Feasibility and acceptability of a whole-school social-marketing intervention to prevent unintended teenage pregnancies and promote sexual health: evidence for progression from a pilot to a phase III randomised trial in English secondary schools.

BACKGROUND: Reducing unintended teenage pregnancy and promoting adolescent sexual health remains a priority in England. Both whole-school and social-marketing interventions are promising approaches to addressing these aims. However, such interventions have not been rigorously trialled in the UK and it is unclear if they are appropriate for delivery in English secondary schools. We developed and pilot trialled Positive Choices, a new whole-school social marketing intervention to address unintended teenage pregnancy and promote sexual health. Our aim was to assess the feasibility and acceptability of the intervention and trial methods in English secondary schools against pre-defined progression criteria (relating to randomisation, survey follow-up, intervention fidelity and acceptability and linkage to birth/abortion records) prior to carrying out a phase III trial of effectiveness and cost-effectiveness. METHODS: Pilot RCT with integral process evaluation involving four intervention and two control schools in south-east England. The intervention comprised a student needs survey; a student/staff-led school health promotion council; a classroom curriculum for year-9 students (aged 13-14); whole-school student-led social-marketing activities; parent information; and a review of local and school-based sexual health services. Baseline surveys were conducted with year 8 (aged 12-13) in June 2018. Follow-up surveys were completed 12 months later. Process evaluation data included audio recording of staff training, surveys of trained staff, staff log books and researcher observations of intervention activities. Survey data from female students were linked to records of births and abortions to assess the feasibility of these constituting a phase III primary outcome. RESULTS: All six schools were successfully randomised and retained in the trial. Response rates to the survey were above 80% in both arms at both baseline and follow-up. With the exception of the parent materials, the fidelity target for implementation of essential elements in three out of four schools was achieved. Student surveys indicated 80% acceptability among those who reported awareness of the programme and interviews with staff suggested strong acceptability. Linkage to birth/abortion records was feasible although none occurred among participants. CONCLUSIONS: The criteria for progression to a phase III trial were met. Our data suggest that a whole-school social-marketing approach may be appropriate for topics that are clearly prioritised by schools. A phase III trial of this intervention is now warranted to establish effectiveness and cost-effectiveness. Births and terminations are not an appropriate primary outcome measure for such a trial. TRIAL REGISTRATION: ISRCTN65324176.

Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine.

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.

Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Degree of value alignment - a grounded theory of rural nurse resignations.

INTRODUCTION: The shortage of nurses willing to work in rural Australian healthcare settings continues to worsen. Australian rural areas have a lower retention rate of nurses than metropolitan counterparts, with more remote communities experiencing an even higher turnover of nursing staff. When retention rates are lower, patient outcomes are known to be poorer. This article reports a study that sought to explore the reasons why registered nurses resign from rural hospitals in the state of New South Wales, Australia. METHODS: Using grounded theory methods, this study explored the reasons why registered nurses resigned from New South Wales rural hospitals. Data were collected from 12 participants using semi-structured interviews; each participant was a registered nurse who had resigned from a rural hospital. Nurses who had resigned due to retirement, relocation or maternity leave were excluded. Interviews were transcribed verbatim and imported into NVivo software. The constant comparative method of data collection and analysis was followed until a core category emerged. RESULTS: Nurses resigned from rural hospitals when their personal value of how nursing should occur conflicted with the hospital's organisational values driving the practice of nursing. These conflicting values led to a change in the degree of value alignment between the nurse and hospital. The degree of value alignment occurred in three dynamic stages that nurses moved through prior to resigning. The first stage, sharing values, was a time when a nurse and a hospital shared similar values. The second stage was conceding values where, due to perceived changes in a hospital's values, a nurse felt that patient care became compromised and this led to a divergence of values. The final stage was resigning, a stage where a nurse 'gave up' as they felt that their professional integrity was severely compromised. The findings revealed that when a nurse and organisational values were not aligned, conflict was created for a nurse about how they could perform nursing that aligned with their internalised professional values and integrity. Resignation occurred when nurses were unable to realign their personal values to changed organisational values - the organisational values changed due to rural area health service restructures, centralisation of budgets and resources, cumbersome hierarchies and management structures that inhibited communication and decision making, out-dated and ineffective operating systems, insufficient and inexperienced staff, bullying, and a lack of connectedness and shared vision. CONCLUSIONS: To fully comprehend rural nurse resignations, this study identified three stages that nurses move through prior to resignation. Effective retention strategies for the nursing workforce should address contributors to a decrease in value alignment and work towards encouraging the coalescence of nurses' and hospitals' values. It is imperative that strategies enable nurses to provide high quality patient care and promote a sense of connectedness and a shared vision between nurse and hospital. Senior managers need to have clear ways to articulate and imbue organisational values and be explicit in how these values accommodate nurses' values. Ward-level nurse managers have a significant responsibility to ensure that a hospital's values (both explicit and implicit) are incorporated into ward culture.

Traumatic injuries associated with horseback riding.

BACKGROUND: According to the Center for Disease Control and Prevention (CDC), an estimated 30 million people ride horses each year in the United States. Horseback riding related injuries are common, with an estimated 50,000 emergency room visits annually. The popularity of recreational horseback riding has increased in South Florida and the incidence of associated traumatic injuries is a reflection of this. MATERIAL AND METHODS: Retrospective review of patients admitted to a state designated Level I trauma center that sustained horseback riding associated injuries between January 2000 and December 2003. Information extracted from the Trauma Center's data base included demographics, mechanism of injury and toxicology screening. RESULTS: During the review period, twenty-seven patients were identified. There were 12 men and 15 women. The average age was 36 years. The injuries occurred during pleasure riding in 23 patients and thoroughbred related activities in 4 patients. Multiple severe injuries were common and documented in 24 patients. All patients required hospitalization with an average stay of 5 days. Five patients had a positive toxicology screen on admission. No deaths were documented in this review. CONCLUSION: Horseback riding related injuries tends to be serious. Alcohol and recreational drugs may contribute to exacerbate the extent of these injuries. The use of proper protective equipment, instructions for safe riding, and discouraging drug and alcohol use during riding activities should be emphasized.

Evaluation of a commercial latex agglutination assay for serological diagnosis of leptospirosis.

Leptospirosis is a febrile zoonosis of worldwide distribution. A latex agglutination assay was evaluated in two studies, the first using a panel of well-characterized sera from patients with leptospirosis and from patients with other disease states and the second, a prospective hospital-based study, evaluating sera from 186 consecutive patients admitted to hospital with acute febrile illness. The confirmed leptospirosis serum panel included paired acute- and convalescent-phase specimens from 40 cases, of which 34 gave positive latex tests (case sensitivity, 85%; 95% confidence interval [95% CI], 70 to 94%). The other diseases represented in the panel of 112 specimens from nonleptospirosis patients included autoimmune diseases, brucellosis, dengue, melioidosis, malaria, syphilis, toxoplasmosis, viral hepatitis, and a number of other viral infections. The specificity of latex agglutination using this panel was 81% (95% CI, 73 to 87%). Among the patients with acute febrile illness, there were 25 cases of leptospirosis and 161 patients with other diagnoses. The sensitivity and specificity of latex agglutination in this group were 88% (95% CI, 72 to 97%) and 98% (95% CI, 95 to 100%), respectively. In this evaluation, the two distinct groups of specimens gave similar results for sensitivity, but specificity was different in each study. The sensitivity and specificity observed for the hospital study were similar to those obtained in evaluations of other rapid tests in the same population. The results of this study suggest that multiple evaluations of new diagnostic assays should be performed, because performance characteristics may vary in different populations.

Leptospirosis among patients presenting with dengue-like illness in Puerto Rico.

Leptospirosis is difficult to distinguish from dengue fever without laboratory confirmation. Sporadic cases/clusters of leptospirosis occur in Puerto Rico, but surveillance is passive and laboratory confirmation is rare. We tested for leptospirosis using an IgM ELISA on sera testing negative for dengue virus IgM antibody and conducted a case-control study assessing risk factors for leptospirosis, comparing clinical/laboratory findings between leptospirosis (case-patients) and dengue patients (controls). Among 730 dengue-negative sera, 36 (5%) were positive for leptospirosis. We performed post mortem testing for leptospirosis on 12 available specimens from suspected dengue-related fatalities; 10 (83%) tested positive. Among these 10 fatal cases, pulmonary hemorrhage and renal failure were the most common causes of death. We enrolled 42 case-patients and 84 controls. Jaundice, elevated BUN, hyperbilirubinemia, anemia, and leukocytosis were associated with leptospirosis (p < .01 for all). Male sex, walking in puddles, rural habitation, and owning horses were independently associated with leptospirosis. Epidemiological, clinical, and laboratory criteria may help distinguish leptospirosis from dengue and identify patients who would benefit from early antibiotic treatment.

Leptospirosis mimicking acute cholecystitis among athletes participating in a triathlon.

Leptospirosis, a disease acquired by exposure to contaminated water, is characterized by fever accompanied by various symptoms, including abdominal pain. An acute febrile illness occurred in athletes who participated in an Illinois triathlon in which the swimming event took place in a freshwater lake. Of 876 athletes, 120 sought medical care and 22 were hospitalized. Two of the athletes had their gallbladders removed because of abdominal pain and clinical suspicion of acute cholecystitis. We applied an immunohistochemical test for leptospirosis to these gallbladders and demonstrated bacterial antigens staining (granular and filamentous patterns) around blood vessels of the serosa and muscle layer. Rare intact bacteria were seen in 1 case. These results show that leptospirosis can mimic the clinical symptoms of acute cholecystitis. If a cholecystectomy is performed in febrile patients with suspicious environmental or animal exposure, pathologic studies for leptospirosis on formalin-fixed, paraffin-embedded tissues may be of great value.

Viral latency--the papillomavirus model.

To investigate the prevalence and the natural history of human papillomavirus infections, we monitored HPV DNA shedding as a consequence of immunosuppression, with the expectation that latent viral infections would reactivate and become detectable. The study populations consisted of women who were in end-stage renal failure, those who ultimately received kidney transplantations, and those who had HIV/AIDS with various degrees of immune depression at entry. For each woman, cervico-vaginal lavage to sample viral shedding from the lower genital tract was performed at approximately six month intervals, and the cohorts have been followed since 1996. Nested polymerase chain reaction amplification of papillomavirus DNA using novel pairs of primers was followed by diagnostic restriction endonuclease cleavage or by DNA sequencing. This strategy is particularly capable of identifying single and multiple infections and determining the genotypes of any viruses present. Of the 225 women in the HIV cohort, 177 (79%) were HPV-positive and 111 (49%) shed from two up to eight different HPV types over the course of the survey. Thirty-five different mucosotropic HPV types, virtually all that have ever been described worldwide, were isolated from these 225 women, and nine additional new (provisional) types were discovered. As is always the case, HPV-6 was very common. However, all the other frequently detected HPV types (45, 52, 53, 54, 58, 74) were more prevalent than the types typically reported forthe general population (HPV-11, 16, 18, 31, 33, 35). Notably, the 14 members of the A3 phylogenetic subgroup (HPV-61, 62, 72, 81, 83, 84, and all the new types) were by far the most frequently observed viral types in the AIDS cohort. The HPV prevalence in the cohorts of kidney transplantation candidates and recipients was only slightly lower than that in the AIDS cohort. We conclude that HPV infections are extraordinarily common and are normally held in a sub-clinical state by functional immune systems, but can be reactivated by immunosuppressive conditions. The question of how so many distinct types persist in the human population and can be repeatedly isolated from specimens collected around the world raises complex issues concerning the nature of viral transmission, reproduction, shedding, and mutational drift. These molecular epidemiological observations signal the likelihood that HPV is part of the commensal microflora of human epithelia. Their prevalence elicits a caution that latent HPV DNA may be present in primary human epithelial tissues.

Evaluation of the indirect hemagglutination assay for diagnosis of acute leptospirosis in Hawaii.

Timely diagnosis of leptospirosis is important to ensure a favorable clinical outcome. The definitive serologic assay, the microscopic agglutination test (MAT), requires paired sera and is not useful for guiding early clinical management. The only screening test approved for use in the United States, the indirect hemagglutination assay (IHA), has not undergone extensive field evaluation. To assess the performance of the leptospirosis IHA in Hawaii, serum from patients evaluated for leptospirosis between 1992 and 1997 were tested with the IHA at the Hawaii State Laboratories Division and with the MAT at the Centers for Disease Control and Prevention. Leptospirosis was considered confirmed by a fourfold rise in MAT titer and/or a positive culture. A total of 92 (41%) of 226 specimens from 114 persons with confirmed leptospirosis were found positive by IHA. Only 18 (15%) of 119 specimens obtained within 14 days of onset were IHA positive, compared to 74 (69%) of 107 specimens collected more than 14 days after onset (P <0.001). Repeat testing ultimately resulted in 78 (68%) of the confirmed cases having at least one specimen found positive by IHA. Thirteen different presumptive infecting serogroups were identified among 251 specimens with an MAT titer of >/=200 and obtained from persons with confirmed or probable leptospirosis. Fifty (68%) of 73 specimens with Icterohaemorrhagiae as the presumptive infecting serogroup were found positive by IHA, compared to 44 (47%) of 93 specimens with Australis as the presumptive infecting serogroup (P, 0.01). The IHA test was positive for 3 (1%) of 236 specimens from 154 persons without leptospirosis. The sensitivity of the leptospirosis IHA in Hawaii was substantially below figures reported previously, particularly early in the course of illness, limiting its usefulness for diagnosing acute infection. Since the presumptive infecting serogroup affected IHA results and the prevalence of serovars varies with geography, the performance of the IHA should be assessed locally. More sensitive leptospirosis screening tests are needed in Hawaii.

Analysis of the 1998 outbreak of leptospirosis in Missouri in humans exposed to infected swine.

OBJECTIVE: To determine the extent of leptospirosis in persons exposed to infected swine, confirm the source of disease, define risk factors for infection, and identify means for preventing additional infections during an outbreak in Missouri in 1998. DESIGN: Cross-sectional study. SAMPLE POPULATION: 240 people and 1,700 pigs. PROCEDURE: An epidemiologic investigation was conducted of people exposed to infected pigs from the University of Missouri-Columbia swine herd. The investigation included review of health of the pigs, a cross-sectional study of the people handling the pigs, serologic testing of human and porcine sera, and risk-factor analysis for leptospirosis within the human population. RESULTS: Serologic testing of samples collected at the time of the investigation indicated that 59% of the pigs had titers to leptospires, denoting exposure. Of the 240 people in the exposed study population, 163 (68%) were interviewed, and of these, 110 (67%) submitted a blood sample. Nine (8%) cases of leptospirosis were confirmed by serologic testing. Risk factors associated with leptospirosis included smoking (odds ratio [OR], 14.4; 95% confidence interval [CI], 1.39 to 137.74) and drinking beverages (OR, 5.1; 95% CI, 1.04 to 24.30) while working with infected pigs. Washing hands after work was protective (OR, 0.2; 95% CI, 0.03 to 0.81). CONCLUSIONS AND CLINICAL RELEVANCE: Leptospirosis is a risk for swine producers and slaughterhouse workers, and may be prevented through appropriate hygiene, sanitation, and animal husbandry. It is essential to educate people working with animals or animal tissues about measures for reducing the risk of exposure to zoonotic pathogens.

Risk factors associated with leptospirosis in northeastern Thailand, 1998.

Leptospirosis is a zoonotic disease of worldwide distribution caused by spirochetes of the genus Leptospira. Humans are infected through direct contact with infected animals or through exposure to fresh water or soil contaminated by infected animal urine. Leptospirosis is characterized by acute fever that can be followed by a more severe, sometimes fatal illness that may include jaundice and renal failure (Weil's disease), meningitis, myocarditis, hemorrhagic pneumonitis, or hemodynamic collapse. To identify potential risk factors for leptospirosis in Thailand, we conducted a matched case-control study in Nakornratchasrima Province of the northeastern region. Fifty-nine cases and 118 controls were included in the study. Four activities in the two weeks prior to illness were independently associated with leptospirosis infection: walking through water (odds ratio [OR] = 4.9, 95% confidence interval [CI] = 1.7-14.1), applying fertilizer in wet fields for more than 6 hr a day (OR = 3.4, 95% CI = 1.5-7.8), plowing in wet fields for more than 6 hr a day (OR = 3.5, 95% CI = 1.1-11.6), and pulling out rice plant sprouts in wet fields for more than 6 hr a day (OR = 3.1, 95% CI = 1.02-9.3). Identification of these risk factors on admission might prove useful for early diagnosis and treatment of leptospirosis in Thailand.

Asymptomatic infection and risk factors for leptospirosis in Nicaragua.

As part of an investigation of a 1995 outbreak of leptospirosis in Nicaragua, a cross-sectional serologic survey was conducted in the town of El Sauce. Of 566 persons, 85 (15%) were positive for IgM anti-Leptospira antibodies, indicating recent leptospirosis infection. Asymptomatic leptospirosis infection was common, with only 25 (29.4%) of the 85 seropositive inhabitants reporting a febrile illness in the 2 months before the survey. Multivariable analysis revealed that having an indoor water source remained independently protective against leptospirosis. Gathering wood was independently associated with infection. These findings suggest that asymptomatic infection with Leptospira is common in endemic areas of Leptospira transmission. Improvement in water sanitation and behavioral modifications to reduce environmental exposure may reduce the risk of leptospirosis in endemic regions.

Increase of leptospirosis in dengue-negative patients after a hurricane in Puerto Rico in 1996 [correction of 1966].

Leptospirosis has rarely been reported in Puerto Rico, although in the period from 1948 to 1952, 208 cases of leptospirosis and an island-wide seroprevalence of antibody to Leptospira of 14% were documented. In Puerto Rico in October 1996, following rainfall and a period of flooding generated by Hurricane Hortense, serum specimens of 4 patients with suspected dengue fever that were negative for dengue tested positive for Leptospira-specific IgM antibodies in a dipstick assay. Subsequently, we used an island-wide dengue laboratory-based surveillance system to determine the increase in leptospirosis after hurricane-generated floods. All anti-dengue IgM-negative patients (n = 142) with disease onset from August 8 to October 6, 1996 from prehurricane and posthurricane groups were investigated for leptospirosis. Laboratory-confirmed leptospirosis cases were defined as microscopic agglutination test titers > or = 1 :400 to 1 or more serovars, or positive immunohistochemistry in autopsy tissues. Four (6%) of 72 prehurricane and 17 (24%) of 70 posthurricane patients had laboratory-confirmed cases of leptospirosis (relative risk [RR] = 4.4, 95% confidence interval [CI] = 1.6-12.4). The mean age of case-patients was 34 years (range = 13-64). Eighteen (86%) of 21 confirmed case-patients were males, including one patient who died (31 years old). Patients were located in 18 (38%) of 48 municipalities that submitted serum samples. Clinical features significantly associated with leptospirosis were eye pain (RR = 1.5, 95% CI = 1.3-1.9), joint pain (RR = 1.4, 95% CI = 1.1-1.6), diarrhea (RR = 1.7, 95% CI = 1.2-2.5), and jaundice (RR = 3.3, 95% CI = 1.5-7.2). This study demonstrates the utility of a dengue laboratory-based surveillance system for the detection of an increase of leptospirosis, which most likely would have gone unrecognized. Leptospirosis is treatable with antibacterial agents; knowledge of this diagnosis may significantly reduce morbidity and mortality.

International multicenter evaluation of the clinical utility of a dipstick assay for detection of Leptospira-specific immunoglobulin M antibodies in human serum specimens.

We performed a multicenter evaluation of a robust and easily performed dipstick assay for the serodiagnosis of human leptospirosis. The assay is aimed at the detection of Leptospira-specific immunoglobulin M (IgM) antibodies. The study involved 2,665 serum samples collected from 2,057 patients with suspected leptospirosis in 12 countries on five continents with different levels of endemicity and different surveillance systems. The patients were grouped as laboratory-confirmed leptospirosis case patients and noncase patients based on the results of culturing and the microscopic agglutination test. Paired samples from 27.7% of the subjects were tested. Of the 485 case patients, 87.4% had a positive dipstick result for one or more samples. Of the 1,513 noncase patients, only 7.2% had a positive result. Whereas most (88.4%) of the positive samples from the case patients showed moderate to strong (2+ to 4+) staining in the dipstick assay, most (68.1%) of the positive samples from the noncase patients showed weak (1+) staining. The sensitivity of the dipstick assay increased from 60.1% for acute-phase serum samples to 87.4% for convalescent-phase samples. The specificities for these two groups of samples were 94.1 and 92.7%, respectively. The dipstick assay detected a broad variety of serogroups. The results of the dipstick assay were concordant (observed agreement, 93.2%; kappa value, 0.76) with the results of an enzyme-linked immunosorbent assay for the detection of specific IgM antibodies, a test which is often used in the laboratory diagnosis of current or recent leptospirosis. This study demonstrated that this easily performed dipstick assay is a valuable and useful test for the quick screening for leptospirosis; has a wide applicability in different countries with different degrees of endemicity; can be used at all levels of the health care system, including the field; and will be useful for detecting and monitoring outbreaks of leptospirosis.

Instillation of allogeneic lung macrophages and dendritic cells cause differential effects on local IFN-gamma production, lymphocytic bronchitis, and vasculitis in recipient murine lungs.

Lung allograft rejection is believed to be initiated by donor lung accessory cells, namely macrophages and dendritic cells, interacting with recipient lymphocytes leading to up-regulated Th1 type (IFN-gamma) cellular immunity culminating in graft destruction. The purpose of this study was to determine the individual role of donor lung macrophages and dendritic cells in the rejection response. Utilizing a murine model that reproduces the immunology and histology of acute rejection, C57BL/6 mouse (I-a(b), H-2(b)) lung dendritic cells (DC-enriched lung cells), purified alveolar macrophages (I-a-negative macrophages), or various ratios of I-a-negative macrophages/DC were instilled into BALB/c mouse (I-a(d), H-2(d)) lungs followed by an assessment of local IFN-gamma production and grading of rejection pathology. The data show that DC, and not I-a-negative macrophages, induced IFN-gamma production in recipient lungs. However, the local production of IFN-gamma was not always associated with histological changes characteristic of rejection pathology. In contrast to either cell type alone, instillation of C57BL/6 I-a-negative macrophages and DC, together, were required to induce rejection pathology in BALB/c lungs. In addition, the rejection response was dependent on interactions between donor I-a-negative macrophages and DC.

Epidemic leptospirosis associated with pulmonary hemorrhage-Nicaragua, 1995.

In October 1995, epidemic "hemorrhagic fever," without jaundice or renal manifestations, was reported in rural Nicaragua following heavy flooding; 2259 residents were evaluated for nonmalarial febrile illnesses (cumulative incidence, 6.1%) and 15 (0.7%) died with pulmonary hemorrhage. A case-control study found that case-patients were more likely than controls to have ever walked in creeks (matched odds ratio [MOR], 15.0; 95% confidence interval [CI], 1.7-132.3), have household rodents (MOR, 10.4; 95% CI, 1.1-97.1), or own dogs with titers >/=400 to Leptospira species (MOR, 23.4; 95% CI, 3.6-infinity). Twenty-six of 51 case-patients had serologic or postmortem evidence of acute leptospirosis. Leptospira species were isolated from case-patients and potential animal reservoirs. This leptospirosis epidemic likely resulted from exposure to flood waters contaminated by urine from infected animals, particularly dogs. Leptospirosis should be included in the differential diagnosis for nonmalarial febrile illness, particularly during periods of flooding or when pulmonary hemorrhage occurs.

Comparison of two rapid latex agglutination tests for detection of cryptococcal capsular polysaccharide.

The Murex Cryptococcus Test was compared with the Cryptococcal Antigen Latex Agglutination System (CALAS) for detecting cryptococcal polysaccharide in 173 cerebrospinal fluid (CSF) specimens and 117 serum samples with 99% and 97% concordance, respectively. Eighteen CSF samples and 17 serum samples were positive in both assays, and 249 were negative. The sensitivity and specificity of the Murex relative to the CALAS were 90% and 100%, respectively, for CSF, and 81% and 100%, respectively, for serum. Six discrepancies were arbitrated by retesting, using a third analytic method, review of other laboratory and clinical data, or both. The reaction in 1 CSF specimen was considered false positive by the CALAS, and the reactions in 2 serum samples were false negatives by the Murex. For 3 patients with previous cryptococcal meningitis but no active disease, only the CALAS detected antigen, suggesting that the Murex has less analytic sensitivity in this context. Titer differences dictate that direct comparisons between the 2 tests are not feasible. There were no false-positive reactions in limited testing with either method using specimens from patients with concurrent noncryptococcal infections or in rheumatoid factor-positive serum samples. Infections caused by Cryptococcus neoformans serotypes A or AD were detected equally by both assays. Based on our study, we have elected to continue to use the CALAS for routine testing for cryptococcal antigen.

Improved method for single-bolus kinetic measurements using a noncleared reference indicator.

After intravenous injection of a tracer as a single bolus, its concentration decreases as it mixes with the plasma, disperses throughout the circulation, and enters body pools. Kinetic values that are dependent on early concentrations may be in considerable error because mixing is not instantaneous throughout the circulation, and this problem is particularly acute in the mammalian fetus, with its distinctive circulatory pattern. To minimize this error, a method was developed in which the noncleared reference tracer 125I-labeled albumin was injected together with a representative, rapidly cleared metabolite 14C-labeled palmitic acid, and the former was used to correct for mixing delay. A total of 19 disappearance curves were studied after intravenous injection into seven near-term fetal sheep. Kinetic values were calculated with and without correction for mixing delay. Taking account of mixing delay increased the calculated volume of distribution 41% [from 44 +/- 4 (SE) to 62 +/- 3 ml/kg, P < 0.001], increased plasma clearance rate 13% (from 41 +/- 2 to 47 +/- 1 ml-min-1.kg-1, P < 0.002), decreased the rate constant for irreversible loss 26% (from 1.05 +/- 0.07 to 0.78 +/- 0.04 min-1, P < 0.001), and increased the calculated effective half-life 26% (0.71 +/- 0.06 to 0.90 +/- 0.05 min, P < 0.001). Thus use of the additional reference marker significantly altered calculated results and provided values believed to more accurately describe rapid disappearance from the central mixing compartment into metabolic pools.