protective role of the host immune response to specific antigens, such as CF or toxins, or of specific components of the immune system, such as secretory immunoglobulin A (IgA) in the intestine, is not well defined. Previous studies showed that CF were protective when volunteers were challenged with homologous strains of ETEC after they were either passively immunized with immunoglobulin with specific activity against CF (18, 54) or actively immunized or infected (9, 12, 14, 34, 36, 37, 55). Antitoxic protection based on an immune response to the heat-labile toxin was suggested based on field trials by Clemens et al. (6), who used the B subunit of whole-cell cholera vaccine and induced cross-protection against severe diarrhea caused by ETEC LT in immunized volunteers. The data described above suggest that an ETEC vaccine would have to include the most prevalent colonization factors and have antitoxin activity. Thus, vaccine development is complicated because a vaccine would require several CF, as well as LT, and would require tests of a number of vaccine prototypes. Because there is no established immunological correlate of protection against ETEC diarrhea, the efficacy of vaccine candidates that are developed is likely to be evaluated after a direct challenge to humans with ETEC. The use of human volunteers for studying immunity and the pathogenesis of ETEC infection after oral ingestion of strain B7A or {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407 has been described previously. ETEC strain B7A has been given to nearly 50 volunteers (9, 35, 36). B7A is a serotype O148:H28 strain and expresses LT, ST, CS6 (40), longus (19), and an unidentified adhesin (33). The most common symptoms in volunteers challenged with B7A were diarrhea, abdominal cramps, and malaise. Previous exposure to B7A protected volunteers from illness but not shedding (36). The level of serum antibody response to lipopolysaccharide varied from 20 to 90% (9, 36), but the immune response to other antigens has not been reported. E. coli strain {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407 is the most commonly used ETEC challenge strain and has been given to over 200 volunteers (2, 11-14, 18, 20, 35, 37, 54). It is a serotype O78:K80:H11 strain and was isolated from an adult with severe diarrhea in Dacca, Bangladesh (13). {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407 expresses the enterotoxins LT (50), ST (both STIa and STIb) (41), and CFA/I (13). It also expresses EAST (60), Tia (15), Tib (38), Leo (16), and EatA (46), which may play roles in virulence. The symptoms in volunteers challenged with {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407 were (from most frequent to least frequent) gurgling, abdominal cramps, diarrhea, anorexia, malaise, nausea or vomiting, headache, and fever. The diarrheal stool volumes ranged from 0.1 to 11 liters, and the time until onset of symptoms after challenge was typically 2 days. Nearly all challenged volunteers shed {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407, and shedding lasted approximately 1 week unless the volunteers were treated with antibiotics. Previous exposure to {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407 protected volunteers from illness but not shedding (37). Serum IgG responses to CFA/I, LT, and O78 were detected after challenge (13, 20, 35, 37, 49, 54) in many volunteers, but secretory IgA was assayed in only one study (35). Here we describe the first direct comparison of two well-established ETEC challenge models, B7A-induced clinical illness and {"type":"entrez-nucleotide","attrs":{"text":"H10407","term_id":"875229","term_text":"H10407"}}H10407-induced clinical illness. Clinical presentation, the effect of ciprofloxacin, and the immune responses to CS6, CFA/I, and LT are described below. The mucosal immune response was measured using antibody-secreting cells (ASC), and the systemic response from sera was measured using quantitative methods. This is the first time that the immune response to CS6 has been measured quantitatively after infection with wild-type ETEC.

Background Antibacterial drugs appear to be effective in shortening the illness of a majority of cases of travelers’ diarrhea. Methods This was a subanalysis from two randomized, double-blind, placebo-controlled trials in adult travelers with acute diarrhea treated with rifaximin 200 mg three times a day or placebo for 3 days. Efficacy was assessed by the interval beginning with the first dose of medication and ending with the last unformed stool passed after becoming well [time to last unformed stool (TLUS)]; number of unformed stools passed; percent with clinical improvement; and incidence of wellness achieved. Results Stool pathogens were not identified in pretreatment samples in 122 of 322 (38%) patients and 106 of 230 (46%) randomized to rifaximin and placebo, respectively. Among pathogen-negative patients, rifaximin was more effective than placebo for median TLUS (33 vs 68 h, p < 0.005), mean number of unformed stools passed (6.5 vs 8.6, p < 0.0001), and clinical wellness (77% vs 61%, p = 0.01). The adverse-event profiles between rifaximin and placebo were similar. Conclusions More than one third of patients with travelers’ diarrhea had pathogen-negative illness. Rifaximin was effective in treating the illness without associated side effects. These results are consistent with the hypothesis that undetected bacterial pathogens are the most likely cause of travelers’ diarrhea without definable cause.

Evidence has associated chronic infection by Helicobacter pylori with chronic gastritis, low gastric acid production and an increased risk of life-threatening cholera. However, the relationship of specific patterns of histological damage in the gastric mucosa associated with H. pylori infection and the occurrence of cholera has not been described. The purpose of this study was to compare the gastric pH and histopathological findings in gastric biopsies taken from patients with severe diarrhoeal disease due to Vibrio cholerae with those taken from a control (cholera-negative) population. Thirty-five H. pylori-positive patients who had severe dehydration from culture-confirmed cholera (cases) and 40 patients with H. pylori but with no history of cholera (controls) were recruited. Gastric pH was measured and multiple biopsies were taken from the gastric antrum and body for histopathological examination. The results revealed that patients with severe cholera had a significantly higher prevalence of hypochlorhydria at endoscopy compared with controls. Furthermore, cases had significantly more chronic atrophic gastritis (45.7% vs. 12.5%; P = 0.002) and intestinal metaplasia (37.1% vs. 2.5%; P < 0.01) in the gastric body than controls. Our findings suggest that the nature and location of these gastric lesions may predispose a subset of H. pylori-infected individuals to severe disease by V. cholerae.

Rifaximin was compared with placebo and ciprofloxacin for treatment of travelers' diarrhea in a randomized, double-blind clinical trial. Adult travelers (N = 399) consulting travel clinics in Mexico, Guatemala, and India were randomized to receive rifaximin 200 mg three times a day, ciprofloxacin (500 mg two times a day and placebo once a day), or placebo three times a day for 3 days. Patients recorded in daily diaries the time and consistency of each stool and documented symptoms for 5 days after treatment. Stool samples were collected for microbiologic evaluations before and after treatment. The median time to last unformed stool (TLUS) in the rifaximin group (32.0 hours) was less than one half that in the placebo group (65.5 hours; P = 0.001; risk ratio 1.6; 95% confidence interval 1.2, 2.2; primary efficacy endpoint). The median TLUS in the ciprofloxacin group was 28.8 hours (P = 0.0003 versus placebo; P = 0.35 versus rifaximin). Rifaximin was less effective than ciprofloxacin for invasive intestinal bacterial pathogens. Oral rifaximin is a safe and effective treatment of travelers' diarrhea caused by noninvasive pathogens.

Salmonella enterica serovar Typhi strains with mutations in the Salmonella pathogenicity island-2 (SPI-2) may represent an effective strategy for human vaccine development, and a vectoring system for heterologous antigens. S. Typhi (Ty2 aroC-ssaV-) M01ZH09 is an attenuated, live, oral typhoid vaccine harboring defined deletion mutations in ssaV, which encodes an integral component in the SPI-2 type III secretion system (TTSS), as well as a mutation in an aromatic biosynthetic pathway needed for bacterial growth in vivo (aroC). SPI-2 mutant vaccines have yet to be evaluated in a large, randomized human trial. A simplified or single-oral dose oral typhoid vaccine using the SPI-2 strategy would offer significant advantages over the currently licensed typhoid vaccines. We performed a double-blinded, placebo-controlled, dose-escalating clinical trial in 60 healthy adult volunteers to determine the tolerability and immunogenicity of a single dose of M01ZH09. Three groups of 20 healthy adult volunteers were enrolled; 16 in each group received a single oral dose of the freeze-dried vaccine at 5 x 10(7), 5 x 10(8) or 5 x 10(9)CFU in a bicarbonate buffer. Four volunteers in each cohort received placebo in the same buffer. Adverse events were infrequent and not statistically different between vaccine and placebo recipients, although two subjects in the mid-range dose and three subjects in the highest dose had temperature measurements >37.5 degrees C. No blood or urine cultures were positive for M01ZH09, and fecal shedding was brief. The immune response was dose-related; the highest vaccine dose (5 x 10(9)CFU) was the most immunogenic. All tested subjects receiving the highest dose had a significant ASC response (mean 118 spots/10(6) cells). A >or=4-fold increase in antibody titer for S. Typhi LPS or flagellin was detected in 75% of volunteers in the highest-dose cohort by day 28. The SPI-2 mutant vaccine, M01ZH09, is a promising typhoid vaccine candidate and deserves further study as a vectoring system for heterologous vaccine antigens.

The occurrence and distribution of Vibrio cholerae in sea water and plankton along the coast of Peru were studied from October 1997 to June 2000, and included the 1997-98 El Nino event. Samples were collected at four sites in coastal waters off Peru at monthly intervals. Of 178 samples collected and tested, V. cholerae O1 was cultured from 10 (5.6%) samples, and V. cholerae O1 was detected by direct fluorescent antibody assay in 26 out of 159 samples tested (16.4%). Based on the number of cholera cases reported in Peru from 1997 to 2000, a significant correlation was observed between cholera incidence and elevated sea surface temperature (SST) along the coast of Peru (P < 0.001). From the results of this study, coastal sea water and zooplankton are concluded to be a reservoir for V. cholerae in Peru. The climate-cholera relationship observed for the 1997-98 El Nino year suggests that an early warning system for cholera risk can be established for Peru and neighbouring Latin American countries.

To characterize posttreatment recurrence of Helicobacter pylori in Peru, 192 adults with H. pylori-positive gastric biopsy specimens were monitored by (14)C-Urea breath test, after eradication of H. pylori by use of amoxicillin, clarithromycin, and omeprazole. The cumulative risk of recurrence at 18 months was 30.3% (95% confidence interval, 21.4%-39.3%). Randomly amplified polymorphic DNA patterns and DNA sequence data established that, among 28 pairs of H. pylori isolates from pretreatment and recurrent infections, 6 (21%) were genetically similar, suggesting recrudescence of the previous infection, and 22 (79%) were different, suggesting reinfection with a new strain that differed from that involved in the initial infection. Eating mainly outside of the home was a risk factor for infection with a new strain (adjusted relative risk [RR], 5.07), whereas older age was a protective factor (adjusted RR, 0.20). Although an increase in the anti-H. pylori IgG antibody titer corresponded to recurrence, pretreatment and recurrent infections were similar with respect to quantitative culture colony counts and histologic characteristics, suggesting that neither prior eradication nor the memory immune response measurably alters the risk or burden of recurrent infection. Although eradication with antibiotics was successful, the high rate of reinfection suggests that treatment is unlikely to have a lasting public health effect in this setting.

Campylobacter jejuni is a major cause of pediatric diarrhea in developing countries-free-ranging chickens are presumed to be a common source. Campylobacter strains from monthly surveillance and diarrhea cases were compared by means of restriction-fragment length polymorphism (RFLP), rapid amplified polymorphic DNA, and Lior serotyping. RFLP analysis of 156 human and 682 avian strains demonstrated identical strains in chickens and humans in 29 (70.7%) of 41 families, and 35%-39% of human isolates from diarrhea and nondiarrhea cases were identical to a household chicken isolate. Isolation of the same RFLP type from a household chicken and a human within 1 month was highly protective against diarrhea (odds ratio, 0.07; P

We conducted a phase I trial with healthy adults to evaluate WRSS1, a live, oral Δ virG Shigella sonnei vaccine candidate. In a double-blind, randomized, dose-escalating fashion, inpatient volunteers received a single dose of either placebo ( n = 7) or vaccine ( n = 27) at 3 × 10 3 CFU (group 1), 3 × 10 4 CFU (group 2), 3 × 10 5 CFU (group 3), or 3 × 10 6 CFU (group 4). The vaccine was generally well tolerated, although a low-grade fever or mild diarrhea occurred in six (22%) of the vaccine recipients. WRSS1 was recovered from the stools of 50 to 100% of the vaccinees in each group. The geometric mean peak anti-lipopolysaccharide responses in groups 1 to 4, respectively, were 99, 39, 278, and 233 for immunoglobulin (IgA) antibody-secreting cell counts; 401, 201, 533, and 284 for serum reciprocal IgG titers; and 25, 3, 489, and 1,092 for fecal IgA reciprocal titers. Postvaccination increases in gamma interferon production in response to Shigella antigens occurred in some volunteers. We conclude that WRSS1 vaccine is remarkably immunogenic in doses ranging from 10 3 to 10 6 CFU but elicits clinical reactions that must be assessed in further volunteer trials.

Transcutaneous immunization (TCI) is a new method for vaccine delivery that has been shown to induce immunity relevant to enteric disease vaccines. We evaluated the clinical safety and immunogenicity of a recombinant subunit vaccine against enterotoxigenicEscherichia coli(ETEC) delivered by TCI. Adult volunteers received patches containing the recombinant ETEC colonization factor CS6, either with heat-labile enterotoxin (LT) or patches containing CS6 alone. The vaccine was administered at 0, 1, and 3 months, and serum antibodies and antibody-secreting cells (ASCs) were assessed. Among the 26 volunteers that completed the trial, there were no responses to CS6 in the absence of LT. In the groups receiving both CS6 and LT, 68 and 53% were found to have serum anti-CS6 immunoglobulin G (IgG) and IgA, respectively; 37 and 42% had IgG and IgA anti-CS6 ASCs. All of the volunteers receiving LT had anti-LT IgG, and 90% had serum anti-LT IgA; 79 and 37% had anti-LT IgG and IgA ASCs. Delayed-type hypersensitivity (DTH), suggesting T-cell responses, was seen in 14 of 19 volunteers receiving LT and CS6; no DTH was seen in subjects receiving CS6 alone. This study demonstrated that protein antigens delivered by a simple patch could induce significant systemic immune responses but only in the presence of an adjuvant such as LT. The data suggest that an ETEC vaccine for travelers delivered by a patch may be a viable approach worthy of further evaluation.

Peru-15 is a live attenuated oral vaccine derived from a Vibrio cholerae O1 El Tor Inaba strain by a series of deletions and modifications, including deletion of the entire CT genetic element. Peru-15 is also a stable, motility-defective strain and is unable to recombine with homologous DNA. We wished to determine whether a single oral dose of Peru-15 was safe and immunogenic and whether it would provide significant protection against moderate and severe diarrhea in a randomized, double-blind, placebo-controlled human volunteer cholera challenge model. A total of 59 volunteers were randomly allocated to groups to receive either 2 × 10 8 CFU of reconstituted, lyophilized Peru-15 vaccine diluted in CeraVacx buffer or placebo (CeraVacx buffer alone). Approximately 3 months after vaccination, 36 of these volunteers were challenged with approximately 10 5 CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Among vaccinees, 98% showed at least a fourfold increase in vibriocidal antibody titers. After challenge, 5 (42%) of the 12 placebo recipients and none (0%) of the 24 vaccinees had moderate or severe diarrhea (≥3,000 g of diarrheal stool) ( P = 0.002; protective efficacy, 100%; lower one-sided 95% confidence limit, 75%). A total of 7 (58%) of the 12 placebo recipients and 1 (4%) of the 24 vaccinees had any diarrhea ( P < 0.001; protective efficacy, 93%; lower one-sided 95% confidence limit, 62%). The total number of diarrheal stools, weight of diarrheal stools, incidence of fever, and peak stool V. cholerae excretion among vaccinees were all significantly lower than in placebo recipients. Peru-15 is a well-tolerated and immunogenic oral cholera vaccine that affords protective efficacy against life-threatening cholera diarrhea in a human volunteer challenge model. This vaccine may therefore be a safe and effective tool to prevent cholera in travelers and is a strong candidate for further evaluation to prevent cholera in an area where cholera is endemic.

Accurately assessing mucosal immune responses to candidate vaccines remains a technical challenge. ELISPOT is widely used as a surrogate of mucosal immune response by directly enumerating circulating antibody secreting cells (ASCs), while antibody in lymphocyte supernatant (ALS) titers the total amount of antibody secreted by ASC ex vivo using ELISA. ALS is more practical than ELISPOT because the ASC supernatant is frozen for ELISA that can be conducted at any time, with any antigen, and in any laboratory. We compared IgA and IgG responses to serotype-specific Shigella LPS using ELISPOT and ALS in subjects following vaccination or infection with Shigella. ALS results correlated well with ELISPOT results, and the ALS method was both sensitive and specific for the detection of antibody responses against Shigella LPS. Based on these observations, the ALS assay is a practical and flexible alternative to ELISPOT for measuring mucosal IgA responses to Shigella LPS antigen.

An outbreak of acute gastroenteritis involving 249 persons, 32% of whom were hospitalized, occurred on a U.S. Army installation in 1990. Campylobacter jejuni was isolated from 81 of 163 (50%) persons cultured. Seventeen isolates of C. jejuni available for serotyping were Lior serotype 5. The outbreak remained restricted to one recruit barracks area and adjacent Junior Reserve Officer Training Corps cadet barracks. Infection of sequential cohorts of recruits over an interval of 3 weeks suggested a continuing or intermittent common source. Contaminated food was not implicated because affected persons ate at separate dining facilities and other facilities with the same food sources had no associated illnesses. There was a strong association between the amount of water consumed by recruits and risk of diarrhea (chi-square test for trend, p0.001). Samples of drinking water collected in the affected area had no residual chlorine and when cultured yielded greater than 200 colonies of coliform bacteria per 100 mL of water sampled. Although Campylobacter was not isolated from water, living and dead birds were found in an elevated water storage tank providing drinking water to the affected area. This and other similar outbreaks indicate that contamination of water storage tanks can lead to large outbreaks of Campylobacter enteritis.

Epidemiologic and experimental data provide evidence that a critical level of serum immunoglobulin G (IgG) antibodies to the surface polysaccharide ofVibrio choleraeO1 (lipopolysaccharide) and ofVibrio choleraeO139 (capsular polysaccharide [CPS]) is associated with immunity to the homologous pathogen. The immunogenicity of polysaccharides, especially in infants, may be enhanced by their covalent attachment to proteins (conjugates). Two synthetic schemes, involving 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) as activating agents, were adapted to prepare four conjugates ofV. choleraeO139 CPS with the recombinant diphtheria toxin mutant, CRMH21G. Adipic acid dihydrazide was used as a linker. When injected subcutaneously into young outbred mice by a clinically relevant dose and schedule, these conjugates elicited serum CPS antibodies of the IgG and IgM classes with vibriocidal activity to strains of capsulatedV. choleraeO139. Treatment of these sera with 2-mercaptoethanol (2-ME) reduced, but did not eliminate, their vibriocidal activity. These results indicate that the conjugates elicited IgG with vibriocidal activity. Conjugates also elicited high levels of serum diphtheria toxin IgG. Convalescent sera from 20 cholera patients infected withV. choleraeO139 had vibriocidal titers ranging from 100 to 3,200: absorption with the CPS reduced the vibriocidal titer of all sera to ≤50. Treatment with 2-ME reduced the titers of 17 of 20 patients to ≤50. These data show that, like infection withV. choleraeO1, infection withV. choleraeO139 induces vibriocidal antibodies specific to the surface polysaccharide of this bacterium (CPS) that are mostly of IgM class. Based on these data, clinical trials with theV. choleraeO139 CPS conjugates with recombinant diphtheria toxin are planned.

PCR techniques applied to diarrheal stools reliably diagnose Shigella and enteroinvasive Escherichia coli (EIEC) infections. Identification of PCR products using agarose gel electrophoresis (AGE) and hybridization with DNA probes has several shortcomings. Automated methods of identifying PCR products that process larger numbers of specimens can facilitate epidemiologic studies and standardize results. In this study, we used ELISA following PCR to detect ipaH gene sequences of Shigella and EIEC from 89 diarrheal stools. Results of ELISA were compared with AGE with and without DNA probe, and with culture. Two specimen preparation methods were compared as well: boiling/centrifugation, and purification with silicon dioxide (SiO(2)). Both PCR product-detection methods identified significantly more infections than did culture. PCR-ELISA detected significantly more infections than PCR-AGE when processed using SiO2 (P = 0.014). PCR-ELISA allows screening of larger numbers of specimens, automates test results, and avoids use of mutagenic reagents. PCR-ELISA is faster than PCR-AGE when testing large numbers of specimens, although not when testing small numbers of specimens.

The protective efficacy of an oral inactivated whole cell Vibrio cholerae plus recombinant B subunit cholera vaccine was determined against El Tor cholera among Peruvian children and adults (2-65 years old) in a randomized, double-blind manner. Study subjects received 2 doses of vaccine or placebo 2 weeks apart, followed by a booster dose 10 months later. Surveillance for cholera was performed actively, with 2 visits per week to each household, and passively, at a local hospital. Stool samples were collected during diarrhea episodes and were cultured for V. cholerae. A total of 17,799 persons received 2 doses of vaccine or placebo, and 14,997 of these persons received the booster dose. After 2 doses (first surveillance period), V. cholerae biotype O1 was isolated from 17 vaccinees and 16 placebo recipients, demonstrating vaccine efficacy (VE) of -4%. After 3 doses (second surveillance period), V. cholerae O1 was isolated from 13 vaccinees and 32 placebo recipients, demonstrating VE of 61% (95% confidence interval ?CI, 28%-79%). In the second surveillance period, the VE for illness requiring hospitalization was 82% (95% CI, 27%-96%). VE was also higher for persons >15 years old (VE, 72%; 95% CI, 28%-89%).

To assess the safety, immunogenicity, and lot stability of the whole cell/recombinant B subunit cholera vaccine, 2 lots manufactured in June 1991 and February 1992 were tested in January 1995. Two oral doses of vaccine or placebo given 2 weeks apart were given with buffer to 216 Peruvian adults and children. Symptoms were elicited for 3 days after each dose. Serum and plasma specimens obtained from each volunteer before vaccination and 10-14 days after the second dose were tested for vibriocidal and anti-cholera toxin antibodies. The vaccine was well-tolerated. Nearly half of the 100 vaccinees had pre-vaccination vibriocidal titersor = 1:40. Elevated titers were observed in 22% of 37 children 2-5 years of age compared with 66% of 63 vaccinees 6-65 years (P0.001). Aor =2-fold serum vibriocidal response was observed in 55% of 100 vaccinees and 6% of 32 placebo recipients. An elevated pre-vaccination titer (or =1:40) did not change the proportion of vaccinees who responded with aor =2-fold increase in vibriocidal titer (51% versus 59%, difference not significant), but did change the proportion responding with aor =4-fold increase (41% versus 22%; P0.05). The vibriocidal seroconversion rate was lowest in children 2-5 years old despite low pre-vaccination titers. Two-fold or greater serum antitoxic responses in IgA and IgG were observed in90% of the vaccinees;or =4-fold responses were seen in 65-70% of the vaccinees with a 6-8-fold increase over baseline. Plasma specimens were as good as sera for determining anti-toxic antibodies by ELISA, but were less satisfactory for determining vibriocidal antibody titers.

The genetic and functional status of the p53 gene may be an important factor in guiding therapeutic strategies for patients with cancer. The purpose of this study was to determine whether p53 immunohistochemistry (IHC) accurately reflects the mutational status of the p53 gene and to determine whether p53 IHC independently predicts tumor responsiveness to radiation therapy for patients with HNSCC. p53 IHC was performed using the monoclonal antibody DO7 on tumors from 85 patients with HNSCC treated with primary or adjuvant radiation. The p53 status in all of these tumors was previously assessed by direct sequence analysis of exons 5 through 9: 49 tumors were p53 wild-type, and 36 harbored p53 gene mutations. All patients were well characterized with respect to locoregional recurrence, distant spread, and survival. Positive p53 staining was observed in 53 of the 85 cases (62%). Only 27 (51%) of these 53 IHC-positive cases harbored gene mutations in exons 5 through 9; 23 (72%) of the 32 IHC-negative cases did not harbor mutations. The overall correlation rate between IHC and sequencing was 59% (P < .04, chi2). Discordant results were observed for 35 (41%) cases, including 26 IHC-positive cases and 9 IHC-negative cases. In 7 of 9 cases, false-negative staining was due to a nonsense or splice-site mutation. p53 IHC was not predictive of overall survival (P = .37) or disease-free survival (P = .95). In a sizable number of cases, p53 IHC does not reflect the mutational status of the p53 gene. Specific types of alterations (eg, truncating mutations) and other factors may contribute to this poor correlation. Moreover, p53 IHC does not appear to be an independent predictor of tumor responsiveness to radiation in patients with HNSCC.

Rifaximin is an oral antibiotic indicated for treatment of traveler's diarrhea. Rifaximin pharmacokinetics were evaluated in individuals challenged with Shigella flexneri . Peak plasma rifaximin concentrations were low after nine consecutive doses, and no accumulation was observed. Rifaximin serum levels were minimal and similar to those previously reported in studies of healthy volunteers.

Lactobacillus GG (L-GG), an acid- and bile-resistant strain that colonizes the intestinal mucosa, has been used to manage diarrhea in children. Our objective was to evaluate the prophylactic use of L-GG to prevent diarrhea in children at high risk from a developing country in a randomized, placebo-controlled trial.Two hundred four undernourished children 6 to 24 months old from an indigent peri-urban Peruvian town received either L-GG or placebo in flavored gelatin once daily, 6 days a week, for 15 months. Episodes of diarrhea were documented by daily home visits, and diagnostic studies were done in a subset of cases. Recovery of L-GG in stool from subjects and from family contacts was examined.Subjects in the L-GG group had significantly fewer episodes of diarrhea (5.21 episodes diarrhea/child/year ['ecy'] L-GG group, 6. 02 ecy placebo group; P =.028). The decreased incidence of diarrhea in the L-GG group was greatest in the 18- to 29-month age group (P =. 004) and was largely limited to nonbreastfed children (Breastfed: 6. 59 ecy L-GG, 6.32 ecy placebo, P =.7; Nonbreastfed: 4.69 ecy L-GG, 5. 86 ecy placebo, P =.005). The duration of diarrhea episodes and the causes of diarrhea were similar in both groups, except adenovirus was more common in the placebo group.L-GG supplementation may be useful as a prophylactic measure to control diarrhea in undernourished children at increased risk, especially nonbreastfed children in the toddler age group.This article features a placebo-controlled trial of Lactobacillus GG (L-GG) for diarrhea prevention in undernourished children in Peru. The purpose of the study was to evaluate the use of L-GG as prophylactic treatment for diarrhea. The study population included 204 undernourished children aged 6-24 months, 99 of which were on L-GG and 105 on placebo. Subjects were followed by daily home visits to document diarrhea episodes and diagnostic studies were conducted. Results revealed that children receiving L-GG experienced fewer episodes of diarrhea, which were more pronounced among 18-29 month old children and largely limited to non-breast-fed children. Moreover, the duration of diarrhea episodes and its causes were similar in both groups, except that adenovirus was detected more frequently in the placebo group. In conclusion, L-GG supplementation would decrease diarrhea incidence in high-risk children.

Diarrhea and wasting are among the most debilitating and deadly manifestations of AIDS, yet only limited information is available regarding the etiology, clinical consequences, and immunologic effects of infection with diarrheal agents. Peruvian AIDS patients presenting with and without diarrhea were followed prospectively to examine the relations among diarrheal pathogens, clinical presentations, CD4 lymphocyte count, weight loss, and survival. Patients with chronic diarrhea had lower CD4 lymphocyte counts (P = .001) and lost more weight (P < .001). Weight loss and a decreased CD4 lymphocyte count were associated with increased mortality (P = .011 and P = .003, respectively). Mean CD4 lymphocyte count varied significantly by diarrheal agent. Clostridium difficile was the most prevalent pathogen and was associated with significantly increased mortality before and after adjustment for coinfection, length of follow-up, CD4 lymphocyte count, and weight loss (P = .006). C. difficile may be a more important and more prevalent etiologic agent in AIDS than previously recognized and may represent a preventable cause of death in patients with immunosuppression.

To determine whether military personnel deployed outside the United States are at increased risk of Helicobacter pylori infection, we evaluated U.S. Army personnel who served in the Persian Gulf from August 1990 to April 1991. Of 204 subjects from whom paired predeployment and postdeployment serum specimens were obtained, 76 (37%) were seropositive for IgG antibody to H. pylori before deployment by an enzyme-linked immunosorbent assay. Of the 111 initially seronegative subjects evaluated before and after a 7.5-month deployment, five (4.5%) seroconverted. The calculated annual seroconversion rate was 7.3%. In a postdeployment questionnaire, 62% of soldiers reported an episode of diarrhea while deployed, but there was not an increased rate of diarrhea or upper gastrointestinal symptoms in soldiers who were infected before deployment or in those who seroconverted. These data suggest that the risk of H. pylori infection increases during long-term deployment and that acute infection is not distinguishable from other gastrointestinal illnesses encountered during deployment.

To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a single-dose, oral cholera vaccine was developed by combining two live, attenuated vaccine strains, CVD 103-HgR (classical, Inaba) and CVD 111 (El Tor, Ogawa). The vaccines were formulated in a double-chamber sachet; one chamber contained lyophilized bacteria, and the other contained buffer. In the first study, 23 U.S. adult volunteers received CVD 103-HgR at 10(8) CFU plus CVD 111 at 10(8), 10(7), or 10(6) CFU, CVD 111 alone at 10(7) CFU, or placebo. In the second study, 275 Peruvian adults were randomized to receive CVD 103-HgR at 10(9) CFU plus CVD 111 at 10(9) or 10(8) CFU, CVD 111 alone at 10(9) CFU, CVD 103-HgR alone at 10(9) CFU, or placebo. Three of 15 U.S. volunteers who received CVD 111 at 10(7) or 10(8) CFU developed mild diarrhea, compared to none of 4 who received CVD 111 at 10(6) CFU and 1 of 4 who received placebo. Twelve (63%) of 19 vaccine recipients shed the El Tor vaccine strain. All but one volunteer developed significant Ogawa and Inaba vibriocidal antibody titers. Volunteers who received CVD 111 at 10(7) CFU had geometric mean Ogawa titers four to five times higher than those of volunteers who received the lower dose. In the second study, all dosage regimens were well tolerated in Peruvians. About 20% of volunteers who received CVD 111 at the high dose excreted the El Tor organism, compared to 7% in the low-dose group. CVD 111 was detected in the stools of two placebo recipients, neither of whom had symptoms or seroconverted. In all vaccine groups, 69 to 76% developed fourfold rises in Inaba vibriocidal antibodies. Among those who received the bivalent vaccine, 53 to 75% also developed significant rises in Ogawa vibriocidal antibodies. We conclude that it is feasible to produce a single-dose, oral bivalent vaccine that is safe and immunogenic against both biotypes (El Tor and classical) and both serotypes (Inaba and Ogawa) of cholera for populations in both developed and developing parts of the world.

Helicobacter pylori strains may be either cagA+ or cagA−, and in logitudinal studies, infection with a cagA+ strain has been associated with increased risk for the development of atrophic gastritis and cancer of the distal stomach. We sought to determine the relative proportion of strains producing CagA in different geographic locales, and the extent to which CagA seroprevalence varied in countries with different gastric and esophageal cancer rates. Using an enzyme-linked immunosorbent assay (ELISA) to detect serum IgG to CagA, we examined sera from 468 asymptomatic H. pylori-infected adults from Canada, Peru, China, Thailand, The Netherlands and 3 different ethnic groups in New Zealand. The CagA seroprevalence in Peru and Thailand (82.2% and 78.8%, respectively) were each substantially higher than for the Chinese (37.9%), Canadian (41.9%), Dutch (39.0%) and New Zealand (28.2%) subjects, but within each population, rates were relatively constant across gender and age groups. Reported gastric but not esophageal cancer rates for the 8 studied populations were significantly associated with H. pylori seroprevalence. Variation in CagA positivity rates was not significantly associated with variation in either gastric or esophageal cancer rates. Our data suggest that CagA seroprevalence is not the major factor influencing gastric cancer rates. Int. J. Cancer 72:453–456, 1997. © 1997 Wiley-Liss, Inc.