Tranexamic acid in life-threatening military injury and the associated risk of infective complications.

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce mortality from severe haemorrhage. Although recent data suggest that TXA has anti-inflammatory properties, few analyses have investigated the impact of TXA on infectious complications in injured patients. The aim was to examine the association between TXA administration and infection risk among injured military personnel. METHODS: Patients who received TXA were matched by Injury Severity Score with patients who did not receive TXA. Conditional logistic regression was used to examine risk factors associated with infections within 30 days. A Cox proportional analysis evaluated risk factors in a time-to-first-infection model. RESULTS: A total of 335 TXA recipients were matched with 626 patients who did not receive TXA. A greater proportion of TXA recipients had an infection compared with the comparator group (P < 0·001). Univariable analysis estimated an unadjusted odds ratio (OR) of 2·47 (95 per cent c.i. 1·81 to 3·36) for the association between TXA and infection risk; however, TXA administration was not significant in multivariable analysis (OR 1·27, 0·85 to 1·91). Blast injuries, intensive care unit (ICU) admission, and receipt of 10 units or more of blood within 24 h after injury were independently associated with infection risk. The Cox proportional model confirmed the association with ICU admission and blood transfusion. Traumatic amputations were also significantly associated with a reduced time to first infection. CONCLUSION: In life-threatening military injuries matched for injury severity, TXA recipients did not have a higher risk of having infections nor was the time to develop infections shorter than in non-recipients. Extent of blood loss, blast injuries, extremity amputations and ICU stay were associated with infection.

Combat trauma-associated invasive fungal wound infections: epidemiology and clinical classification.

The emergence of invasive fungal wound infections (IFIs) in combat casualties led to development of a combat trauma-specific IFI case definition and classification. Prospective data were collected from 1133 US military personnel injured in Afghanistan (June 2009-August 2011). The IFI rates ranged from 0·2% to 11·7% among ward and intensive care unit admissions, respectively (6·8% overall). Seventy-seven IFI cases were classified as proven/probable (n = 54) and possible/unclassifiable (n = 23) and compared in a case-case analysis. There was no difference in clinical characteristics between the proven/probable and possible/unclassifiable cases. Possible IFI cases had shorter time to diagnosis (P = 0·02) and initiation of antifungal therapy (P = 0·05) and fewer operative visits (P = 0·002) compared to proven/probable cases, but clinical outcomes were similar between the groups. Although the trauma-related IFI classification scheme did not provide prognostic information, it is an effective tool for clinical and epidemiological surveillance and research.

Longitudinal assessment of cardiac diastolic function in HIV-infected patients.

Asymptomatic isolated diastolic dysfunction (DD), with normal left ventricular systolic function, may be the first indication of underlying cardiac disease in HIV-negative populations. We previously reported a high prevalence (37%) of DD among asymptomatic HIV-infected patients at low risk for AIDS and cardiovascular disease (CVD). We performed a longitudinal assessment of interval echocardiographic changes in this cohort over a four-year period. Repeat transthoracic echocardiograms (TTEs) utilized standard techniques. Sixty (of the original 91) HIV-infected patients, predominately men, underwent repeat TTE (median follow-up 3.7 years, interquartile range [IQR] 3.5, 4.0). Cohort characteristics (median; IQR) include age 42.0 (36.5, 46.0) years, HIV duration 16.4 years (8.1, 18.9), current CD4 count 572.0 cells/mm(3) (436.5, 839.0), antiretroviral therapy (ART) duration 8.1 years (4.8, 13.4) and Framingham risk score 1.0 (0.0, 2.0). DD was observed in 28/60 patients on re-evaluation (47%, 95% confidence interval [CI] 34%, 60%); 31% (11/36) of patients had new onset DD for an overall incidence of 8.2/100 person-years. On follow-up, subjects with DD were older, had a trend towards higher body mass index, hypertension and longer duration of HIV infection compared with subjects without DD. We confirmed a high prevalence of DD (47%) in asymptomatic HIV-infected patients at low risk for AIDS and CVD.

Safety and immunogenicity of a Shigella flexneri 2a Invaplex 50 intranasal vaccine in adult volunteers.

Shigellosis is a leading cause of diarrhea worldwide prompting vaccine development. The Shigella flexneri Invaplex 50 is a macromolecular complex containing IpaB, IpaC, and LPS, formulated from an aqueous extract of virulent Shigella delivered via nasal administration. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. An open-label dose-escalating phase 1 study evaluated a 3-dose (2-week intervals) regimen via nasal pipette delivery. Thirty-two subjects were enrolled into one of four vaccine dose groups (10, 50, 240, or 480 microg). The vaccine was well tolerated with minor short-lived nasal symptoms without evidence of dose effect. Antibody-secreting cell (ASC) responses were elicited at doses > or =50 microg with the highest IgG ASC, Invaplex 50 (100%) and S. flexneri 2a LPS (71%), as well as, serologic responses (43%) occurring with the 240 microg dose. Fecal IgA responses, Invaplex 50 (38.5%) and LPS (30.8%), were observed at doses > or =240 microg. The Invaplex 50 nasal vaccine was safe with encouraging mucosal immune responses. Follow-on studies will optimize dose, delivery mechanism and assess efficacy in a S. flexneri 2a challenge study.

Caught in the act: in vivo development of macrolide resistance to Campylobacter jejuni infection.

We report the first instance of macrolide resistance developing in vivo following appropriate antibiotic use in a healthy volunteer as a part of a controlled human infection with Campylobacter jejuni. In vivo development of macrolide resistance may be an important contributor to antibiotic resistance in C. jejuni.

Case series study of traveler's diarrhea in U.S. military personnel at Incirlik Air Base, Turkey.

Military personnel with traveler's diarrhea (n=202) while deployed to Incirlik Air Base, Turkey, from June to September 2002 were evaluated for pathogen-specific immune responses. Serologic and fecal immunoglobulin A (IgA) titers to enterotoxigenic Escherichia coli antigens (CS6, CS3, and LT) were quite low. In contrast, subjects with Campylobacter infections had high serologic and fecal IgA responses.

A multi-centre, randomised, double-blind 14-week extension study examining the long-term safety and efficacy profile of the ezetimibe/simvastatin combination tablet.

The objective of this study was to compare the efficacy and safety profile of ezetimibe/simvastatin (EZE/SIMVA) tablet and SIMVA monotherapy. This was an extension study of a randomised, double-blind, placebo-controlled study in patients with primary hypercholesterolaemia. Protocol-compliant patients who completed the 12-week base study were eligible to enter a randomised, double-blind, 14-week extension study and were administered 1 of 8 daily treatments: EZE/SIMVA 10/10-, 10/20-, 10/40- or 10/80-mg, or SIMVA 10-, 20-, 40- or 80-mg. Patients receiving these treatments during the base study remained on the same treatment in the extension. Patients administered placebo or EZE 10-mg monotherapy during the base study were re-randomised to EZE/SIMVA 10/10 mg or SIMVA 80 mg. The primary analysis was mean per cent change in low-density lipoprotein cholesterol (LDL-C) from baseline to extension study end-point. Mean changes from baseline in LDL-C of -38.8% and -53.7% were observed for pooled SIMVA and pooled EZE/SIMVA respectively. The between treatment difference of -14.9% (95% confidence interval: -16.4, -13.3) was statistically significant (p < 0.001). The incremental LDL-C lowering effect of EZE/SIMVA compared with the corresponding dose of SIMVA alone was consistent across the dose range (p < 0.001 for each between-group comparison). More patients receiving EZE/SIMVA than SIMVA achieved LDL-C concentrations < 100 mg/dl and < 70 mg/dl (p < 0.001 for both goals). EZE/SIMVA was generally well tolerated with a safety profile similar to SIMVA monotherapy. There were no significant between-group differences in the incidences of clinically significant elevations in liver transaminase or creatine kinase levels. In conclusion, EZE/SIMVA had a comparable safety and tolerability profile and was more efficacious than SIMVA monotherapy for up to 6 months.

An observational clinic-based study of diarrheal illness in deployed United States military personnel in Thailand: presentation and outcome of Campylobacter infection.

Campylobacter is a leading cause of traveler's diarrhea in Thailand. Since resistance to quinolones is high among Campylobacter isolates, empiric therapy with quinolones for traveler's diarrhea may be ineffective in this region. We conducted an observational study among 169 U.S. military personnel with acute diarrhea and compared their microbiologic findings to those of 77 asymptomatic personnel deployed to Thailand in May 1998. Of 146 pathogenic bacterial isolates, the most common were nontyphoidal Salmonella (n = 31), enterotoxigenic Escherichia coli (n = 24), and C. jejuni/coli (n = 23). Campylobacter was strongly associated with disease (odds ratio = 5.9; 95% confidence interval = 1.3-37.3), with a more severe clinical presentation, and with a reduced functional ability at presentation (P = 0.02). In vitro resistance to ciprofloxacin was observed in 96% of the Campylobacter isolates. Sub-optimal treatment response to ciprofloxacin was observed in 17% of the cases of Campylobacter infection versus 6% due to other causes. These results highlight the importance of Campylobacter as a cause of severe traveler's diarrhea in Thailand and illustrates the ongoing problem with antibiotic-resistant strains and associated treatment problems.

Campylobacter jejuni enteritis.

We report the development of Campylobacter jejuni enteritis in a patient with preexisting humoral and cellular immune recognition of C. jejuni antigens. This is one of few studies in which the immunologic status of a person with regard to C. jejuni before and after C. jejuni infection is directly compared, and it is the only study of which we are aware that includes measurements of cellular immunity. The findings may be important to Campylobacter vaccine development efforts.

Diarrhea in the returned traveler.

Diarrhea in the returned traveler is a common problem that can be caused by a number of different pathogens. A history of the patient's travel and exposures, the duration of illness, the response to prior treatment, and the clinical syndrome can help to establish a good etiologic differential diagnosis on which further therapy can be based. Many of these patients can be treated empirically with antibiotics, either a fluoroquinolone or azithromycin, without further microbiologic evaluation. Those patients with severe or persistent disease or comorbid illnesses, or those who have failed empiric therapy, should undergo further microbiologic evaluation with directed stool cultures and ova and parasite screening. For those patients with negative evaluations, further empiric therapy may be warranted if syndromes are suggestive of specific agents of infection, such as by Giardia or Cyclospora species. Other patients may require endoscopic evaluation to exclude diagnoses such as tropical sprue or inflammatory bowel disease.

The Health Insurance Portability and Accountability Act: security and privacy requirements.

The security and privacy requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and their implications for pharmacy are discussed. HIPAA was enacted to improve the portability of health care insurance for persons leaving jobs. A section of the act encourages the use of electronic communications for health care claims adjudication, mandates the use of new standard code sets and transaction sets, and establishes the need for regulations to protect the security and privacy of individually identifiable health care information. Creating these regulations became the task of the Department of Health and Human Services. Regulations on security have been published for comment. Regulations on privacy and the definition of standard transaction sets and code sets are complete. National identifiers for patients, providers, and payers have not yet been established. The HIPAA regulations on security and privacy will require that pharmacies adopt policies and procedures that limit access to health care information. Existing pharmacy information systems may require upgrading or replacement. Costs of implementation nationwide are estimated to exceed $8 billion. The health care community has two years from the finalization of each regulation to comply with that regulation. The security and privacy requirements of HIPAA will require pharmacies to review their practices regarding the storage, use, and disclosure of protected health care information.

Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins.

PURPOSE: Elevated plasma concentrations of low-density lipoproteins (LDL) increase risk for coronary heart disease. However, lipoprotein profiles rich in small, dense LDL particles confer greater risk than those that mainly consist of large, buoyant LDL. This may be due, in part, to the greater oxidative susceptibility of small, dense LDL. In the current studies, we tested whether differences in the oxidative behavior of buoyant and dense LDL arise from differences in their immediate metabolic precursors, intermediate-density lipoproteins. SUBJECTS AND METHODS: We compared the properties of intermediate-density lipoproteins and buoyant and dense LDL subfractions in 9 subjects with the large, buoyant LDL phenotype versus 6 with the small, dense LDL phenotype. Oxidative susceptibility was evaluated based on conjugated diene formation and parinaric acid oxidation induced by copper. Antioxidants (ubiquinol-10 and alpha-tocopherol) were measured by high-performance liquid chromatography. RESULTS: Oxidative susceptibility was increased and antioxidant concentrations were decreased with increasing lipoprotein density (intermediate intermediate-density lipoproteins to buoyant LDL to dense LDL). Intermediate-density lipoproteins from subjects with the small, dense LDL phenotype had a greater oxidative susceptibility (by the parinaric acid test) and lower antioxidant concentrations than corresponding particles from subjects with the large, buoyant LDL phenotype. CONCLUSIONS: Differences in oxidative susceptibility between large, buoyant and small, dense LDL particles are apparent in their lipoprotein precursors. These results suggest that lipoprotein oxidative susceptibility may be metabolically programmed and that intermediate-density lipoproteins may contribute to the increased risk associated with the small, dense LDL phenotype.

Relative sensitivities of plasma lecithin:cholesterol acyltransferase, platelet-activating factor acetylhydrolase, and paraoxonase to in vitro gas-phase cigarette smoke exposure.

In order to identify potential atherogenic properties of gas-phase cigarette smoke, we utilized an in vitro exposure model to determine whether the activities of several putative anti-atherogenic enzymes associated with plasma lipoproteins were compromised. Exposure of heparinized human plasma to gas-phase cigarette smoke produced a dose-dependent reduction in the activity of platelet-activating factor acetylhydrolase (PAF-AH). Reductions of nearly 50% in PAF-AH activity were observed following exposure to gas-phase smoke from four cigarettes over an 8-h period. During this time of exposure, lecithin:cholesterol acyltransferase (LCAT) was rendered almost completely inactive (>80%). In contrast, paraoxonase was totally unaffected by cigarette smoke. Supplementation of plasma with 1 mM reduced glutathione was found to protect both PAF-AH and LCAT from cigarette smoke, suggesting that cysteine modifications may have contributed to the inhibition of these two enzymes. To evaluate this possibility, we blocked the free cysteine residues of these enzymes with the reversible thiol-modifying reagent dithiobisnitrobenzoic acid (DTNB). Reversal of the DTNB-cysteine adducts following cigarette smoke exposures revealed that LCAT, but not PAF-AH, was protected. Moreover, high doses (1.0-10 mM) of acrolein and 4-hydroxynonenal, reactive aldehydic species associated with cigarette smoke, completely inhibited plasma LCAT activity, whereas PAF-AH was resistant to such exposures. Taken together, these results indicate a divergence regarding the underlying mechanism of PAF-AH and LCAT inhibition upon exposure to gas-phase cigarette smoke. While LCAT was sensitive to exposure to volatile aldehydic products involving, in part, cysteine and/or active site modifications, the enzyme PAF-AH exhibited an apparent resistance. The latter suggests that the active site of PAF-AH is in a microenvironment that lacks free cysteine residues and/or is shielded from volatile aldehydic combustion products. Based on these results, we propose that cigarette smoke may contribute to atherogenesis by inhibiting the activities of plasma PAF-AH and LCAT, but the nature of this inhibition differs for the enzymes.

Increased low density lipoprotein degradation in aorta of irradiated mice is inhibited by preenrichment of low density lipoprotein with alpha-tocopherol.

We previously reported that upper thoracic exposure to ionizing radiation (IR) accelerates fatty streak formation in C57BL/6 mice and that such effects are inhibited by overexpression of the antioxidant enzyme CuZn-superoxide dismutase (SOD). Notably, IR-accelerated lesion formation is strictly dependent on a high fat diet (i.e., atherogenic lipoproteins) but does not involve alterations in circulating lipid or lipoprotein levels. We thus proposed that IR promotes changes in the artery wall that enhance the deposition of lipoprotein lipids. To address this hypothesis, we examined the effects of IR on aortic accumulation and degradation of low density lipoproteins (LDL). Ten-week-old C57BL/6 mice were exposed to a single (8-Gy) dose of (60)Co radiation to the upper thoracic area or were sham irradiated (controls) and were then placed on the high fat diet. Five days postexposure, the mice received either (125)I-labeled LDL ((125)I-LDL) (which was used to measure intact LDL) or (125)I-labeled tyramine cellobiose ((125)I-TC)-LDL (which was used to measure both intact and cell-degraded LDL) via tail vein injection. On the basis of trichloroacetic acid (TCA)-precipitable counts in retroorbital blood samples, > or =95% of donor LDL was cleared within 24 h and there were no differences in time-averaged plasma concentrations of the two forms of LDL among irradiated and control mice. Aortic values increased markedly within the first hour and thereafter exhibited a slow increase up to 24 h. There were no differences between irradiated and control mice at 1 h, when values primarily reflected LDL entry, but a divergence was observed thereafter. At 24 h, (125)I-TC-associated counts were 1.8-fold higher in irradiated mice (P = 0.10). In contrast, (125)I-LDL-associated counts were 30% lower in irradiated mice (P< 0.05), suggesting that most of the retained (125)I-TC was associated with LDL degradation products. Consistent with the proposed involvement of oxidative or redox-regulated events, IR-induced LDL degradation was lower in SOD-transgenic than wild-type mice (P<0.05). The importance of LDL oxidation was suggested by observations that IR-induced LDL degradation was significantly reduced by preenriching LDL with alpha-tocopherol. On the basis of these results, we propose that IR elicits SOD-inhibitable changes in the artery wall that enhance LDL oxidation and degradation leading to the deposition of LDL-borne lipids. These studies provide additional support for the role of oxidation in lipoprotein lipid deposition and atherogenesis and suggest that IR promotes an arterial environment that stimulates this process in vivo.

Associations of HDL, HDL(2), and HDL(3) cholesterol and apolipoproteins A-I and B with lifestyle factors in healthy women and men: the Stanford Five City Project.

BACKGROUND: Measures of the two major high-density lipoprotein (HDL) subfractions, HDL(2) and HDL(3), and the major apolipoproteins of HDL and low-density lipoprotein (LDL), Apo A-I and Apo B, may be etiologically important factors in the development of coronary artery disease. The association of lifestyle factors with these lipoprotein-related variables remains unclear. METHODS: HDL-C, HDL(2)-C, HDL(3)-C, Apo A-I, and Apo B levels were determined in a population-based sample of 1,027 healthy women and men aged 25-64 years, from four California cities who participated in the 1989/1990 survey of the Stanford Five City Project. In this cross-sectional study we examined the independent associations of these lipoprotein-related variables with body mass index (BMI), cigarette smoking, daily energy expenditure, alcohol intake, dietary intake, and hormone use (oral contraceptives and estrogen replacement therapy). RESULTS: In general, BMI and alcohol intake were the strongest independent predictors of the lipoprotein-related variables. The negative association of BMI with HDL-C was attributable primarily to the association with the HDL(2)-C subfraction, while for alcohol intake the positive association with HDL-C was attributable primarily to the association with HDL(3)-C, particularly in men. Among men, but not women, energy expenditure was a significant independent predictor of each of the lipoprotein-related variables, with positive associations observed for HDL-C, HDL(2)-C, HDL(2)-C, and Apo A-I and a negative association observed for Apo B (P < 0.005). CONCLUSIONS: Data from this population-based sample suggest that specific lifestyle factors are more strongly associated with some lipoprotein-related variables than with others, with notable gender differences.