The utility of delta troponin in diagnosing significant coronary artery disease in patients with symptomatic atrial fibrillation.

BACKGROUND: Troponin I (cTnI) elevation is common in patients with atrial fibrillation (AF) but does not reliably indicate underlying coronary ischemia. We investigated whether dynamic changes in cTnI value (delta troponin) are useful in revealing significant coronary artery disease (sCAD) in patients presenting with symptomatic AF. METHODS: We conducted a retrospective case-control study analyzing serial cTnI values in 231 patients presenting with symptomatic AF who had an objective assessment for underlying CAD within 6 months of the index admission. Diagnostic performance of an elevated cTnI (>0.04 µg/L) only, and elevated cTnI coupled with Youden Index derived cutoffs for absolute and relative changes in troponin, for distinguishing patients with sCAD, was evaluated. RESULTS: A total of 107 patients had an elevated cTnI on serial measurements. In this group, the area under the receiver operating characteristic curve was 0.69 [95% confidence interval (CI), 0.56-0.81] for relative delta troponin and 0.71 (95% CI, 0.59-0.83) for absolute delta troponin. The optimal diagnostic cutoff for relative delta troponin was > -0.42, and > -0.055 µg/L for absolute delta troponin. The specificity of elevated troponin to diagnose sCAD increased from 56 to 77% when relative delta troponin was added, and to 88% with absolute delta troponin. Although the sensitivity of cTnI elevation (57.1%) decreased to 50% for relative and 35.7% for absolute delta troponin, the negative predictive values were high and similar at 86%. CONCLUSION: When added to the troponin peak, delta troponin is a promising test for the diagnosis of significant coronary artery disease in patients presenting with symptomatic AF with elevated cTnI. This result requires prospective validation in a larger cohort of patients.

The in-vivo dynamics of Plasmodium falciparum HRP2: implications for the use of rapid diagnostic tests in malaria elimination.

BACKGROUND: Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of PfHRP2 over the course of a malaria infection can inform optimal use of RDTs. METHODS: A previously published mathematical model was refined to mimic the production and decay of PfHRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal PfHRP2 concentrations were measured. RESULTS: The refinement of the PfHRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10-15 g (95% CI 25.0-42.1 × 10-15 g) of PfHRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11-3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of PfHRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range. CONCLUSIONS: The updated mathematical model can predict the growth and clearance of PfHRP2 during the production and decay of a mono-infection with P. falciparum, increasing the understanding of PfHRP2 antigen dynamics. This model can guide the optimal use of PfHRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.

Destructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer.

Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed > 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy; 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRRadj = 2.1, 95% confidence interval (CI) 1.4-3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.

Acute Mountain Sickness Following Incremental Trekking to High Altitude: Correlation With Plasma Vascular Endothelial Growth Factor Levels and the Possible Effects of Dexamethasone and Acclimatization Following Re-exposure.

Purpose: The recognition and treatment of high-altitude illness (HAI) is increasingly important in global emergency medicine. High altitude related hypobaric hypoxia can lead to acute mountain sickness (AMS), which may relate to increased expression of vascular endothelial growth factor (VEGF), and subsequent blood-brain barrier (BBB) compromise. This study aimed to establish the relationship between AMS and changes in plasma VEGF levels during a high-altitude ascent. VEGF level changes with dexamethasone, a commonly used AMS medication, may provide additional insight into AMS. Methods: Twelve healthy volunteers ascended Mt Fuji (3,700 m) and blood samples were obtained at distinct altitudes for VEGF analysis. Oxygen saturation (SPO2) measurements were also documented at the same time-point. Six out of the 12 study participants were prescribed dexamethasone for a second ascent performed 48 h later, and blood was again collected to establish VEGF levels. Results: Four key VEGF observations could be made based on the data collected: (i) the baseline VEGF levels between the two ascents trended upwards; (ii) those deemed to have AMS in the first ascent had increased VEGF levels (23.8-30.3 pg/ml), which decreased otherwise (23.8-30.3 pg/ml); (iii) first ascent AMS participants had higher VEGF level variability for the second ascent, and similar to those not treated with dexamethasone; and (iv) for the second ascent dexamethasone participants had similar VEGF levels to non-AMS first ascent participants, and the variability was lower than for first ascent AMS and non-dexamethasone participants. SPO2 changes were unremarkable, other than reducing by around 5% irrespective of whether measurement was taken for the first or second ascent. Conclusion: First ascent findings suggest a hallmark of AMS could be elevated VEGF levels. The lack of an exercise-induced VEGF level change strengthened the notion that elevated plasma VEGF was brain-derived, and related to AMS.

Vaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial.

BACKGROUND: Control of human hookworm infection would be greatly aided by the development of an effective vaccine. We aimed to develop a live attenuated human hookworm vaccine. METHODS: This was a two-part clinical trial done at Q-Pharm in Brisbane (QLD, Australia) using a live ultraviolet C (UVC)-attenuated Necator americanus larvae vaccine. Part one was an open-label, dose-finding study using 50 L3 larvae suspended in water to a volume of 200 µL, attenuated with UVC exposure of 700 µJ (L3-700) or 1000 µJ (L3-1000). Part two was a randomised, double-blind, placebo-controlled, challenge study, in which participants were randomly assigned 2:1 to the vaccine group or placebo group. Healthy hookworm-naive adults aged 18-65 years with body-mass index 18-35 kg/m2 received two doses of either placebo (Tabasco sauce) or vaccine (50 L3-700) on day 1 and day 42, followed by challenge with 30 unattenuated L3 larvae to both groups. All participants received a single oral dose of 400 mg albendazole 4 weeks after each inoculation and a 3-day course (400 mg orally daily) initiated on day 161 after the challenge phase, to eliminate any remaining infection. The primary outcome of part 1 was the level of larval attenuation the resulted in a grade 2 or 3 dermal adverse event. The primary outcome of part 2 was safety and tolerability, assessed by frequency and severity of adverse events in all randomly assigned participants. Prespecified exploratory outcomes in the challenge study were faecal N americanus DNA concentration, the number of N americanus larvae recovered per g of faeces cultured, hookworm antigen-specific serum IgG antibody responses, and hookworm antigen-specific peripheral blood cytokine responses. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617001007325). FINDINGS: Between Sept 19, 2017, and Oct 24, 2018, seven participants were enrolled into three cohorts in part one (two participants in cohort 1, who received L3-700; two participants in cohort 2, who received L3-700; and three participants in cohort 3, who received L3-1000) and a further 15 were enrolled into part two. There were no serious adverse events in part one or part two. In part one, a greater number of skin penetration sites were observed after administration of L3-700 than L3-1000 (mean 15·75 [95% CI 11·18 to 20·32] with L3-700 vs 4·33 [-1·40 to 10·07] with L3-1000). Similarly, greater erythema (median 225 mm2 [IQR 150 to 325] vs 25 mm2 [12·5 to 80]) and a longer duration of the dermal reaction (median 8·0 days [IQR 3·5 to 11·5] vs 2·0 days [2·0 to 4·5]) were observed after L3-700 than L3-1000. The mean number of adverse events per participant did not differ between the groups (3·25 [95% CI 1·48 to 5·02] vs 3·00 [1·04 to 4·96]). Thus, L3-700 was used for vaccination in part two. In part two, ten participants were randomly assigned to receive L3-700 and five to placebo. Significantly more adverse events occurred after vaccination with attenuated larvae than with placebo (incident rate ratio [IRR] 2·13 [95% CI 2·09 to 5·51]; p=0·0030). There was no difference between groups in the frequency of adverse events after challenge (IRR 1·25 [0·78 to 2·01]; p=0·36). Most adverse events were mild in severity, with only one severe adverse event reported (erythematous and indurated pruritic rash >100 mm in a vaccine group participant after challenge). The eosinophil count increased in all participants after challenge, with a significantly greater increase among vaccinated participants than placebo participants (1·55 × 109 cells per L [IQR 0·92 to 1·81] in the vaccine group vs 0·49 × 109 cells per L [0·43 to 0·63] in the placebo group; p=0·014). Vaccinated participants had an IgG response to larval extract after challenge that was higher than that in placebo participants (increase in IgG titre 0·22 [IQR 0·10 to 0·41] vs 0·03 [-0·40 to 0·06]; p=0·020). Significantly fewer larvae per g of faeces were recovered in the vaccine group than in the placebo group after challenge (median larvae per g 0·8 [IQR 0·00 to 3·91] vs 10·2 [5·1 to 18·1]; p=0·014). The concentration of N americanus DNA in faeces was not significantly different between the vaccinated group and the placebo group (log10 DNA intensity 4·28 [95% CI 3·92 to 4·63] vs 4·88 [4·31 to 5·46]; p=0·14). Peripheral blood mononuclear cells from vaccinated participants exhibited significantly greater cytokine production at day 112 than placebo participants for IFNγ, TNFα, IL-2, IL-4, and IL-5 (p<0·05), but not IL-10. INTERPRETATION: Vaccination with UVC-attenuated N americanus larvae is well tolerated, induces humoral and cellular responses to hookworm antigens, and reduces larval output after challenge with unattenuated larvae. Larger studies are required to confirm protective efficacy. FUNDING: National Health and Medical Research Council of Australia.

Analytical validation of a real-time hydrolysis probe PCR assay for quantifying Plasmodium falciparum parasites in experimentally infected human adults.

BACKGROUND: Volunteer infection studies have become a standard model for evaluating drug efficacy against Plasmodium infections. Molecular techniques such as qPCR are used in these studies due to their ability to provide robust and accurate estimates of parasitaemia at increased sensitivity compared to microscopy. The validity and reliability of assays need to be ensured when used to evaluate the efficacy of candidate drugs in clinical trials. METHODS: A previously described 18S rRNA gene qPCR assay for quantifying Plasmodium falciparum in blood samples was evaluated. Assay performance characteristics including analytical sensitivity, reportable range, precision, accuracy and specificity were assessed using experimental data and data compiled from phase 1 volunteer infection studies conducted between 2013 and 2019. Guidelines for validation of laboratory-developed molecular assays were followed. RESULTS: The reportable range was 1.50 to 6.50 log10 parasites/mL with a limit of detection of 2.045 log10 parasites/mL of whole blood based on a parasite diluted standard series over this range. The assay was highly reproducible with minimal intra-assay (SD = 0.456 quantification cycle (Cq) units [0.137 log10 parasites/mL] over 21 replicates) and inter-assay (SD = 0.604 Cq units [0.182 log10 parasites/mL] over 786 qPCR runs) variability. Through an external quality assurance program, the QIMR assay was shown to generate accurate results (quantitative bias + 0.019 log10 parasites/mL against nominal values). Specificity was 100% after assessing 164 parasite-free human blood samples. CONCLUSIONS: The 18S rRNA gene qPCR assay is specific and highly reproducible and can provide reliable and accurate parasite quantification. The assay is considered fit for use in evaluating drug efficacy in malaria clinical trials.

Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients.

PURPOSE: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients. METHODS: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRsadj) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated. RESULTS: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RRadj 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RRadj 0.40, 95% CI 0.22-0.74). No other significant associations were seen. CONCLUSION: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.

Bacterial colonisation of the endotracheal tube in ventilated very preterm neonates: A retrospective cohort study.

AIM: To determine the rate, type and timing of bacterial endotracheal tube (ETT) colonisation in neonates born <32 weeks gestational age (GA); and if bacterial colonisation is associated with chronic lung disease (CLD), septicaemia, length-of-stay or mortality. METHODS: All intubated newborns born <32 weeks GA were included. Endotracheal aspirates were routinely obtained three times-per-week. Cohort was divided into three colonisation groups: no growth, normal respiratory flora only, significant bacteria. Logistic regression was performed to identify if ETT bacterial colonisation was associated with CLD, septicaemia or mortality. A general linear model was fitted for length-of-stay. RESULTS: ETT aspirates were sent from 1054 infants: no growth n = 319, only normal respiratory flora n = 357, and significant bacteria n = 378. ETTs became colonised in 70%, most in the first week of life (82%). Most grew normal respiratory flora (642 infants). In those with significant bacteria, 40% grew Gram-negative species; Klebsiella in 34%. Staphylococcus aureus grew in 104 patients. Adjusted odds ratios for CLD (43% of cohort) compared with no growth were, for normal respiratory flora, 0.58 (95% confidence interval (CI) 0.34-0.99) and, for significant bacteria, 0.48 (95% CI 0.24-0.93). With no overall association between colonisation group and CLD in the adjusted model P = 0.07. The odds of septicaemia (10% of cohort) were 4.50 (95% CI 1.98-10.23, P < 0.001) times greater for significant bacteria compared with no growth. No significant associated was found with mortality or length-of-stay. CONCLUSIONS: Bacterial colonisation of ETTs is common. It is associated with more septicaemia. There was no significant association with CLD, longer admission or mortality.

Centralised versus outreach models of cystic fibrosis care should be tailored to the needs of the individual patient.

Cystic fibrosis (CF) is a common life-limiting genetic condition. As the disease progresses access to specialist tertiary multi-disciplinary care services may become necessary. For patients living in regional/remote Australia, accessing such services may be a challenge. Here, we describe long-term outcomes for CF patients according to their access to specialist CF centre care in childhood.

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease.

INTRODUCTION: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled. METHODS: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year). RESULTS: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1-9); L3-20, 1 (0-9); and L3-40, 0 (0-3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, -0.6 [-1.3 to 0.2]; L3-20, -0.5 [-0.8 to 0.2]; and L3-40, -1.1 [-1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9-44] vs 45.9 [39.2-52.6]). DISCUSSION: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.

Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From Malaria Volunteer Infection Studies.

BACKGROUND: Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. METHODS: We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hours (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n = 66), sporozoites via mosquito bite (n = 336), or injection (n = 51). RESULTS: The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% confidence interval [CI], .73-.77/day), PMR48 was 31.9 (95% CI, 28.7-35.4), PMRLC was 16.4 (95% CI, 15.1-17.8), and parasite life-cycle was 38.8 hours (95% CI, 38.3-39.2 hours). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI, .67-.75/day; PMR48 26.6, 95% CI, 22.2-31.8) but significantly higher (P < .001) than in sporozoite studies (0.47/day, 95% CI, .43-.50/day; PMR48 8.6, 95% CI, 7.3-10.1). CONCLUSIONS: Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.

A validation study of microscopy versus quantitative PCR for measuring Plasmodium falciparum parasitemia.

Microscopy and 18S qPCR are the most common and field-friendly methods for quantifying malaria parasite density, and it is important that these methods can be interpreted as giving equivalent results. We compared results of quantitative measurement of Plasmodium falciparum parasitemia by microscopy and by 18S qPCR in a phase 2a study. Microscopy positive samples (n = 355; median 810 parasites/µL [IQR 40-10,471]) showed close agreement with 18S qPCR in mean log10/mL transformed parasitemia values by paired t test (difference 0.04, 95%CI - 0.01-0.10, p = 0.088). Excellent intraclass correlation (0.97) and no evidence of systematic or proportional differences by Passing-Bablok regression were observed. 18S qPCR appears to give equivalent parasitemia values to microscopy, which indicates 18S qPCR is an appropriate alternative method to quantify parasitemia in clinical trials.

Transmission of bacteria in bronchiectasis and chronic obstructive pulmonary disease: Low burden of cough aerosols.

BACKGROUND AND OBJECTIVE: Aerosol transmission of Pseudomonas aeruginosa has been suggested as a possible mode of respiratory infection spread in patients with cystic fibrosis (CF); however, whether this occurs in other suppurative lung diseases is unknown. Therefore, we aimed to determine if (i) patients with bronchiectasis (unrelated to CF) or chronic obstructive pulmonary disease (COPD) can aerosolize P. aeruginosa during coughing and (ii) if genetically indistinguishable (shared) P. aeruginosa strains are present in these disease cohorts. METHODS: People with bronchiectasis or COPD and P. aeruginosa respiratory infection were recruited for two studies. Aerosol study: Participants (n = 20) underwent cough testing using validated cough rigs to determine the survival of P. aeruginosa aerosols in the air over distance and duration. Genotyping study: P. aeruginosa sputum isolates (n = 95) were genotyped using the iPLEX20SNP platform, with a subset subjected to the enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) assay to ascertain their genetic relatedness. RESULTS: Aerosol study: Overall, 7 of 20 (35%) participants released P. aeruginosa cough aerosols during at least one of the cough aerosol tests. These cough aerosols remained viable for 4 m from the source and for 15 min after coughing. The mean total aerosol count of P. aeruginosa at 2 m was two colony-forming units. Typing study: No shared P. aeruginosa strains were identified. CONCLUSION: Low viable count of P. aeruginosa cough aerosols and a lack of shared P. aeruginosa strains observed suggest that aerosol transmission of P. aeruginosa is an unlikely mode of respiratory infection spread in patients with bronchiectasis and COPD.

A Randomized Trial of Baby Triple P for Preterm Infants: Child Outcomes at 2 Years of Corrected Age.

OBJECTIVE: To determine the efficacy of a hospital-based intervention that transitions into existing community support, in enhancing developmental outcomes at 2 years of corrected age in infants born at less than 32 weeks. STUDY DESIGN: In total, 323 families of 384 infants born <32 weeks were randomized to receive intervention or care-as-usual. The intervention teaches parents coping skills, partner support, and effective parenting strategies over 4 hospital-based and 4 home-phone sessions. At 2 years of corrected age maternally reported child behavior was assessed by the Infant and Toddler Social Emotional Adjustment Scale. Observed child behavior was coded with the Revised Family Observation Schedule. Cognitive, language, and motor skills were assessed with the Bayley Scales of Infant and Toddler Development III. RESULTS: Mean gestational age of infants was 28.5 weeks (SD = 2.1), and mothers' mean age was 30.6 years (SD = 5.8). A total of 162 families (n = 196 infants) were allocated to intervention and 161 families (n = 188 infants) received care-as-usual. There was no significant adjusted difference between treatment groups on dysregulation (0.2; 95% CI -2.5 to 3.0, P = .9) externalizing (0.3; 95% CI -1.6 to 2.2, P = .8), internalizing (-1.5; 95% CI -4.3 to 1.3, P = .3), observed aversive (0.00; -0.04 to 0.04, P = .9), or nonaversive behavior (-0.01; 95% CI -0.05 to 0.03, P = .7). Intervention children scored significantly higher on cognition (3.5; 95% CI 0.2-6.8, P = .04) and motor skill (5.5; 95% CI 2.5-8.4, P < .001), and approached significance on language (3.8; 95% CI -0.3 to 7.9, P = .07). CONCLUSIONS: Baby Triple P for Preterm Infants increases cognitive and motor skills but does not impact behavior. The results are evidence that hospital-based interventions can improve some developmental outcomes for infants <32 weeks. TRIAL REGISTRATION: ACTRN 12612000194864.

Probiotics for the Prevention of Gestational Diabetes Mellitus in Overweight and Obese Women: Findings From the SPRING Double-Blind Randomized Controlled Trial.

OBJECTIVE: Given the role of gut microbiota in regulating metabolism, probiotics administered during pregnancy might prevent gestational diabetes mellitus (GDM). This question has not previously been studied in high-risk overweight and obese pregnant women. We aimed to determine whether probiotics (Lactobacillus rhamnosus and Bifidobacterium animalis subspecies lactis) administered from the second trimester in overweight and obese women prevent GDM as assessed by an oral glucose tolerance test (OGTT) at 28 weeks' gestation. Secondary outcomes included maternal and neonatal complications, maternal blood pressure and BMI, and infant body composition. RESEARCH DESIGN AND METHODS: This was a double-blind randomized controlled trial of probiotic versus placebo in overweight and obese pregnant women in Brisbane, Australia. RESULTS: The study was completed in 411 women. GDM occurred in 12.3% (25 of 204) in the placebo arm and 18.4% (38 of 207) in the probiotics arm (P = 0.10). At OGTT, mean fasting glucose was higher in women randomized to probiotics (79.3 mg/dL) compared with placebo (77.5 mg/dL) (P = 0.049). One- and two-hour glucose measures were similar. Preeclampsia occurred in 9.2% of women randomized to probiotics compared with 4.9% in the placebo arm (P = 0.09). Excessive weight gain occurred in 32.5% of women in the probiotics arm (55 of 169) compared with 46% in the placebo arm (81 of 176) (P = 0.01). Rates of small for gestational age (<10th percentile) were 2.4% in the probiotics arm (5 of 205) and 6.5% in the placebo arm (13 of 199) (P = 0.042). There were no differences in other secondary outcomes. CONCLUSIONS: The probiotics used in this study did not prevent GDM in overweight and obese pregnant women.

Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei.

The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.

Evaluation of safety and immunogenicity of a group A streptococcus vaccine candidate (MJ8VAX) in a randomized clinical trial.

BACKGROUND: Group A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults. METHODS: A randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 µg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)-specific antibodies in serum samples. RESULTS: No serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies. CONCLUSIONS: Intramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies. TRIAL REGISTRATION: ACTRN12613000030774.

Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients.

Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388-1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis.

Addition of Supervised Exercise Training to a Post-Hospital Disease Management Program for Patients Recently Hospitalized With Acute Heart Failure: The EJECTION-HF Randomized Phase 4 Trial.

OBJECTIVES: This study sought to measure the impact on all-cause death or readmission of adding center-based exercise training (ET) to disease management programs for patients with a recent acute heart failure (HF) hospitalization. BACKGROUND: ET is recommended for patients with HF, but evidence is based mainly on ET as a single intervention in stable outpatients. METHODS: A randomized, controlled trial with blinded outcome assessor, enrolling adult participants with HF discharged from 5 hospitals in Queensland, Australia. All participants received HF-disease management program plus supported home exercise program; intervention participants were offered 24 weeks of supervised center-based ET. Primary outcome was all-cause 12-month death or readmission. Pre-planned subgroups included age (<70 years vs. older), sex, left ventricular ejection fraction (≤40% vs. >40%), and exercise adherence. RESULTS: Between May 2008 and July 2013, 278 participants (140 intervention, 138 control) were enrolled: 98 (35.3%) age ≥70 years, 71 (25.5%) females, and 62 (23.3%) with a left ventricular ejection fraction of >40%. There were no adverse events associated with ET. There was no difference in primary outcome between groups (84 of 140 [60.0%] intervention vs. 90 of 138 [65.2%] control; p = 0.37), but a trend toward greater benefit in participants age <70 years (OR: 0.56 [95% CI: 0.30 to 1.02] vs. OR: 1.56 [95% CI: 0.67 to 3.64]; p for interaction = 0.05). Participants who exercised to guidelines (72 of 101 control and 92 of 117 intervention at 3 months) had a significantly lower rate of death and readmission (91 of 164 [55.5%] vs. 41 of 54 [75.9%]; p = 0.008). CONCLUSIONS: Supervised center-based ET was a safe, feasible addition to disease management programs with supported home exercise in patients recently hospitalized with acute HF, but did not reduce combined end-point of death or readmission. (A supervised exercise programme following hospitalisation for heart failure: does it add to disease management?; ACTRN12608000263392).