Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PF-06817024 in Healthy Participants, Participants with Chronic Rhinosinusitis with Nasal Polyps, and Participants with Atopic Dermatitis: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study.

PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF-06817024 doses in healthy participants (Part 1), a single dose of PF-06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF-06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF-06817024 was generally well tolerated in all participant populations. Most participants experienced a treatment-emergent adverse event (healthy participants, 78.4% and 100%; participants with chronic rhinosinusitis with nasal polyps, 90.9% and 88.9%; and participants with atoptic dermatitis, 60.0% and 62.5% in the PF-06817024 and placebo groups, respectively). No substantial deviations from dose proportionality were observed for single intravenous doses of 10-1000 mg, indicating linear PK in healthy participants. Mean terminal half-life ranged from 83 to 94 days after single intravenous administration in healthy participants and was similar to that observed after administration in the studied patient populations. Incidences of antidrug antibodies in the studied populations were 10.8%, 9.1%, and 5.0% for healthy participants, participants with chronic rhinosinusitis with nasal polyps, and participants with atoptic dermatitis, respectively. In addition, dose-dependent increases were observed in total serum interleukin-33 levels of treated participants, indicating target engagement. Overall, the PK and safety profile of PF-06817024 supports further investigation of the drug as a potential treatment for allergic diseases.

A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a 14 C-Microtracer Approach.

Zimlovisertib (PF-06650833) is a selective, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with anti-inflammatory effects. This phase 1, open-label, fixed-sequence, two-period, single-dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a 14 C-microtracer approach. All six participants received 300 mg 14 C-zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and 14 C-zimlovisertib 135 µg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of 14 C-zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300-mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose-normalized area under the concentration-time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%).

The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.

OBJECTIVE: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting. METHODS: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology. RESULTS: In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers. CONCLUSION: These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.

BACKGROUND: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects. METHODS: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD. RESULTS: PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed. CONCLUSIONS: PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015.

Case Series Using Montelukast in Patients with Memory Loss and Dementia.

Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro-inflammation has been suggested as a cause of dementia [1]. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation [2]. Animal studies have shown that administering Montelukast improves memory function [3]. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia.

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis.

We previously reported that i) a Western diet increased levels of unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDL receptor null (LDLR(-/-)) mice, and ii) supplementing standard mouse chow with unsaturated (but not saturated) LPA produced dyslipidemia and inflammation. Here we report that supplementing chow with unsaturated (but not saturated) LPA resulted in aortic atherosclerosis, which was ameliorated by adding transgenic 6F tomatoes. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 (but not LysoPC 18:0) resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. PF8380 (a specific inhibitor of autotaxin) significantly ameliorated the LysoPC 18:1-induced dyslipidemia. Supplementing chow with LysoPC 18:1 dramatically increased the levels of unsaturated LPA species in small intestine, liver, and plasma, and the increase was significantly ameliorated by PF8380 indicating that the conversion of LysoPC 18:1 to LPA 18:1 was autotaxin dependent. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, liver, and plasma but was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was autotaxin independent. We conclude that i) intestinally derived unsaturated (but not saturated) LPA can cause atherosclerosis in LDLR(-/-) mice, and ii) autotaxin mediates the conversion of unsaturated (but not saturated) LysoPC to LPA.

Use of buccal mucosa grafts for urethral reconstruction in children: a retrospective cohort study.

BACKGROUND: The use of buccal mucosa grafts (BMG) for urethral reconstruction has increased in popularity over the last several decades. Our aim was to describe our institutional experience with and outcomes after BMG urethroplasty. METHODS: We conducted a retrospective cohort study of boys undergoing BMG urethral reconstruction. Preoperative and perioperative characteristics and postoperative outcomes were evaluated. RESULTS: Twenty-nine patients (median age 8.2 years) underwent BMG urethroplasty from 1995-2012. Of the 10 patients undergoing 1-stage repairs, 6 had tubularized grafts, the last of which was performed in 2000 due to an unacceptably high revision rate (100%). A 2-stage approach was elected for 19 patients (median follow-up 21.3 months). Complications including stricture, fistula, or chordee were seen in 60% of patients completing both stages and 32% required ≥1 revision. However, 71% of 2-stage patients were free of significant problems at last follow-up. CONCLUSIONS: We found BMG to be a reasonable option for use in complex pediatric urethral reconstruction. Tubularized grafts had poor results, and we no longer use them. We favor a 2-stage approach for all patients except those with "simple" non-hypospadiac strictures. Although revision procedures were not uncommon, the majority of patients were ultimately free of long-term problems.

Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy.

OBJECTIVE: We compared positive surgical margin (PSM) rates for patients with high risk prostate cancer (HRCaP) who underwent open radical retropubic (RRP), robotic (RALP), and laparoscopic (LRP) prostatectomy at a single institution. MATERIALS AND METHODS: We performed a retrospective review of our prospectively maintained IRB approved database identifying prostate cancer patients who underwent RRP, RALP, or LRP between January 2000 and March 2010. Patients were considered to have HRCaP if they had biopsy or final pathologic Gleason score ≥ 8, or preoperative PSA ≥ 20, or pathologic stage ≥ T3a. A positive surgical margin (PSM) was defined by the presence of tumor at the inked surface of the specimen. Patients who received neoadjuvant hormonal therapy and those who underwent a perineal prostatectomy were excluded from the study. RESULTS: Of the 445 patients in this study, surgical technique for prostatectomy included RRP (n = 153), RALP (n = 152), and LRP (n = 140). PSM rate for the three groups were not different: 52.9% RRP, 50% RALP, and 41.4% LRP, (p = 0.13). The PSM rate did not differ when comparing RRP to a combined group of RALP and LRP (p = 0.16). Among patients with a PSM, there was no statistical difference between the three groups in terms of the number of patients with a pathologic stage of T3 or higher (p = 0.83). On univariate analysis, a higher preoperative PSA value was associated with a positive margin (p = 0.04). CONCLUSION: In this HRCaP series, the PSM rate did not differ based on the surgical approach. On univariate analysis, patients with a higher preoperative PSA value were more likely to have a PSM.

Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy

Objective We compared positive surgical margin (PSM) rates for patients with high risk prostate cancer (HRCaP) who underwent open radical retropubic (RRP), robotic (RALP), and laparoscopic (LRP) prostatectomy at a single institution. Materials and Methods We performed a retrospective review of our prospectively maintained IRB approved database identifying prostate cancer patients who underwent RRP, RALP, or LRP between January 2000 and March 2010. Patients were considered to have HRCaP if they had biopsy or final pathologic Gleason score ≥ 8, or preoperative PSA ≥ 20, or pathologic stage ≥ T3a. A positive surgical margin (PSM) was defined by the presence of tumor at the inked surface of the specimen. Patients who received neoadjuvant hormonal therapy and those who underwent a perineal prostatectomy were excluded from the study. Results Of the 445 patients in this study, surgical technique for prostatectomy included RRP (n = 153), RALP (n = 152), and LRP (n = 140). PSM rate for the three groups were not different: 52.9% RRP, 50% RALP, and 41.4% LRP, (p = 0.13). The PSM rate did not differ when comparing RRP to a combined group of RALP and LRP (p = 0.16). Among patients with a PSM, there was no statistical difference between the three groups in terms of the number of patients with a pathologic stage of T3 or higher (p = 0.83). On univariate analysis, a higher preoperative PSA value was associated with a positive margin (p = 0.04). Conclusion In this HRCaP series, the PSM rate did not differ based on the surgical approach. On univariate analysis, patients with a higher preoperative PSA value were more likely to have a PSM. .

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines.

MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in development, differentiation, cell proliferation, and death as well as the complex process of acquired drug resistance. The goal of this study was to identify specific miRNAs and their potential protein targets that confer acquired resistance to gemcitabine in urothelial carcinoma of the bladder (UCB) cell lines. Gemcitabine-resistant cells were established from 6 cell lines following exposure to escalating concentrations of the drug and by passaging cells in the presence of the drug over a 2- to 3-month period. Differential miRNA expression was identified in a microarray format comparing untreated controls with resistant cell lines, representing the maximum tolerated concentration, and results were validated via qRT-PCR. The involvement of specific miRNAs in chemoresistance was confirmed with transfection experiments, followed by clonogenic assays and Western blot analysis. Gemcitabine resistance was generated in 6 UCB cell lines. Microarray analysis comparing miRNA expression between gemcitabine-resistant and parental cells identified the differential expression of 66 miRNAs. Confirmation of differential expression was recorded via qRT-PCR in a subset of these miRNAs. Within this group, let-7b and let-7i exhibited decreased expression, while miR-1290 and miR-138 displayed increased expression levels in gemcitabine-resistant cells. Transfection of pre-miR-138 and pre-miR-1290 into parental cells attenuated cell death after exposure to gemcitabine, while transfection of pre-miR-let-7b and pre-miR-let-7i into the resistant cells augmented cell death. Mucin-4 was up-regulated in gemcitabine-resistant cells. Ectopic expression of let-7i and let-7b in the resistant cells resulted in the down-regulation of mucin-4. These results suggest a role for miRNAs 1290, 138, let-7i, and let-7b in imparting resistance to gemcitabine in UCB cell lines in part through the modulation of mucin-4. Alterations in these miRNAs and/or mucin-4 may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine in UCB.

Management of complex anterior urethral strictures with multistage buccal mucosa graft reconstruction.

OBJECTIVE: To describe the indications and outcomes of salvage urethral reconstruction using the combination of urethrectomy and buccal graft replacement. MATERIALS AND METHODS: We retrospectively identified 91 consecutive patients who had undergone multistage urethral reconstruction from 2003 to 2009. The demographic and surgical outcomes data, including the need for first stage revision, pre- and postoperative urine flow rates, and reconstruction failure was collected for all patients. RESULTS: Of the 91 patients, 51 (56%) subsequently underwent urethral tubularization, 17 (19%) were pending closure, and 23 (25%) had undergone the first stage only, with no plan for completion. The stricture etiology included hypospadias in 41 (45.1%), lichen sclerosus in 29 (31.9%), and a combination of the 2 in 10 (11%). Of the 91 patients, 54.9% had panurethral disease, with the remaining involving varying lengths of the anterior urethra. The mean follow-up was 15 months (range 12-69). A total of 17 patients (18.7%) required revision of their first stage, with 4 requiring ≥2 repairs. Seven patients (7.7%) required revision of their second stage, with 2 undergoing multiple revisions. The urine flow rates increased on average from 6.7 mL/s preoperatively to 21.5 mL/s postoperatively (P <.00001). In 9 patients (9.9%) reconstruction failed, and they required scheduled balloon dilation or a chronic indwelling catheter to maintain urethral patency. CONCLUSION: Urethrectomy with salvage reconstruction using buccal mucosal grafts in a staged fashion is the optimal option for complex anterior urethral stricture resolution in these challenging patients. Surgical revision of the first or second stage could be required in up to 25% of challenging patients. Despite the high complexity and severity of the urethral stricture burden, a 90% success rate was achieved.

Urological complications and vesicoureteral reflux following pediatric kidney transplantation.

PURPOSE: Ureteral complications of renal transplantation can dramatically impact renal outcomes. We studied whether complications are associated with preexisting genitourinary pathology or transplant using a deceased donor allograft. MATERIALS AND METHODS: We retrospectively reviewed all patients undergoing renal transplantation at our institution between 2000 and 2010. We abstracted patient demographic details, donor type (living vs deceased), end-stage renal disease etiology, reimplant technique, stent use, preoperative and postoperative imaging, history of lower genitourinary pathology and postoperative complication management. RESULTS: A total of 211 kidneys were transplanted into 206 patients (mean age 13.7 years, mean followup 4.6 years). Most patients (89%) underwent extravesical ureteroneocystostomy without stenting (97%), with roughly half (47%) of transplants being from living donors. Preexisting urological pathology was present in 34% of cases. Postoperative obstruction or extravasation occurred in 16 cases (7.6%), of which 15 were acute. Complications were not associated with donor type, preexisting urological pathology other than posterior urethral valves, surgical technique, etiology of end-stage renal disease or patient age. However, posterior urethral valves or other preexisting genitourinary pathology was not associated with an increased likelihood of genitourinary complications. Posterior urethral valves were associated with development of postoperative vesicoureteral reflux (OR 6.7, p = 0.004) but were not associated with stent placement, surgical technique, donor type or etiology of end-stage renal disease. CONCLUSIONS: Patients with posterior urethral valves undergoing renal transplantation are at increased risk for postoperative vesicoureteral reflux but not for other acute surgical complications. There is no association between donor type, etiology of end-stage renal disease, surgical technique or patient age and increased complications.

Robotic versus open distal ureteral reconstruction and reimplantation for benign stricture disease.

BACKGROUND AND PURPOSE: Minimally invasive techniques are currently used for numerous urologic procedures, given decreased morbidity and equivalent outcomes to open surgery. There is, however, a relative paucity of data related to robot-assisted ureteral reimplantation (RAUR) in adult patients for benign stricture disease. We sought to determine the periprocedure outcomes of open distal ureteral reimplantation vs RAUR at our institution. PATIENTS AND METHODS: We retrospectively identified 10 consecutive mid/distal RAUR procedures performed by one surgeon since 2005. Twenty-four patients undergoing open mid/distal ureter reconstruction over the same period were identified, and 10 controls matched for age and body mass index (BMI) were used for comparison. Demographic, operative, and clinical/radiographic outcomes were compared. RESULTS: Etiology of the strictures included stone disease (n=8, 40%), iatrogenic injury during previous abdominopelvic surgery (n=10, 50%), or other causes (n=2, 10%). None of the robotic procedures necessitated conversion to open surgery. No intraoperative complications occurred. Six neocystostomies, three psoas hitches, and one Boari flap were completed in an open fashion. Four neocystostomies, four psoas hitches, and two Boari flaps were performed in the RAUR group. Estimated blood loss (30.6 vs 327.5 mL, P=0.001) and length of hospital stay (2.4 vs 5.1 d, P=0.01) were significantly reduced in the robotic group. Median BMI (29.4±5.3 vs 26.5±5.2, P=0.130) and operative time in minutes (306.6 vs 270.0 min, P=0.316) were higher in the robotic group, although these were not statistically significant. None of the patients in either group had clinical or radiologic evidence of recurrent stricture disease at a median follow-up of 30 and 24 months in the open and RAUR groups, respectively. The retrospective comparative nature of this study may introduce selection bias. CONCLUSIONS: In experienced hands, RAUR for mid/distal benign ureteral strictures appears to be a reasonable alternative to open surgery.

Future opportunities for advancing glucose test device electronics.

Advancements in the field of printed electronics can be applied to the field of diabetes testing. A brief history and some new developments in printed electronics components applicable to personal test devices, including circuitry, batteries, transmission devices, displays, and sensors, are presented. Low-cost, thin, and lightweight materials containing printed circuits with energy storage or harvest capability and reactive/display centers, made using new printing/imaging technologies, are ideal for incorporation into personal-use medical devices such as glucose test meters. Semicontinuous rotogravure printing, which utilizes flexible substrates and polymeric, metallic, and/or nano "ink" composite materials to effect rapidly produced, lower-cost printed electronics, is showing promise. Continuing research advancing substrate, "ink," and continuous processing development presents the opportunity for research collaboration with medical device designers.

Hyaline membrane and neonatal radiology--Ian Donald's first venture into imaging research.

While he was working at the Royal Postgraduate Medical School, Ian Donald (later Regius Professor of Midwifery, University of Glasgow and a pioneer of diagnostic ultrasound) collaborated with Albert Claireaux and Robert Steiner on histological and radiological studies of hyaline membrane disease. In 1953, Donald and Steiner published thefirst radiological study of a series of cases. The success of this research stimulated Donald's interest in imaging technologies.

Demonstration of fusion-evaporation and direct-interaction nuclear reactions using high-intensity laser-plasma-accelerated ion beams.

Heavy-ion induced nuclear reactions in materials exposed to energetic ions produced from high-intensity (approximately 5 x 10(19) W/cm(2)) laser-solid interactions have been experimentally investigated for the first time. Many of the radionuclides produced result from the creation of "compound nuclei" with the subsequent evaporation of proton, neutron, and alpha particles. Results are compared with previous measurements with monochromatic ion beams from a conventional accelerator. Measured nuclide yields are used to diagnose the acceleration of ions from laser-ablated plasma to energies greater than 100 MeV.

Experimental study of proton emission from 60-fs, 200-mJ high-repetition-rate tabletop-laser pulses interacting with solid targets.

Measurements of proton emission have been made from a variety of solid targets irradiated by a 60-fs, 200-mJ, 7 x 10(18)-W cm(-2) laser system operating at 2 Hz. Optimum target conditions were found in terms of target material and thickness. For Mylar targets of thickness 20-40 microm, a maximum proton energy of 1.5 MeV was measured. For aluminum targets, a maximum energy of 950 keV was measured for 12 microm, and for copper, 850 keV for 12.5 microm.

The decay of chlorine associated with the pipe wall in water distribution systems.

Free chlorine decay rates in water distribution systems for bulk and wall demands should be modelled separately as they have different functional dependencies. Few good quality determinations of in situ wall demand have been made due to the difficulty of monitoring live systems and due to their complexity. Wall demands have been calculated from field measurements at 11 locations in a distribution system fed from a single source. A methodology for the laboratory determination has been evolved and shown to give results that are similar to the in situ results. Pipe materials were classified as either having high reactivity (unlined iron mains) or low reactivity (PVC, MDPE and cement-lined ductile iron). The results indicate that wall decay rates for the former are limited by chlorine transport and for the latter by pipe material characteristics. The wall decay rate is inversely related to initial chlorine concentration for low reactivity pipes. In general, water velocity increases wall decay rates though the statistical confidence is low for low reactivity pipes. A moderate biofilm coating did not influence the wall decay rate for low reactivity pipes.

Photonuclear physics when a multiterawatt laser pulse interacts with solid targets

When a laser pulse of intensity 10(19) W cm(-2) interacts with solid targets, electrons of energies of some tens of MeV are produced. In a tantalum target, the electrons generate an intense highly directional gamma-ray beam that can be used to carry out photonuclear reactions. The isotopes 11C, 38K, (62,64)Cu, 63Zn, 106Ag, 140Pr, and 180Ta have been produced by (gamma,n) reactions using the VULCAN laser beam. In addition, laser-induced nuclear fission in 238U has been demonstrated, a process which was theoretically predicted at such laser intensities more than ten years ago. The ratio of the 11C and the 62Cu beta(+) activities yields shot-by-shot temperatures of the suprathermal electrons at laser intensities of approximately 10(19) W cm(-2).

Effect of the plasma density scale length on the direction of fast electrons in relativistic laser-solid interactions

The angular distribution of bremsstrahlung gamma rays produced by fast electrons accelerated in relativistic laser-solid interaction has been studied by photoneutron activation in copper. We show that the gamma-ray beam moves from the target normal to the direction of the k(laser) vector as the scale length is increased. Similar behavior is found also in 2D particle-in-cell simulations.