Tobacco Harm Reduction with Vaporised Nicotine (THRiVe): A Feasibility Trial of Nicotine Vaping Products for Smoking Cessation Among People Living with HIV.

People living with HIV (PLHIV) have high rates of tobacco smoking. Nicotine vaping products (NVPs) may promote tobacco smoking cessation and/or harm reduction. This study aimed to trial the feasibility of NVPs for promoting tobacco smoking cessation among PLHIV. The Tobacco Harm Reduction with Vaporised Nicotine (THRiVe) study was a mixed-methods trial among 29 PLHIV who used tobacco daily. Participants trialled a 12-week intervention of NVPs. This study reports descriptive analyses of quantitative data on tobacco abstinence and associated adverse events. Short-term abstinence (7-day point prevalence; i.e., no tobacco use for 7 days) was achieved by 35% of participants at Week 12 and 31% reported short-term abstinence at Week 24. Sustained medium-term abstinence (8 weeks' abstinence) was achieved by 15% of participants at Week 12 and 31% at Week 24. Most adverse events were mild. NVPs may represent a feasible and potentially effective short-to-medium term tobacco smoking cessation aid and/or harm reduction strategy among PLHIV.

The Development of an Exercise Advisor App for Type 1 Diabetes: Digitization Facilitates More Individualized Guidance.

Maintaining blood glucose levels in the target range during exercise can be onerous for people with type 1 diabetes (T1D). Using evidence-based research and consensus guidelines, we developed an exercise advisor app to reduce some of the burden associated with diabetes management during exercise. The app will guide the user on carbohydrate feeding strategies and insulin management strategies before, during, and after exercise and provide targeted and individualized recommendations. As a basis for the recommendations, the decision trees for the app use various factors including the type of insulin regimen, time of activity, previous insulin boluses, and current glucose level. The app is designed to meet the various needs of people with T1D for different activities to promote safe exercise practices.

Use of Connected Pen as a Diagnostic Tool to Evaluate Missed Bolus Dosing Behavior in People with Type 1 and Type 2 Diabetes.

Objective: This study used connected pen to determine missed bolus dose (MBD) frequency during masked and unmasked continuous glucose monitoring (CGM) periods and examined its link with time-in-range (TIR), time-above-range (TAR), time-below-range (TBR), and key participant characteristics in people with diabetes. Methods: This was a 12-week, single-arm, exploratory, two-period study for people with type 1 diabetes (T1D) or type 2 diabetes (T2D). The primary objective was to estimate the average number of MBD during masked and real-time CGM use. The secondary objective was to estimate the average percent TIR and its relationship to MBD. An exploratory objective was to investigate the participant characteristics that were associated with MBD. Data were analyzed for differences in MBD by diabetes type and other participant characteristics, by CGM period, and by hypoglycemic fear scores. Results: Participants (n = 64; T1D, n = 38; T2D, n = 26) were 48 ± 11.9 years old and 44% were female. From the masked to the unmasked period, MBD, %TAR, %TBR, and glycated hemoglobin decreased significantly (0.74 MBD/day to 0.62 MBD/day, P = 0.008; 53.6%-48.1%, P = 0.004; 4.49%-2.93%, P < 0.001; mean 8.8%-8.4%, P < 0.001, respectively), while %TIR increased significantly (41.9%-49.0%, P < 0.001). MBD/day was negatively associated with TIR (P = 0.016) and positively associated with TAR (P = 0.015) for T1D and positively associated with TBR (P = 0.024) for T2D in the masked period only. MBD was significantly associated with fear of hypoglycemia for T2D, but not T1D. Conclusions: MBD is associated with reduced TIR when CGM is masked and tailored therapeutic approaches are needed for T1D and T2D populations.

Views and preferences of people living with HIV about smoking, quitting and use of nicotine products.

AIMS AND BACKGROUND: People living with HIV (PLHIV) have a higher rate of smoking and experience a greater burden of tobacco-related disease than the general population. This study aimed to understand the role smoking plays in the lives of PLHIV, participants' views of traditionally available nicotine products (e.g., nicotine replacement therapy or NRT) and novel nicotine products (e.g., nicotine vaping products or NVPs) as both short-term quit aids and long-term substitutes for cigarettes. METHODS: Semi-structured focus groups were conducted with PLHIV who smoked. Focus groups were transcribed and analysed using a combination of deductive and inductive thematic analysis. A brief questionnaire of nicotine product use and interest was also completed and the quantitative data presented using descriptive statistics. RESULTS: Fifty-four participants took part in 11 focus groups. Participants' views of smoking, quitting and nicotine products were diverse. Commitment to smoking and interest in quitting were categorised into three groups across a smoking-quitting continuum: committed to smoking, ambivalent about smoking and reluctantly smoking. NRT was criticised for a range of side effects and primarily considered as a short-term cessation aid. NVPs generated debate. NVPs that closely resembled cigarettes were viewed as the most acceptable product and were considered to be more suitable than NRT for long-term use. DISCUSSION AND CONCLUSIONS: Understanding the unique needs, goals and views of PLHIV related to smoking, quitting smoking and using nicotine products could inform development of novel and tailored smoking interventions for PLHIV. NVPs should be further examined as potential long-term substitutes for PLHIV who are ambivalent about smoking. However, traditional smoking cessation assistance (approved cessation aids and counselling) is likely to be most appropriate for PLHIV who are reluctantly smoking.

Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.).

Mucus-responsive functionalized emulsions: design, synthesis and study of novel branched polymers as functional emulsifiers.

Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus.

Understanding the Prevalence of Smoking Among People Living with HIV (PLHIV) in Australia and Factors Associated with Smoking and Quitting.

Understanding contributors to smoking and quitting cigarettes is important to developing effective cessation programs and addressing smoking related morbidity and mortality among people living with HIV (PLHIV). Using data from a large cross-sectional study of Australian PLHIV we provide a smoking prevalence estimate and explore the relationship between socio-demographic variables and smoking status. We also explore the relationship between HIV diagnosis and antiretroviral therapy (ART) initiation and quitting smoking. Of the 1011 respondents included in the analysis, 30.6% were current smokers. The strongest predictor of smoking was regular cannabis use (AOR 6.2, 95% CI 3.6-10.8) while the strongest predictor of being a past smoker was receiving ART (AOR 2.4, 95% CI 1.2-4.7). Quitting also increased around the time of diagnosis and ART initiation, highlighting the potential for these events to be optimal times to address smoking among PLHIV.

Experiences of Adults With Type 1 Diabetes Using Glucose Sensor-Based Mobile Technology for Glycemic Variability: Qualitative Study.

BACKGROUND: Adults with type 1 diabetes (PWDs) face challenging self-management regimens including monitoring their glucose values multiple times a day to assist with achieving glycemic targets and reduce the risk of long-term diabetes complications. Recent advances in diabetes technology have reportedly improved glycemia, but little is known about how PWDs utilize mobile technology to make positive changes in their diabetes self-management. OBJECTIVE: The aim of this qualitative study was to explore PWDs' experiences using Sugar Sleuth, a glucose sensor-based mobile app and Web-based reporting system, integrated with the FreeStyle Libre glucose monitor that provides feedback about glycemic variability. METHODS: We used a qualitative descriptive research design and conducted semistructured interviews with 10 PWDs (baseline mean glycated hemoglobin, HbA1c) 8.0%, (SD 0.45); 6 males and 4 females, aged 52 years (SD 15), type 1 diabetes (T1D) duration 31 years (SD 13), 40% (4/10, insulin pump) following a 14-week intervention during which they received clinical support and used Sugar Sleuth to evaluate and understand their glucose data. Audio-recorded interviews were transcribed, coded, and analyzed using thematic analysis and NVivo 11 (QSR International Pty Ltd). RESULTS: A total of 4 main themes emerged from the data. Participants perceived Sugar Sleuth as an Empowering Tool that served to inform lifestyle choices and diabetes self-management tasks, promoted preemptive self-care actions, and improved discussions with clinicians. They also described Sugar Sleuth as providing a Source of Psychosocial Support and offering relief from worry, reducing glycemic uncertainty, and supporting positive feelings about everyday life with diabetes. Participants varied in their Approaches to Glycemic Data: 40% (4/10) described using Sugar Sleuth to review data, understand glycemic cause and effect, and plan for future self-care. On the contrary, 60% (6/10) were reluctant to review past data; they described receiving benefits from the immediate numbers and trend arrows, but the app still prompted them to enter in the suspected causes of glucose excursions within hours of their occurrence. Finally, only 2 participants voiced Concerns About Use of Sugar Sleuth; they perceived the app as sometimes too demanding of information or as not attuned to the socioeconomic backgrounds of PWDs from diverse populations. CONCLUSIONS: Results suggest that Sugar Sleuth can be an effective educational tool to enhance both patient-clinician collaboration and diabetes self-management. Findings also highlight the importance of exploring psychosocial and socioeconomic factors that may advance the understanding of PWDs' individual differences when using glycemic technology and may promote the development of customized mobile tools to improve diabetes self-management.

Post-Transplant CD34+ Selected Stem Cell "Boost" for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies.

Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34+ selected stem cell "boost" without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34+ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34+ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34+ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34+ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34+ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34+ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34+ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.

Branched copolymer-stabilised nanoemulsions as new candidate oral drug delivery systems.

The delivery of drugs to the bloodstream via oral administration may suffer from a number of complications including poor dissolution, first pass metabolism and the active intervention of efflux transporters such as P-glycoproteins; drugs which are efflux substrates may cause considerable problems across many clinical conditions. Here we have employed a branch-polymer stabilised nanoemulsion strategy to create highly robust oil droplets (e.g. peanut oil, castor oil and soybean oil) containing different dissolved antiretroviral drugs used in the daily fight against HIV/AIDS. Although very limited difference in permeation through a Caco-2 gut epithelium model was seen for efavirenz, the permeation of the protease inhibitor lopinavir was considerably higher (approximately 10-fold) when applied to an epithelium monolayer in emulsion form than the control within an aqueous DMSO vehicle. The presented nanoemulsion approach may allow drug-specific permeation improvements for various drug substances.

Genome-wide evolutionary dynamics of influenza B viruses on a global scale.

The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly-sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co-circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally.

From clinical sample to complete genome: Comparing methods for the extraction of HIV-1 RNA for high-throughput deep sequencing.

The BEEHIVE (Bridging the Evolution and Epidemiology of HIV in Europe) project aims to analyse nearly-complete viral genomes from >3000 HIV-1 infected Europeans using high-throughput deep sequencing techniques to investigate the virus genetic contribution to virulence. Following the development of a computational pipeline, including a new de novo assembler for RNA virus genomes, to generate larger contiguous sequences (contigs) from the abundance of short sequence reads that characterise the data, another area that determines genome sequencing success is the quality and quantity of the input RNA. A pilot experiment with 125 patient plasma samples was performed to investigate the optimal method for isolation of HIV-1 viral RNA for long amplicon genome sequencing. Manual isolation with the QIAamp Viral RNA Mini Kit (Qiagen) was superior over robotically extracted RNA using either the QIAcube robotic system, the mSample Preparation Systems RNA kit with automated extraction by the m2000sp system (Abbott Molecular), or the MagNA Pure 96 System in combination with the MagNA Pure 96 Instrument (Roche Diagnostics). We scored amplification of a set of four HIV-1 amplicons of ∼1.9, 3.6, 3.0 and 3.5kb, and subsequent recovery of near-complete viral genomes. Subsequently, 616 BEEHIVE patient samples were analysed to determine factors that influence successful amplification of the genome in four overlapping amplicons using the QIAamp Viral RNA Kit for viral RNA isolation. Both low plasma viral load and high sample age (stored before 1999) negatively influenced the amplification of viral amplicons >3kb. A plasma viral load of >100,000 copies/ml resulted in successful amplification of all four amplicons for 86% of the samples, this value dropped to only 46% for samples with viral loads of <20,000 copies/ml.

Bolus Estimation--Rethinking the Effect of Meal Fat Content.

BACKGROUND: Traditionally, insulin bolus calculations for managing postprandial glucose levels in individuals with type 1 diabetes rely solely on the carbohydrate content of a meal. However, recent studies have reported that other macronutrients in a meal can alter the insulin required for good postprandial control. Specifically, studies have shown that high-fat (HF) meals require more insulin than low-fat (LF) meals with identical carbohydrate content. Our objective was to assess the mechanisms underlying the higher insulin requirement observed in one of these studies. MATERIALS AND METHODS: We used a combination of previously validated metabolic models to fit data from a study comparing HF and LF dinners with identical carbohydrate content in seven subjects with type 1 diabetes. For each subject and dinner type, we estimated the model parameters representing the time of peak meal-glucose appearance (τ(m)), insulin sensitivity (S(I)), the net hepatic glucose balance, and the glucose effect at zero insulin in four time windows (dinner, early night, late night, and breakfast) and assessed the differences in model parameters via paired Wilcoxon signed-rank tests. RESULTS: During the HF meal, the τ(m) was significantly delayed (mean and standard error [SE]: 102 [14] min vs. 71 [4] min; P = 0.02), and S(I) was significantly lower (7.25 × 10(-4) [1.29 × 10(-4)] mL/µU/min vs. 8.72 × 10(-4) [1.08 × 10(-4)] mL/µU/min; P = 0.02). CONCLUSIONS: In addition to considering the putative delay in gastric emptying associated with HF meals, we suggest that clinicians reviewing patient records consider that the fat content of these meals may alter S(I).

Molecular Epidemiology and Evolution of Influenza Viruses Circulating within European Swine between 2009 and 2013.

UNLABELLED: The emergence in humans of the A(H1N1)pdm09 influenza virus, a complex reassortant virus of swine origin, highlighted the importance of worldwide influenza virus surveillance in swine. To date, large-scale surveillance studies have been reported for southern China and North America, but such data have not yet been described for Europe. We report the first large-scale genomic characterization of 290 swine influenza viruses collected from 14 European countries between 2009 and 2013. A total of 23 distinct genotypes were identified, with the 7 most common comprising 82% of the incidence. Contrasting epidemiological dynamics were observed for two of these genotypes, H1huN2 and H3N2, with the former showing multiple long-lived geographically isolated lineages, while the latter had short-lived geographically diffuse lineages. At least 32 human-swine transmission events have resulted in A(H1N1)pdm09 becoming established at a mean frequency of 8% across European countries. Notably, swine in the United Kingdom have largely had a replacement of the endemic Eurasian avian virus-like ("avian-like") genotypes with A(H1N1)pdm09-derived genotypes. The high number of reassortant genotypes observed in European swine, combined with the identification of a genotype similar to the A(H3N2)v genotype in North America, underlines the importance of continued swine surveillance in Europe for the purposes of maintaining public health. This report further reveals that the emergences and drivers of virus evolution in swine differ at the global level. IMPORTANCE: The influenza A(H1N1)pdm09 virus contains a reassortant genome with segments derived from separate virus lineages that evolved in different regions of the world. In particular, its neuraminidase and matrix segments were derived from the Eurasian avian virus-like ("avian-like") lineage that emerged in European swine in the 1970s. However, while large-scale genomic characterization of swine has been reported for southern China and North America, no equivalent study has yet been reported for Europe. Surveillance of swine herds across Europe between 2009 and 2013 revealed that the A(H1N1)pdm09 virus is established in European swine, increasing the number of circulating lineages in the region and increasing the possibility of the emergence of a genotype with human pandemic potential. It also has implications for veterinary health, making prevention through vaccination more challenging. The identification of a genotype similar to the A(H3N2)v genotype, causing zoonoses at North American agricultural fairs, underlines the importance of continued genomic characterization in European swine.

Structural and compositional characterization of the adhesive produced by reef building oysters.

Oysters have an impressive ability to overcome difficulties of life within the stressful intertidal zone. These shellfish produce an adhesive for attaching to each other and building protective reef communities. With their reefs often exceeding kilometers in length, oysters play a major role in balancing the health of coastal marine ecosystems. Few details are available to describe oyster adhesive composition or structure. Here several characterization methods were applied to describe the nature of this material. Microscopy studies indicated that the glue is comprised of organic fiber-like and sheet-like structures surrounded by an inorganic matrix. Phospholipids, cross-linking chemistry, and conjugated organics were found to differentiate this adhesive from the shell. Symbiosis in material synthesis could also be present, with oysters incorporating bacterial polysaccharides into their adhesive. Oyster glue shows that an organic-inorganic composite material can provide adhesion, a property especially important when constructing a marine ecosystem.

The relationship between language production and verbal short-term memory: the role of stress grouping.

This study investigates the influence of stress grouping on verbal short-term memory (STM). English speakers show a preference to combine syllables into trochaic groups, both lexically and in continuous speech. In two serial recall experiments, auditory lists of nonsense syllables were presented with either trochaic (STRONG-weak) or iambic (weak-STRONG) stress patterns, or in monotone. The acoustic correlates that carry stress were also manipulated in order to examine the relationship between input and output processes during recall. In Experiment 1, stressed and unstressed syllables differed in intensity and pitch but were matched for spoken duration. Significantly more syllables were recalled in the trochaic stress pattern condition than in the iambic and monotone conditions, which did not differ. In Experiment 2, spoken duration and pitch were manipulated but intensity was held constant. No effects of stress grouping were observed, suggesting that intensity is a critical acoustic factor for trochaic grouping. Acoustic analyses demonstrated that speech output was not identical to the auditory input, but that participants generated correct stress patterns by manipulating acoustic correlates in the same way in both experiments. These data challenge the idea of a language-independent STM store and support the notion of separable phonological input and output processes.

Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study.

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged < or =10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation.

Acceleration of Aux/IAA proteolysis is specific for auxin and independent of AXR1.

Aux/IAA proteins are short-lived transcriptional regulators involved in auxin signaling. Using Aux/IAA luciferase (LUC) fusion proteins expressed in Arabidopsis thaliana, we previously showed that rapid degradation of these proteins requires conserved Aux/IAA domain II and that exogenous auxin accelerates their degradation. To further examine auxin-mediated increases in proteolysis, the degradation of two other LUC fusion proteins, a non-cleavable ubiquitin LUC fusion (UB1-72::LUC) and SAUR15::LUC was determined in vivo in seedlings. Their half-lives were 20 +/- 4 and 104 +/- 10 min, respectively. SAUR15::LUC half-life was not affected by pre-incubation with 2,4-D. Auxin did not have an equivalent effect on UB(1-72)::LUC steady-state levels as compared to PsIAA6:LUC. LUC fused to an Aux/IAA domain II degraded more rapidly following auxin application, demonstrating that this region is sufficient for auxin-mediated acceleration of proteolysis. Hormonal cross-talk at the level of Aux/IAA proteolysis was examined. 1-aminocyclopropane-1-carboxylic acid (ACC), benzyladenine (BA), abscisic acid (ABA), and brassinolide (BL) did not affect the degradation rate of IAA1::LUC, and gibberellic acid (GA3) and salicylic acid (SA) did not specifically affect the steady-state levels of Aux/IAA::LUC proteins. An Aux/IAA::LUC transgene was crossed into the auxin resistant-1 (axr1-12) background. In axr1-12, the half-life of PsIAA6(1-73)::LUC increased 4.5-fold, but proteolysis still accelerated in response to exogenous auxin. These data suggest that auxin is the only phytohormone that accelerates Aux/IAA proteolysis, and that this acceleration is specific for Aux/IAA proteins. In addition, AXR1 plays an important role in rapid basal proteolysis of Aux/IAA proteins, but is not required for auxin-mediated acceleration of their degradation.

Reproductive system tumors in mice exposed to various types of fat perinatally.

Studies of human populations have produced conflicting evidence on whether increased intake of dietary fat increases the risk of female reproductive system cancer. Some animal studies have indicated that the perinatal period of development is the sensitive time for this effect. Since type of fat has been linked to cancer risk, the question is raised as to whether the perinatal period is also sensitive to type of fat. To test this question, mice were exposed perinatally to either corn oil, fish oil, olive oil, or lard, and tumor frequencies were determined for female offspring at the end of their lifespan. No significant differences were found between the 4 groups with respect to reproductive system tumor frequency. Also, there were no significant differences with respect to the variables of lifespan or body weight. Thus, there was no indication that the perinatal period of development was sensitive to type of fat with respect to carcinogenic effects.