Trabecular bone score in patients with chronic kidney disease.

Patients with chronic kidney disease have high risk of osteoporotic fractures. Lower trabecular bone score (TBS) was associated with poorer kidney function and higher fracture risk when kidney function was normal. Addition of TBS to The Fracture Risk Assessment Tool with bone mineral density did not improve fracture risk prediction. INTRODUCTION: We sought to determine whether trabecular bone score (TBS) either independently or adjusted for The Fracture Risk Assessment Tool (FRAX) could predict risk of major osteoporotic fractures (MOFs) in a large population-based sample of patients with all stages of chronic kidney disease (CKD). METHODS: We used population-based administrative databases to identify patients above age 20 years who had dual-energy X-ray absorptiometry (DXA) scan and serum creatinine measured within 1 year, during the years 2005 to 2010. Patients were excluded if they were on dialysis or had a functioning renal transplant. We stratified patients by estimated glomerular filtration rate (eGFR). We collected femoral neck bone mineral density (BMD), lumbar spine TBS, incident major osteoporotic fractures (MOF) and hip fractures, and other clinical characteristics. RESULTS: Among 8289 patients, there were 6224 (75.1%) with eGFR ≥ 60 mL/min/1.73 m2, 1624 (19.6%) with eGFR 30-60 mL/min/1.73 m2, and 441 (5.3%) with eGFR < 30 mL/min/1.73 m2. There were 593 patients (7.2%) with MOFs and 163 (2.0%) with hip fractures. Lower TBS score was associated with increased risk of MOF and hip fractures across all eGFR strata in unadjusted Cox proportional hazards models but after adjusting for FRAX with BMD, lower TBS was only statistically significant for MOF prediction for eGFR ≥ 60 mL/min/1.73 m2. CONCLUSION: Lower TBS scores were associated with lower eGFR and increased fracture risk in patients with eGFR ≥ 60 mL/min/1.73 m2. However, the addition of TBS to the FRAX score with BMD did not significantly improve fracture risk prediction in patients with CKD.

Design and rationale of the atrial fibrillation occurring transiently with stress (AFOTS) incidence study.

BACKGROUND: Atrial fibrillation (AF) is often detected for the first time in patients hospitalized for medical illness or non-cardiovascular surgery. AF occurring transiently with stress (AFOTS) describes this manifestation of AF, which may either be the result of a non-cardiac stressor, or existing paroxysmal AF that was not previously detected. Current estimates of AFOTS incidence are imprecise: ranging from 1 to 44%, owing to the marked heterogeneity in patient populations, identification and methods used to detect AFOTS. METHODS: The prospective, two-centre epidemiological AFOTS Incidence study will enroll 250 consecutive participants without a history of AF but with at increased risk of AF (Age ≥ 65 or >50 with one risk factor for AF) admitted to intensive care units (ICUs) for medical illness or non-cardiac surgery. Upon admission, participants will wear an ECG patch monitor that will remain in place for 14 days, or until discharge from hospital. Patients' consent to participation is deferred for up to 72 h after admission. The primary endpoint is the incidence of AF lasting ≥30 s. The study is powered to detect an AF incidence of 17% ±â€¯5%. RESULTS: We conducted a vanguard feasibility study, and 55 participants have completed participation. The median duration of monitoring was seven days. AF was detected by the clinical team in 8 participants (14%; 95% Confidence Interval 7-26%). CONCLUSIONS: The AFOTS Incidence study will employ a systematic and highly sensitive protocol for detecting AFOTS in medical illness and non-cardiac surgery ICU patients. This study is feasible and will provide a reliable estimate of the true incidence of AFOTS in this population.

Steroids in cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory reaction that may contribute to postoperative complications. Preventing this reaction with steroids may improve outcomes. We performed a systematic review to evaluate the impact of prophylactic steroids on clinical outcomes in patients undergoing on-pump cardiac surgery. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL for randomised controlled trials (RCTs) comparing perioperative corticosteroid administration with a control group in adults undergoing CPB. Outcomes of interest included mortality, myocardial infarction, and new onset atrial fibrillation. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Fifty-six RCTs published between 1977 and 2015 were included in this meta-analysis. Mortality was not significantly different between groups [3.0% (215/7258 patients) in the steroid group and 3.5% (252/7202 patients) in the placebo group; relative risk (RR), 0.85; 95% confidence interval (CI), 0.71-1.01; P=0.07; I2 = 0%]. Myocardial injury was more frequent in the steroid group [8.0% (560/6989 patients), compared with 6.9% (476/6929 patients); RR, 1.17, 95% CI, 1.04-1.31; P=0.008; I2=0%]. New onset atrial fibrillation was lower in the steroid group [25.7% (1792/6984 patients) compared with 28.3% (1969/6964 patients), RR, 0.91, 95% CI, 0.86-0.96, P=0.0005, I2=43%]; this beneficial effect was limited to small trials (P for interaction <0.00001). CONCLUSIONS: After randomising 16 013 patients, steroid administration at the time of cardiac surgery had an unclear impact on mortality, increased the risk of myocardial injury, and the impact on atrial fibrillation should be viewed with caution given that large trials showed no effect.

Efficacy and safety of inhaled anaesthetic for postoperative sedation during mechanical ventilation in adult cardiac surgery patients: a systematic review and meta-analysis.

The aim was to evaluate the efficacy and safety of volatile anaesthetic for postoperative sedation in adult cardiac surgery patients through a systematic review and meta-analysis. We retrieved randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Web of Science, clinical trials registries, conference proceedings, and reference lists of included articles. Independent reviewers extracted data, including patient characteristics, type of intraoperative anaesthesia, inhaled anaesthetic used, comparator sedation, and outcomes of interest, using pre-piloted forms. We assessed risk of bias using the Cochrane Tool and evaluated the strength of the evidence using the GRADE approach. Eight studies enrolling 610 patients were included. Seven had a high and one a low risk of bias. The times to extubation after intensive care unit (ICU) admission and sedation discontinuation were, respectively, 76 [95% confidence interval (CI) -150 to - 2, I2=79%] and 74 min (95% CI - 126 to - 23, I2=96%) less in patients who were sedated using volatile anaesthetic. There was no difference in ICU or hospital length of stay. Patients who received volatile anaesthetic sedation had troponin concentrations that were 0.71 ng ml-1 (95% CI 0.23-1.2) lower than control patients. Reporting on other outcomes was varied and not suitable for meta-analysis. Volatile anaesthetic sedation may be associated with a shorter time to extubation after cardiac surgery but no change in ICU or hospital length of stay. It is associated with a significantly lower postoperative troponin concentration, but the impact of this on adverse cardiovascular outcomes is uncertain. Blinded randomized trials using intention-to-treat analysis are required. PROSPERO registry number: 2016:CRD42016033874. Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016033874.

The effects of progressing and nonprogressing Mycobacterium avium ssp. paratuberculosis infection on milk production in dairy cows.

Longitudinal data from 3 commercial dairy herds in the northeast United States, collected from 2004 to 2011, were analyzed to determine the effect of Mycobacterium avium ssp. paratuberculosis (MAP) infection status and progression path on milk production. Disease status, as indicated by MAP test results, was determined through quarterly ELISA serum testing, biannual fecal culture, and culture of tissues and feces at slaughter. Milk production data were collected from the Dairy Herd Information Association. Animals with positive MAP test results were categorized, based on test results over the full course of the study, as high path (at least one high-positive culture) or low path (at least one positive culture or ELISA). The cumulative numbers of positive ELISA and culture results were recorded. The effects of both MAP infection path, status, and number of positive tests on milk production were analyzed using a mixed linear model with an autocorrelation random effect structure. Low- and high-path animals produced more milk before their first positive test than always-negative animals, especially high-path animals. Although mean production decreased after a first positive test, low-path animals were shown to recover some productivity. High-path animals continued to exhibit a decrease in milk production, especially after their first high-positive fecal culture. These results show that not all animals that test positive for MAP will have long-term production losses. Milk production decreased significantly with each additional positive test. Ultimately, production loss appeared to be a function of MAP infection progression.

Quantifying energy intake in Pacific bluefin tuna (Thunnus orientalis) using the heat increment of feeding.

Using implanted archival tags, we examined the effects of meal caloric value, food type (sardine or squid) and ambient temperature on the magnitude and duration of the heat increment of feeding in three captive juvenile Pacific bluefin tuna. The objective of our study was to develop a model that can be used to estimate energy intake in wild fish of similar body mass. Both the magnitude and duration of the heat increment of feeding (measured by visceral warming) showed a strong positive correlation with the caloric value of the ingested meal. Controlling for meal caloric value, the extent of visceral warming was significantly greater at lower ambient temperature. The extent of visceral warming was also significantly higher for squid meals compared with sardine meals. By using a hierarchical Bayesian model to analyze our data and treating individuals as random effects, we demonstrate how increases in visceral temperature can be used to estimate the energy intake of wild Pacific bluefin tuna of similar body mass to the individuals used in our study.

Variation for host range within and among populations of the parasitic plant Striga hermonthica.

Striga hermonthica is an angiosperm parasite that causes substantial damage to a wide variety of cereal crop species, and to the livelihoods of subsistence farmers in sub-Saharan Africa. The broad host range of this parasite makes it a fascinating model for the study of host-parasite interactions, and suggests that effective long-term control strategies for the parasite will require an understanding of the potential for host range adaptation in parasite populations. We used a controlled experiment to test the extent to which the success or failure of S. hermonthica parasites to develop on a particular host cultivar (host resistance/compatibility) depends upon the identity of interacting host genotypes and parasite populations. We also tested the hypothesis that there is a genetic component to host range within individual S. hermonthica populations, using three rice cultivars with known, contrasting abilities to resist infection. The developmental success of S. hermonthica parasites growing on different rice-host cultivars (genotypes) depended significantly on a parasite population by host-genotype interaction. Genetic analysis using amplified fragment length polymorphism (AFLP) markers revealed that a small subset of AFLP markers showed 'outlier' genetic differentiation among sub-populations of S. hermonthica attached to different host cultivars. We suggest that, this indicates a genetic component to host range within populations of S. hermonthica, and that a detailed understanding of the genomic loci involved will be crucial in understanding host-parasite specificity and in breeding crop cultivars with broad spectrum resistance to S. hermonthica.

The use of transcutaneous oximetry to predict healing complications of lower limb amputations: a systematic review and meta-analysis.

OBJECTIVE: To determine the validity of transcutaneous oximetry (TcPO(2)) as a predictor of lower limb amputation healing complications. DESIGN: A systematic review and meta-analysis. METHODS: We searched five major medical databases, relevant review articles and reference lists and included all studies that evaluated TcPO(2) for its ability to predict lower limb amputation healing failure. We selected eligible articles and conducted data abstraction independently and in duplicate. RESULTS: Thirty-one studies, enrolling 1824 patients with 1960 amputations, met our inclusion criteria. Only one study reported undertaking a multivariable analysis, which demonstrated that a TcPO(2) level below 20 mmHg was an independent predictor of re-amputation occurrence (adjusted odds ratio (OR) 3.08, 95% confidence interval (CI) 1.19-7.98). Fourteen prospective cohort studies reported data that allowed for the calculation of an unadjusted relative risk of lower limb amputation healing complications leading to amputation revision associated with a TcPO(2) level below cut-offs of 10 mmHg (1.80; 95% CI 1.19-2.72), 20 mmHg (1.75; 95% CI 1.27-2.40) 30 mmHg (1.41; 95% CI 1.22-1.62) and 40 mmHg (1.24; 95% CI 1.13-1.39). CONCLUSIONS: This review suggests that TcPO(2) predicts healing complications of lower limb amputations. A value of less than 40 mmHg results in a 24% increased risk of healing complication compared to over 40 mmHg and the risk further increases as the TcPO(2) decreases. There is, however, insufficient evidence to judge whether this tool adds important information beyond clinical data or to suggest an optimal threshold value. There is a need for a large, sufficiently powered study that adjusts for appropriate clinical variables.

Identification of loci associated with tolerance to Johne's disease in Holstein cattle.

Johne's disease, caused by Mycobacterium avium subspecies paratuberculosis (Map), is a fatal disease in cattle. The objective of this study was to identify loci associated with tolerance in cows infected with Map. Tolerance was defined as a cow's fitness at a given level of Map infection intensity. Fitness was measured by Map faecal cultures, and Map infection intensity was measured by culturing four gut tissues. The quantitative phenotype of tolerance was defined by numerical indexes of cultures of peak (peak tolerance, PT) and average (average tolerance, AT) faecal and tissue Map from 245 Holstein cows. The categorical phenotype was defined as: ≥ 100 cfu Map tissue infection, and faecal shedding ≥ 75 cfu (intolerant) or <10 cfu (tolerant cows). In 94 cows, Map was identified in ≥ 1 tissue, including 44 cows with ≥ 100 Map tissue cfu and 36 with ≥ 1 faecal cfu. A genome-wide association analysis was performed after filtering, leaving genotypes for 45,789 SNPs in 90 animals for the quantitative phenotype and 16 cases and 25 controls for the categorical analysis of tolerance. rs41748405:A>C (BTA15) was associated with PT (P = 1.12 × 10(-7)) and AT (P = 2.17 × 10(-6)). Associations were identified with PT and adjacent SNPs ss61512613:A>G and ss61530518:A>G (BTA6) (P < 3.0 × 10(-5)), and with AT for ss61469568:A>G (BTA 2) (P = 3.3 × 10(-5)) and ss86284768:A>G (BTA1) (P = 3.31 × 10(-5)). For the categorical phenotype, an association was found with ss8632653:A>G (BTA6) (P < 5.0 × 10(-5)). This is the first study to identify loci associated with tolerance to Johne's disease.

Short communication: refinement of genetic regions associated with Mycobacterium avium subspecies paratuberculosis tissue infection and tolerance to Johne's disease.

Johne's disease is a highly transmissible bacterial disease caused by Mycobacterium avium ssp. paratuberculosis (MAP). The objective of this study was to refine the locus associated with MAP tissue infection and the locus associated with tolerance to Johne's disease. Using a genome-wide association analysis, single nucleotide polymorphisms associated with MAP tissue infection and tolerance to Johne's disease on Bos taurus autosome (BTA)3 and BTA15, respectively, have previously been identified. A 235-kb region on BTA3 was evaluated with 42 single nucleotide polymorphisms, and a 193-kb region on BTA15 was evaluated with 54 single nucleotide polymorphisms in a group of 209 Holstein cows. Using a single marker association analysis and haplotype tests, we refined a region of 10.6 kb on BTA3 as being associated with MAP tissue infection and a region of 6.5 kb on BTA15 as being associated with tolerance to Johne's disease.

Effect of Johne's disease status on reproduction and culling in dairy cattle.

Among the costs attributed to Mycobacterium avium ssp. paratuberculosis (MAP) infection in dairy cattle, the effects on reproduction and culling are the least documented. To estimate the cost of MAP infections and Johne's disease in a dairy herd, the rates of calving and culling were calculated for cows in each stage of MAP infection relative to uninfected cows. Data from 6 commercial dairy herds, consisting of 2,818 cows with 2,754 calvings and 1,483 cullings, were used for analysis. Every cow in each study herd was tested regularly for MAP, and herds were followed for between 4 and 7 yr. An ordinal categorical variable for Johne's disease status [test-negative, low-positive (low-shedding or ELISA-positive only), or high-shedding] was defined as a time-dependent variable for all cows with at least 1 positive test result or 2 negative test results. A Cox regression model, stratified on herd and controlling for the time-dependent infection variable, was used to analyze time to culling. Nonshedding animals were significantly less likely to be culled in comparison with animals in the low-shedding or ELISA-positive category, and high-shedding animals had nonsignificantly higher culling rates than low-shedding or ELISA-positive animals. Time to calving was analyzed using a proportional rates model, an analog to the Andersen-Gill regression model suitable for recurrent event data, stratifying on herd and weighted to adjust for the dependent censoring caused by the culling effects described above. High-shedding animals had lower calving rates in comparison with low-shedding or ELISA-positive animals, which tended to have higher calving rates than test-negative animals.

Fluid transport in the rabbit gallbladder. A combined physiological and electron microscopic study.

The fine structure of the rabbit gallbladder has been studied in specimens whose functional state was undetermined, which were fixed either in situ or directly after removal from the animal; in specimens whose rate of fluid absorption was determined, either in vivo or in vitro, immediately prior to fixation; and in specimens from bladders whose absorptive function was experimentally altered in vitro. Considerable variation was found in the width of the epithelial intercellular spaces in the bladders whose functional state was undefined. In bladders known to be transporting fluid, either in vivo or in vitro, the intercellular spaces were always distended, as were the subepithelial capillaries. This distension was greatest in bladders which had been functioning in vitro. When either Na(+) or Cl(-) was omitted from the bathing media, there was no fluid transport across the wall of the gallbladder studied in vitro. The epithelial intercellular spaces of biopsies taken from several bladders under these conditions were of approximately 200 A width except for minor distension at the crests of mucosal folds. The addition of the missing ion rapidly led to the reestablishment of fluid transport and the distension of the intercellular spaces throughout most of the epithelium of these bladders. Studies of sodium localization (by fixation with a pyroantimonate-OsO(4) mixture) showed high concentrations of this ion in the distended intercellular spaces. Histochemical studies of ATPase activity showed that this enzyme was localized along the lateral plasma membrane of the epithelial cells. The analogy is drawn between the structure of the gallbladder mucosa and a serial membrane model proposed by Curran to account for coupled solute-solvent transport across epithelia. It is concluded that the intercellular compartment fulfills the conditions for the middle compartment of the Curran model and that active transport of solute across the lateral plasma membrane into the intercellular space may be responsible for fluid absorption by the gall bladder.

A whole genome association analysis identifies loci associated with Mycobacterium avium subsp. paratuberculosis infection status in US holstein cattle.

The purpose of this study was to identify loci associated with Mycobacterium avium subspecies paratuberculosis (Map) infection status in US Holsteins using the Illumina BovineSNP50 BeadChip whole genome single nucleotide polymorphism (SNP) assay. Two hundred forty-five cows from dairies in New York, Pennsylvania and Vermont enrolled in longitudinal herd studies between January 1999 and November 2007 were assessed for the presence of Map in both faecal and tissue samples. An animal was considered tissue infected if any sample contained at least one colony forming unit of Map per gram of tissue (CFU/g) and the same definition was employed for faecal samples. Each animal was genotyped with the Illumina BovineSNP50 BeadChip and after quality assurance filtering, 218 animals and 45 683 SNPs remained. We sought to identify loci associated with four different case/control classifications: presence of Map in the tissue, presence of Map in faeces, presence of Map in both tissue and faeces and presence of Map in tissue but not faeces. A case-control genome wide association study was conducted to test the four different classifications of Map infection status (cases) when compared with a Map-negative control group (control). Regions on chromosomes 1, 5, 7, 8, 16, 21 and 23 were identified with moderate significance (P < 5 x 10(-5)). Two regions, one on chromosome 3 (near EDN2) and another on chromosome 9 (no positional gene candidates), were identified with a high level of association to the presence of Map in tissue and both tissue and faeces respectively (P < 5 x 10(-7), genome-wide Bonferonni P < 0.05).

A longitudinal study on the impact of Johne's disease status on milk production in individual cows.

Longitudinal data from 3 commercial dairy herds in the northeast United States were collected from 2004 to 2007. Johne's disease status, as indicated by Mycobacterium avium ssp. paratuberculosis infection levels, was determined through quarterly ELISA serum testing, biannual fecal culture, and culture of tissues at slaughter. Milk production data were collected from the Dairy Herd Improvement Association. The effect of Johne's disease status on milk production was analyzed using a mixed linear model with an autocorrelation random effect structure. Infected animals produced more milk than uninfected cows before they began shedding M. avium ssp. paratuberculosis. Cows infected with M. avium ssp. paratuberculosis had monthly decreases of 0.05 to 1 kg in daily milk production relative to uninfected animals, with greater decreases in progressive disease categories. Animals with fecal culture results of >30 cfu/g produced approximately 4 kg less milk per day compared with uninfected cows. These results will be valuable in calculating the economic effect of Johne's disease.

Reliability of environmental sampling to quantify Mycobacterium avium subspecies paratuberculosis on California free-stall dairies.

The reliability of environmental sampling to quantify Mycobacterium avium ssp. paratuberculosis (MAP) based on collector and time was evaluated. Fecal slurry samples were collected using a standardized protocol simultaneously by 2 collectors of different experience levels. Samples were collected from 30 cow pens on 4 dairies every other day on 3 occasions while cow movements between pens were minimal. The 4 study herds had moderate MAP seroprevalence and were housed in free-stall dairies in central California. Results of testing the environmental samples for MAP using PCR and culture were strongly correlated. The reliability of environmental sampling simultaneously by different collectors as estimated by the intraclass correlation coefficient was excellent (81%) for PCR and good (67%) for culture and may justify comparison of quantitative results of samples collected by different investigators. The reliability of environmental sampling over a 5-d period was good (67 and 64% for PCR and culture results, respectively), which justifies the utility of environmental sampling to identify pens with a high MAP bioburden between routine cow pen changes on a dairy. Environmental sampling of free-stall pens using the standardized sampling protocol yielded comparable PCR and culture results across collectors with different experience levels and at different times within a 5-d period.

Dynamics of endemic infectious diseases of animal and human importance on three dairy herds in the northeastern United States.

Endemic infectious diseases in dairy cattle are of significant concern to the industry as well as for public health because of their potential impact on animal and human health, milk and meat production, food safety, and economics. We sought to provide insight into the dynamics of important endemic infectious diseases in 3 northeastern US dairy herds. Fecal samples from individual cows and various environmental samples from these farms were tested for the presence of major zoonotic pathogens (i.e., Salmonella, Campylobacter, and Listeria) as well as commensal bacteria Escherichia coli and enterococci. Additionally, the presence of Mycobacterium avium ssp. paratuberculosis was tested in fecal and serum samples from individual cows. Test results and health and reproductive records were maintained in a database, and fecal, plasma, DNA, and tissue samples were kept in a biobank. All bacteria of interest were detected on these farms and their presence was variable both within and between farms. The prevalence of Listeria spp. and L. monocytogenes in individual fecal samples within farm A ranged from 0 to 68.2% and 0 to 25.5%, respectively, over a period of 3 yr. Within farm B, continuous fecal shedding of Salmonella spp. was observed with a prevalence ranging from 8 to 88%; Salmonella Cerro was the predominant serotype. Farm C appeared less contaminated with Salmonella and Listeria, although in the summer of 2005, 50 and 19.2% of fecal samples were positive for Listeria and L. monocytogenes, respectively. The high prevalence of E. coli (89 to 100%), Enterococcus (75 to 100%), and Campylobacter (0 to 81%) in feces suggested they were ubiquitous throughout the farm environment. Fecal culture and ELISA results indicated a low prevalence of Mycobacterium avium ssp. paratuberculosis infection in these farms (0 to 13.6% and 0 to 4.9% for culture-positive and ELISA-positive, respectively), although the occasional presence of high shedders was observed. Results have major implications for food safety and epidemiology by providing a better understanding of infectious disease dynamics on dairy farms. Comprehensive understanding of these infections may lead to better farm management practices and pathogen reduction programs to control and reduce the on-farm contamination of these pathogens and to prevent their further entry into the food-chain.

Transmission parameters of Mycobacterium avium subspecies paratuberculosis infections in a dairy herd going through a control program.

A Johne's disease control program, including stringent management practices and a test-and-cull program (whole-herd fecal-samples taken twice a year), was implemented on a medium-sized Pennsylvania dairy farm that was suffering losses from clinical Johne's disease. The data that emerged from the control program, combined with birthdates, culling dates, lactation information and pedigrees, yielded an extensive longitudinal dataset. The dataset was processed through SAS 9.1 for statistical analysis; herd-level disease dynamics and dam-to-daughter transmission parameters were calculated. After the implementation of the program in 1984, prevalence dropped dramatically from 60% to less than 20% in 1989. After an apparent prevalence peak (25%) in 1991 due to improved test sensitivity, prevalence maintained a plateau of 10% from 1996 to 2000. After the implementation of the program, 9.5% of the offspring from test-negative dams and 26.8% of the offspring from known-infected dams became infected with Mycobacterium avium subspecies paratuberculosis (Map) (chi(2)=14.7; p=0.0001). Calves born shortly following the calving of an infected dam and calves growing up with a future high shedder were more likely to be infected compared to calves without this risk profile. It was concluded that, after the implementation of the control program, the most important causes of infections of susceptible calves were their own dams or infected animals which had calved recently.

Simulation modeling to evaluate the persistence of Mycobacterium avium subsp. paratuberculosis (MAP) on commercial dairy farms in the United States.

We developed a series of deterministic mathematical models of Mycobacterium avium subsp. paratuberculosis (MAP) transmission on commercial US dairies. Our models build upon and modify models and assumptions in previous work to better reflect the pathobiology of the disease. Parameter values were obtained from literature for animal turnover in US dairy herds and rates of transition between disease states. The models developed were used to test three hypotheses. (1) Infectious transmission following intervention is relatively insensitive to the presence of high-shedding animals. (2) Vertical and pseudo-vertical transmission increases prevalence of disease but is insufficient to explain persistence following intervention. (3) Transiently shedding young animals might aid persistence. Our simulations indicated that multiple levels of contagiousness among infected adult animals in combination with vertical transmission and MAP shedding in infected young animals explained the maintenance of low-prevalence infections in herds. High relative contagiousness of high-shedding adult animals resulted in these animals serving as the predominant contributor to transmission. This caused elimination of infection in herds using the test-and-cull intervention tested in these simulations. Addition of vertical transmission caused persistence of infection in a moderately complicated model. In the most complex model that allowed age-based contacts, calf-to-calf transmission was required for persistence.

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia.

Essentials The immunogenesis of Heparin-induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)-heparin occurs early in life, before any heparin exposure. PF4 and PF4-heparin complexes induce the proliferation of CD14+ cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [3 H]thymidine uptake and 5-ethynyl-2'-deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14+ cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin-10 and transforming growth factor-ß1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT.

Once versus twice daily aspirin after coronary bypass surgery: a randomized trial.

Essentials Coronary artery bypass graft (CABG) failure is associated with myocardial infarction and death. We tested whether more frequent dosing improves aspirin (ASA) response following CABG surgery. Twice-daily compared with once-daily dosing reduces ASA hyporesponsiveness after CABG surgery. The efficacy of twice-daily ASA needs to be tested in a trial powered for clinical outcomes. SUMMARY: Background Acetyl-salicylic acid (ASA) hyporesponsiveness occurs transiently after coronary artery bypass graft (CABG) surgery and may compromise the effectiveness of ASA in reducing thrombotic graft failure. A reduced response to ASA 81 mg once-daily after CABG surgery is overcome by four times daily ASA dosing. Objectives To determine whether ASA 325 mg once-daily or 162 mg twice-daily overcomes a reduced response to ASA 81 mg once-daily after CABG surgery. Methods Adults undergoing CABG surgery were randomized to ASA 81 mg once-daily, 325 mg once-daily or 162 mg twice-daily. The primary outcome was median serum thromboxane B2 (TXB2 ) level on postoperative day 4. We pooled the results with those of our earlier study to obtain better estimates of the effect of ASA 325 mg once-daily or in divided doses over 24 h. Results We randomized 68 patients undergoing CABG surgery. On postoperative day 4, patients randomized to receive ASA 81 mg once-daily had a median day 4 TXB2 level of 4.2 ng mL-1 (Q1, Q3: 1.5, 7.5 ng mL-1 ), which was higher than in those randomized to ASA 162 mg twice-daily (1.1 ng mL-1 ; Q1, Q3: 0.7, 2.7 ng mL-1 ) and similar to those randomized to ASA 325 mg once-daily (1.9 ng mL-1 ; Q1, Q3: 0.9, 4.7 ng mL-1 ). Pooled data showed that the median TXB2 level on day 4 in groups receiving ASA 162 mg twice-daily or 81 mg four times daily was 1.1 ng mL-1 compared with 2.2 ng mL-1 in those receiving ASA 325 mg once-daily. Conclusions Multiple daily dosing of ASA is more effective than ASA 81 mg once-daily or 325 mg once-daily at suppressing serum TXB2 formation after CABG surgery. A twice-daily treatment regimen needs to be tested in a clinical outcome study.