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SummarySome healthy people fail to derive pleasure from music despite otherwise preserved perceptual and reward responses. Such ‘musical anhedonia’ implies the existence of music-specific brain reward mechanisms, which could provide a substrate for music to acquire biological value.

Background Mutations in C9ORF72 are an important cause of frontotemporal dementia (FTD) and motor neuron disease. Accumulating evidence suggests that FTD associated with C9ORF72 mutations (C9ORF72-FTD) is distinguished clinically by early prominent neuropsychiatric features that might collectively reflect deranged body schema processing. However, the pathophysiology of C9ORF72-FTD has not been elucidated. Methods We undertook a detailed neurophysiological investigation of five patients with C9ORF72-FTD, in relation to patients with FTD occurring sporadically and on the basis of mutations in the microtubule-associated protein tau gene and healthy older individuals. We designed or adapted behavioural tasks systematically to assess aspects of somatosensory body schema processing (tactile discrimination, proprioceptive and body part illusions and self/non-self differentiation). Results Patients with C9ORF72-FTD selectively exhibited deficits at these levels of body schema processing in relation to healthy individuals and other patients with FTD. Conclusions Altered body schema processing is a novel, generic pathophysiological mechanism that may link the distributed cortico-subcortical network previously implicated in C9ORF72-FTD with a wide range of neuropsychiatric and behavioural symptoms, and constitute a physiological marker of this neurodegenerative proteinopathy.

Public sector decision-making typically involves complex problems that are often not completely understood. In these problems, there are invariably unmodeled issues that can greatly impact the acceptability of solutions. Modeling to Generate Alternatives (MGA) is an approach for addressing unmodeled issues in an optimization context. MGA techniques are used to generate a small number of good, yet very different, solutions to optimization problems. Because these solutions are different in decision space, they may differ considerably in performance when unmodeled objectives are considered. Many problems are sufficiently complex that traditional optimization solution procedures, and therefore traditional MGA techniques, are not readily applicable. Two techniques for performing MGA using genetic algorithms (GAs) are investigated and compared. One of these techniques, which uses specialized MGA operators, is shown to produce solutions that are both better in quality and more different. This technique ...

Objectives: Estrogen is often prescribed for symptoms and sequelae of ovarian estrogen loss after menopause. Methods: To assess efficacy and acceptability of a new, highly soluble estrogen–calcium preparation, we formulated a water-soluble powdered combination of estrogen (0.625 mg estrone piperazine sulfate) and calcium (1 g, ions) as the highly soluble glycerophosphate salt (Estrosol®). Effects of once-daily administration on bone mineral turnover of Estrosol® dissolved in water (n=11) was compared with 0.625 mg conjugated estrogens (Premarin®) + 1 g calcium (Tums® 500 Calcium Supplement) (n=8). All women had had a previous hysterectomy, were between the ages 40 and 75, within 25% of ideal body weight, and had not taken hormonal preparations for at least 3 months. Assessment of bone mineral turnover was by monitoring N-telopeptides and bone specific alkaline phosphatase (BSAP) on 5 occasions: pretreatment and once during each of the 4 months of treatment. Results: Mean N-telopeptide values decreased (p=.005) in both groups: Estrosol®, 29.2% (40 → 29 mmol bone collagen equivalents (BCE)/mmol creatinine), and Premarin® + calcium, 44.8% (33 → 18 mmol). Mean BSAP values also decreased (p=0.007) in both groups: Estrosol®, 12.6% (12.06 → 10.54 mg/l), Premarin® + calcium, 19.1% (11.57 → 9.36 mg/l). The difference between groups for both N-telopeptides and BSAP was not significant, although sample size was small. Symptoms (hot flashes, vaginal dryness) improved similarly in both groups. Symptoms during treatment (breast or nipple tenderness, bloating) also were similar in both groups. Both preparations were well-tolerated. There were no changes in CBC, liver function tests, electrolytes or urinalyses in either group. Conclusions: This pilot study indicates that the combined, highly water-soluble preparation of estrogen and calcium is effective in reducing bone mineral turnover, acceptable and well-tolerated. Use of this single aqueous preparation may lead to better compliance than using two separate pills.

Existing solid waste management (SWM) planning software provides only limited assistance to decision makers struggling to find strategies that address their multifarious concerns. The combinatorial nature (many waste items and many management options) and multiple objectives of the SWM problem severely constrain the effectiveness of a manual search process using these tools. Recognizing this, researchers have proposed several optimization-based search procedures. These methods, however, enjoy limited use due to the substantial expertise required for their application. This paper presents a new computer-based decision support framework that addresses these limitations. The new framework integrates process models that quantify the life-cycle inventory of a range of pollutants and costs for an extensive municipal solid waste system, an optimization search procedure that identifies strategies that meet cost and environmental objectives and site-specific restrictions, and a user-friendly interface that facilitates utilization of these components by practitioners. After describing the software design, the use and value of the tool in typical waste management scenarios is demonstrated through a hypothetical, but realistic, case study in which several alternative SWM strategies are generated and examined.

Structural design, like other complex decision problems, involves many tradeoffs among competing criteria. While mathematical programming models are increasingly realistic, there are often relevant issues that cannot be easily captured, if at all, in a formal system. This paper describes an approach to modelling that recognizes these limitations and allows a designer to explore unmodelled issues in a joint human-computer cognitive system. A prototype based on this approach is presented for topological truss optimization, and three modelling techniques are contrasted for their effectiveness in producing “different” alternatives. The results show that alternatives produced using these techniques are good with respect to modelled objectives, and yet are different, and often better, with respect to interesting objectives not present in the model.

Objective: To determine if the GnRH antagonist (GnRH-a) Ganirelix (Syntex Research, Palo Alto, CA), administered by intranasal (IN) spray to normal women, is absorbed into the systemic circulation and suppresses LH secretion. Design: A single center, open label, nonrandomized, dose-escalation study. Setting: Academic research environment. Patient(s): Normal female volunteers ages 23 to 43 years. Intervention(s): Ganirelix was administered as a single dose by IN spray. The administered doses and the number of women receiving each of them were 0.1 mg (n = 1), 0.3 mg (n = 1), 1 mg (n = 2), 3 mg (n = 5), and 6 mg (n = 5). Blood samples were collected from −15 minutes to 24 hours after dosing. Main Outcome Measure(s): Serum concentrations of Ganirelix and LH. Result(s): Ganirelix was absorbed rapidly. The mean time to maximal serum levels in the 3- and 6-mg groups was 0.67 and 0.53 hour, respectively. Mean serum LH levels were suppressed by ≥35% relative to baseline from 2 to 12 hours after dosing in both groups. The mean maximal percent decrease in serum LH was −62% (at 8 hours after dosing) and −74% (at 6 hours after dosing) in the 3- and 6-mg groups, respectively. Conclusion(s): Single dose IN administration of 3 or 6 mg of Ganirelix suppressed serum LH levels in women, further enhancing the potential clinical utility of this potent GnRH-a. This is the first clinical report of a GnRH-a reducing the secretion of a pituitary gonadotropin when administered by an IN delivery system. Based on the duration and extent of LH suppression observed in this study, Ganirelix, administered by twice daily IN spray, may be effective for the treatment of gonadal hormone-dependent disorders in women.

Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional grey matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p

Phobias are among the few intensely fearful experiences we regularly have in our everyday lives, yet the brain basis of phobic responses remains incompletely understood. Here we describe the case of a 71-year-old patient with a typical clinicoanatomical syndrome of semantic dementia led by selective (predominantly right-sided) temporal lobe atrophy, who showed striking amelioration of previously disabling claustrophobia following onset of her cognitive syndrome. We interpret our patient’s newfound fearlessness as an interaction of damaged limbic and autonomic responsivity with loss of the cognitive meaning of previously threatening situations. This case has implications for our understanding of brain network disintegration in semantic dementia and the neurocognitive basis of phobias more generally.

The long term efficacy and safety of transsphenoidal resection for preoperative diagnosis of PRL-secreting pituitary adenomas in a large series of women have not been described. Four hundred and nine consecutive women at this university tertiary referral center undergoing transsphenoidal resection for preoperative diagnosis of PRL-secreting pituitary adenoma were followed for a minimum of 4 yr. The objective was to determine the efficacy and morbidity of this procedure and to identify features correlating with the resolution of hyperprolactinemia. Outcome measures included referral, preoperative, surgical, postoperative hospitalization, and long-term follow-up information, including recent PRL concentration. Follow-up was ascertained in 83% of patients who were followed for a mean of 9.2 yr. Recurrence of hyperprolactinemia occurred in 47% of total patients, but in only 16% with a single surgical procedure, histological diagnosis of prolactinoma, and postoperative PRL concentration of 5 ng/mL or less. The best single predictor of cure was postoperative day 1 PRL concentration of 5 ng/mL or less. Eighty-eight percent of women desiring conception conceived within 1 yr. Glucocorticoid-dependent hypopituitarism occurred in 23% of patients undergoing postoperative radiotherapy. There was no operative mortality. Operative morbidity was low. Our experience demonstrates that women undergoing transsphenoidal surgery for diagnosis of PRL-secreting adenoma form a heterogeneous patient population. The best long term results are achieved in the pure prolactinoma group, for whom transsphenoidal resection is generally safe and effective.

Summary Background Paralysis or amputation of an arm results in the loss of the ability to orient the hand and grasp, manipulate, and carry objects, functions that are essential for activities of daily living. Brain–machine interfaces could provide a solution to restoring many of these lost functions. We therefore tested whether an individual with tetraplegia could rapidly achieve neurological control of a high-performance prosthetic limb using this type of an interface. Methods We implanted two 96-channel intracortical microelectrodes in the motor cortex of a 52-year-old individual with tetraplegia. Brain–machine-interface training was done for 13 weeks with the goal of controlling an anthropomorphic prosthetic limb with seven degrees of freedom (three-dimensional translation, three-dimensional orientation, one-dimensional grasping). The participant's ability to control the prosthetic limb was assessed with clinical measures of upper limb function. This study is registered with ClinicalTrials.gov, NCT01364480. Findings The participant was able to move the prosthetic limb freely in the three-dimensional workspace on the second day of training. After 13 weeks, robust seven-dimensional movements were performed routinely. Mean success rate on target-based reaching tasks was 91·6% (SD 4·4) versus median chance level 6·2% (95% CI 2·0–15·3). Improvements were seen in completion time (decreased from a mean of 148 s [SD 60] to 112 s [6]) and path efficiency (increased from 0·30 [0·04] to 0·38 [0·02]). The participant was also able to use the prosthetic limb to do skilful and coordinated reach and grasp movements that resulted in clinically significant gains in tests of upper limb function. No adverse events were reported. Interpretation With continued development of neuroprosthetic limbs, individuals with long-term paralysis could recover the natural and intuitive command signals for hand placement, orientation, and reaching, allowing them to perform activities of daily living. Funding Defense Advanced Research Projects Agency, National Institutes of Health, Department of Veterans Affairs, and UPMC Rehabilitation Institute.

Objective—To determine whether apparently healthy captive-born wild felids that were not native to North America and were housed in an area endemic for Cytauxzoon felis harbored the pathogen. Design—Prospective observational case series. Animals—11 captive-born wild felids that were (1 bobcat [Lynx rufus] and 1 cougar [Puma concolor]) or were not (1 lion [Panthera leo] and 8 tigers [Panthera tigris]) native to North America and 6 domestic cats (5 pets and 1 feral). Procedures—Blood was collected, and a PCR assay for C felis was performed. The C felis 18S rRNA gene sequence was characterized in samples that tested positive. Blood smears were evaluated microscopically for intraerythrocytic organisms consistent with C felis. Blood smears from an additional 6 feral domestic cats found dead on the study premises were also evaluated. Results—4 tigers and 6 domestic cats without clinical signs of disease tested positive for C felis infection via PCR assay; intraerythrocytic organisms consistent with C felis were identified in smears from 1 C felis—infected tiger (which also had azotemia) and in smears from 11 of 12 domestic cats. Possible erythrocytic inclusions were identified in 1 tiger that tested negative for C felis. Sequences of C felis 18S rRNA amplicons from all infected tigers shared > 99.8% identity with reported C felis sequences from North American domestic cats and were identical to amplicons from domestic cats on the premises. Conclusions and Clinical Relevance—Captive tigers without clinical signs of disease tested positive for C felis. The PCR assay for C felis appeared to be more reliable than cytologic detection of piroplasms in tigers.

Figure 6 and Figure 8, and their legends, are updated to clearly show noncontiguous lanes in immunoblotting data.

The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.

Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. We show that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation.

Engineering functional cartilaginous grafts using stem cells isolated from osteoarthritic human tissue is of fundamental importance if autologous tissue engineering strategies are to be used in the treatment of diseased articular cartilage. It has previously been demonstrated that human infrapatellar fat pad (IFP)-derived stem cells undergo chondrogenesis in pellet culture; however, the ability of such cells to generate functional cartilaginous grafts has not been adequately addressed. The objective of this study was to explore how environmental conditions regulate the functional development of cartilaginous constructs engineered using diseased human IFP-derived stem cells (FPSCs). FPSCs were observed to display a diminished chondrogenic potential upon encapsulation in a three-dimensional hydrogel compared with pellet culture, synthesizing significantly lower levels of glycosaminoglycan and collagen on a per cell basis. To engineer more functional cartilaginous grafts, we next explored whether additional biochemical and biophysical stimulations would enhance chondrogenesis within the hydrogels. Serum stimulation was observed to partially recover the diminished chondrogenic potential within hydrogel culture. Over 42 days, stem cells that had first been expanded in a low-oxygen environment proliferated extensively on the outer surface of the hydrogel in response to serum stimulation, assembling a dense type II collagen-positive cartilaginous tissue resembling that formed in pellet culture. The application of hydrostatic pressure did not further enhance extracellular matrix synthesis within the hydrogels, but did appear to alter the spatial accumulation of extracellular matrix leading to the formation of a more compact tissue with superior mechanically functionality. Further work is required in order to recapitulate the environmental conditions present during pellet culture within scaffolds or hydrogels in order to engineer more functional cartilaginous grafts using human osteoarthritic FPSCs.

Introduction An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric features may be early and prominent, although a putative cortico-thalamo-cerebellar network has been implicated in the pathogenesis of the clinical phenotype. Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia. Methods We undertook a detailed behavioral analysis of self-other attribution in a 67-year-old male patient with behavioral variant frontotemporal dementia (bvFTD) due to the C9ORF72 expansion by using a novel paradigm requiring differentiation of the effects of self- and non-self-generated actions. The patient's performance was assessed in relation to two older male patients with bvFTD not attributable to the C9ORF72 expansion and four healthy older male subjects. Results Compared with the healthy control group, the patient with the C9OFR72 mutation showed a deficit of self-other differentiation that was disproportionate to his otherwise relatively indolent clinical phenotype. The performance of the other patients with bvFTD was similar to that of healthy subjects. Conclusion We propose that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion. We offer this preliminary observation as a stimulus to further work.

Introduction In the early 1960s, the creation of Cardiac Care Units (CCUs) led to a 50% reduction in the in-hospital mortality of acute myocardial infarction (AMI). Prompt application of closed chest cardiac resuscitation and external defibrillation -- then new technologies -- served to reduce the consequences of the event. Over the ensuing four decades, therapeutic advances in the treatment of AMI (e.g. prompt reperfusion strategies) have favorably altered its natural history, potentially obviating the need for CCU care. Since such care is expensive, identification of a low risk cohort of patients in whom this care is not necessary could allow substantial improvements in the cost of cardiac care. Hypothesis Existing risk models can be used to accurately identify low risk STEMI patients who do not require CCU care after primary PCI. Methods We performed a retrospective chart review of all STEMI cases from 2010 at Carolinas Medical Center. We then assessed them using the TIMI STEMI risk score and a risk assessment algorithm for uncomplicated STEMI developed at Brigham and Women's Hospital (BWH). The BWH STEMI Care Redesign defines low risk STEMI patients as those who are promptly revascularized via successful single vessel PCI with (1) no evidence of ongoing ischemia, (2) EF>40%, (3) absence of CHF, hemodynamic or electrical instability, and (4) who are awake without need of respiratory support. Cost data (fixed and variable) from Quality Advisor™, a product by Premier, was abstracted for each STEMI case, examining specific resources used in CCU and non-CCU units. Results Among 310 consecutive STEMI patients, in-hospital mortality was 3.9%. The BWH risk score identified 46.4% of these patients as low-risk. Among these patients, in-hospital mortality was 0%. Only one of these 144 low-risk patients required subsequent CCU care. None required CPR or defibrillation after revascularization. The TIMI STEMI risk score Conclusion The BWH model, but not the TIMI STEMI risk score, accurately predicted a sizable cohort of STEMI patients at very low risk of in-hospital death and complications. These patients may be appropriate for admission to non-CCU level care immediately following primary PCI. Doing so would be projected to yield a cost savings of >$1000 per patient.

Summary An electron-transparent layer of adhesive is used to restrain magnetic particles from being stripped off the support film by the magnetic field of an objective lens in a TEM.

Babesia conradae ( B. conradae ) causes hemolytic anemia in dogs. This organism has not been reported clinically since it was originally described in southern California in 1991. To date, no anti-protozoal therapies have been associated with clearance of B. conradae . This report describes the use of atovaquone and azithromycin for the treatment of dogs naturally infected with B. conradae and report the re-emergence of B. conradae in southern California. Twelve dogs naturally infected with B. conradae were identified by practicing veterinarians and public health officials in southern California. Treatments consisted of a 10 day course of atovaquone (13.3 mg/kg PO q 8 h) and azithromycin (10–12.5 mg/kg PO q 24 h). Four dogs were treated in a randomized blinded placebo-controlled fashion, four additional cases were treated in a non-random, non-blinded fashion and one dog received no treatment. All dogs were tested for B. conradae DNA by polymerase chain reaction (PCR) initially and then once or 3 times post treatment (60–210 days). B. conradae infected dogs that received treatment did not have any detectable Babesia DNA by PCR after treatment. In contrast, dogs receiving placebo had detectable Babesia DNA by PCR throughout the study period. Combination therapy with atovaquone and azithromycin appears to be effective for acute and chronic babesiosis caused by B. conradae .

The purpose of this study is to evaluate how the toughness of photopolymerizable (meth)acrylate networks is influenced by physiological conditions. By utilizing two ternary (meth)acrylate networks, MA-co-MMA-co-PEGDMA and 2HEMA-co-BMA-co-PEGDMA, relationships between glass transition temperature ( T g ), water content and state, and toughness were studied by varying the weight ratio of the linear monomers (MA to MMA or 2HEMA to BMA). Differential scanning calorimetry and thermogravimetric analysis were performed to evaluate the thermal behavior and water content as a function of either MA or 2HEMA concentration while tensile strain-to-failure tests were performed at 37 °C to determine network toughness. Both networks exhibited a maximum in toughness in PBS in the composition corresponding to a T g close to the testing temperature. This toughness maximum was achieved by adjusting the glass transition temperature and/or hydrophilicity through changes in chemistry. These relationships may be utilized to design tough photopolymerizable networks for use in mechanically rigorous biomedical applications.

SiC photodiodes were fabricated using 6 H single-crystal wafers. These devices have excellent UV responsivity characteristics and very low dark current even at elevated temperatures. The reproducibility is excellent and the characteristics agree with theoretical calculations for different device designs. The advantages of these diodes are that they will operate at high temperatures and are responsive between 200 and 400 nm and not responsive to longer wavelengths because of the wide 3-eV bandgap. The responsivity at 270 nm is between 70% and 85%. Dark-current levels have been measured as a function of temperature that are orders of magnitude below those previously reported. Thus, these diodes can be expected to have excellent performance characteristics for detection of low light level UV even at elevated temperatures. >

To examine the extent of platelet inhibition by prasugrel vs. clopidogrel in a TRITON-TIMI 38 substudy.TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) (n = 125 patients) and, in a subset (n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h post-PCI (or=1 h after loading dose) (P0.001) and at 30 days (P0.001). Maximal platelet aggregation to 20 microM ADP was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h (P = 0.004) and 30 days (P = 0.03). Results were similar with 5 microM ADP. Thienopyridine hyporesponsiveness, prespecified as VASP PRI50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1-2 h (P0.001) and 30 days (P = 0.03).The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.

The rapid discovery of the contaminant source and its mass loading characteristics in a water distribution system (WDS) is vital for generating an efficient control strategy during a contamination event. Previous work on the Adaptive Dynamic Optimization Technique (ADOPT), which was developed as an Evolution Strategy (ES) based procedure, presents an approach to estimate the source characteristics adaptively, given dynamically updated observation data. Although this simulation-optimization approach is promising, it is computationally expensive, which poses challenges in the context of real-time solutions. This paper reports the findings of an investigation that builds upon the prior work by introducing a hybrid heuristic search method for the real-time characterization of a contaminant source. This new method integrates the ES-based ADOPT with a logistic regression (LR) analysis and a local improvement method to expedite the convergence and possibly solve the problem quickly. As a prescreening technique, a LR analysis step is performed prior to ADOPT; this step reduces the search space by eliminating unnecessary source nodes as potential source locations. Then, a local search (LS) approach is embedded into some of the algorithmic steps in ADOPT to serve as a postscreening step that potentially speeds up the convergence in localized regions in the solution space. Numerical experiments for the proposed hybrid approach are performed on an example water distribution network, and the results are compared with those of the standard implementation of ADOPT.

Accurate knowledge of the characteristics of the contamination source during a contamination event is necessary for development of any mitigation and control strategy. Contaminant injected in a system is most likely to be reactive with chlorine; however, it is impractical for water quality monitoring systems to be able to monitor for the presence of all possible contaminants. In any distribution system, chlorine levels and other water quality parameters (pH, conductance, etc.) are routinely monitored to maintain the prescribed disinfection capacity. Any reactive contaminant would affect the chlorine levels resulting in deviations in the expected chlorine levels from those expected under normal operating conditions. Anomalies in the chlorine concentration from that of the expected value can be used as a surrogate to characterize the contaminant source in the system. In the absence of knowing the reactive characteristics of the contaminants, the location of injection, and injection pattern, source identification becomes a difficult problem to solve. Source identification can be posed as an inverse problem. In earlier work authors investigated the effect of the order of reaction kinetics of the contaminant with chlorine and its impact on source identification problem assuming the reaction kinetics to be known. That work is extended to investigate a methodology to address the source identification problem based on chlorine measurements, and the effects of different uncertain contamination conditions. Findings from a range of scenarios will be presented and discussed.

A general approach, called robust optimal design, is developed in a companion paper and applied here to a comprehensive, nonlinear, activated sludge treatment system. The treatment system robustness is related to the sensitivity of steady-state effluent biochemical oxygen demand and total suspended solids concentrations to changes in 55 uncertain model parameter values. Treatment system designs with lower sensitivity of the effluent water quality measures are likely to be more robust than designs with higher sensitivity. The robust optimal design approach is used to generate alternative designs that represent the trade-off between total system cost and robustness. The robust design trends are generally more consistent with recommended design practice than are typical minimum-cost design trends. In particular, improvements in the robustness of effluent biochemical oxygen demand concentration are associated with higher activated sludge mean solids-residence times, whereas typical minimum-cost designs are associated with low solids-residence times. The robustness of the alternative designs is evaluated further using a nonlinear worst-case analysis. The robust optimal design framework should be applicable to many design problems where uncertainty in parameter values is significant.

One important problem with using mathematical optimization models for design of wastewater treatment systems is that parameter values, and thus, model results, are often uncertain. A general approach, called robust optimal design, is developed for extending nonlinear optimization models to include first-order sensitivity-based measures of system robustness. Robustness is defined narrowly as the ability of the system to maintain a level of performance even if the actual parameter values are different from the assumed values; thus less sensitive designs should be more robust. A solution procedure based on nonlinear optimization and system sensitivity analysis techniques is discussed. The approach can be used to generate alternative designs that recognize traditional modeled objectives such as cost and effluent water quality measures, and that also reflect concerns about uncertainty. The approach is applied in a companion paper to a complex activated sludge treatment system with 55 uncertain parameter values.

This randomized, prospective, double-blind, multicenter study compared nephrotoxicity of the nonionic iso-osmolar contrast media (CM) iodixanol versus the ionic low-osmolar CM ioxaglate in patients with chronic renal insufficiency undergoing coronary angiography.The properties of iodinated CM might contribute to the incidence of contrast-induced nephropathy (CIN).Patients with renal impairment undergoing coronary angiography were randomly assigned to iodixanol (n = 72) or ioxaglate (n = 74).Baseline characteristics were well-matched between the 2 groups. The predicted risk score for CIN was similar in the iodixanol and in the ioxaglate groups (11.9 +/- 4.1 vs. 11.8 +/- 4.1), as was the use of N-acetylcysteine (70% vs. 73%). The primary end point of the study, median peak increase of serum creatinine from day 0 through day 3 after angiography, did not differ between the iodixanol (0.09 mg/dl; interquartile range 0.00 to 0.30 mg/dl) and the ioxaglate (0.15 mg/dl; interquartile range 0.00 to 0.40 mg/dl; p = 0.07) groups. The percentages of patients with a peak increase of serum creatinineor=0.5 mg/dl (15.9% in iodixanol vs. 18.2% in ioxaglate),or=1.0 mg/dl (1.4% vs. 4.5%), andor=25% oror=0.5 mg/dl (15.9% vs. 24.2%, respectively) also did not differ significantly between the 2 groups.In high-risk patients undergoing coronary angiographic procedures, use of the nonionic iso-osmolar CM iodixanol does not reduce renal deterioration in patients with renal impairment, compared with the ionic low-osmolar CM ioxaglate. Given that the study was underpowered to compare nephrotoxicity of the 2 groups under the active medical protection of CIN, a larger randomized study is warranted that will enroll patients with higher risks of CIN under a strict control of hydration regimens and adjunctive medications.

The source of contamination in a water distribution system may be identified through a simulation-optimization approach. The optimization method searches for the contaminant source characteristics by iteratively estimating the contaminant plume concentrations until they match observations at sensors. The amount of information available for characterizing the source depends on the number and spatial locations of the sensors, as well as on the temporally varying stream of sensed data. The accuracy of the source characterization depends on the amount of observations available. A major factor affecting this accuracy is the degree of non-uniqueness present in the problem, which may cause misidentification of the source characteristics. As more sensors are added to the network, the non-uniqueness may be reduced and a unique solution may be identified. Thus, a key consideration when solving these problems is to assess whether the solution identified is unique, and if not, what other possible solutions are present. A systematic search for a set of alternatives that are maximally different in solution characteristics can be used to address and quantify non-uniqueness. For example, if the most different set of solutions that are identified by a search procedure are very similar, then that solution will be considered as the unique solution with a higher degree of certainty. Alternatively, identification of a set of maximally different solutions that vary widely in solution characteristics will indicate that nonuniqueness is present in the problem, and the range of solutions can be used as a general representation of the amount of non-uniqueness. This paper investigates the use of evolutionary algorithm (EA)-based alternatives generation procedures to quantify and address non-uniqueness present in a contaminant source identification problem for a water distribution network. As additional sensors may decrease the amount of non-uniqueness, several sensor configurations will be tested to investigate and quantify the improvement in uniqueness as more information is used in the source characterization.

Accidental drinking water contamination has long been and remains a major threat to water security throughout the world. Consequently, contamination source identification is an important and difficult problem in the managing safety in water distribution systems. This problem involves the characterization of the contaminant source based on observations that are streaming from a set of sensors in the distribution network. Since contamination spread in a water distribution network is relatively quick and unpredictable, rapid identification of the source location and related characteristics is important to take contaminant control and containment actions. As the contaminant event unfolds, the streaming data could be processed over time to adaptively estimate the source characteristics. This provides an estimate of the source characteristics at any time after a contamination event is detected, and this estimate is continually updated as new observations become available. We pose and solve this problem using a dynamic optimization procedure that could potentially provide a real-time response. As time progresses, additional data is observed at a set of sensors, changing the vector of observations that should be predicted. Thus, the prediction error function is updated dynamically, changing the objective function in the optimization model. We investigate a new multi population-based search using an evolutionary algorithm (EA) that at any time represents the solution state that best matches the available observations. The set of populations migrates to represent updated solution states as new observations are added over time. At the initial detection period, non-uniqueness is inherent in the source-identification due to inadequate information, and, consequently, several solutions may predict similarly well. To address nonuniqueness at the initial stages of the search and prevent premature convergence of the EA to an incorrect solution, the multiple populations in the proposed methodology are designed to maintain a set of alternative solutions representing different non-unique solutions. As more observations are added, the EA solutions not only migrate to better solution states, but also reduce the number of solutions as the degree of non-uniqueness diminishes. This new dynamic optimization algorithm adaptively converges to the best solution(s) to match the observations available at any time. The new method will be demonstrated for a contamination source identification problem in an illustrative water distribution network.

One important problem with using optimization models for design is that parameter values, and thus model results, are often uncertain. A general and practicable approach, sensitivity constrained nonlinear programming (SCNLP), is developed for extending nonlinear programming models to include functions of the system sensitivity to changes in parameter values. Using SCNLP, sensitivity-based functions can be constructed that represent approximately many meaningful design criteria, including first-order estimates of the variance, reliability, and robustness. Thus SCNLP can be used to generate alternative designs that are good with respect to traditional objectives, and that incorporate explicitly the concerns about uncertainty in parameter values. A solution procedure is presented, and an implementation is discussed briefly. To illustrate the approach, a simple heat exchanger design SCNLP is formulated and solved. More significant design problems can be considered, and an application of SCNLP to a complex was...

Many nonlinear optimization problems are not unimodal, and only local optima can be obtained using gradient algorithms. A heuristic method, Modeling to Generate Alternatives (MGA), is introduced as a method for use in searching for a good local optimum for a highly nonlinear problem. The purpose of the MGA approach in this context is to produce easily a set of points which are feasible and maximally different from each other. By using this set as starting points for a nonlinear programming algorithm, the likelihood of locating more local optima is increased, and thus the likelihood of locating the global optimum or a good local optimum is also increased. Several problems, having multiple local optima and therefore difficult to optimize globally, were obtained from the literature and were used to demonstrate the approach. Two problems are described here: a wastewater treatment plant design model and a facility location model.

Water quality management programs that allow different waste discharge rates during different seasons of the year are an innovative approach for reducing the cost of waste treatment. This paper presents an approach for designing such seasonal waste discharge programs for river basins with several dischargers and illustrates it for the control of biochemical oxygen demand, BOD. By this approach, the risk of water quality violation is defined as the probability of incurring one or more water quality violations in any given year, and the seasonal waste effluent rates of the dischargers are designed to maintain a specified level of risk while minimizing the total waste treatment effort of the dischargers. Two seasonal waste discharge programs are proposed as surrogates for minimizing waste treatment effort, the minimum average uniform treatment program and the maximum total discharge program. Simulations of these programs suggest that either seasonal discharge program would significantly reduce waste treatmen...

In developing management programs to regulate point sources of waterbomewaste, it may be convenient or even necessary to subdivide the dischargers into groups. For simplicity and effectiveness in meeting water quality goals, it is desirable that the regulatory decisions governing one group of dischargers be minimally influenced by those governing other groups. One way to accomplish this is to separate the watercourse into sets of water quality checkpoints such that each set of checkpoints is associated with a group of dischargers and the effect of the dischargers excluded from a given group upon the checkpoints associated with that group is small. This paper presents a quantitative method for effecting such groupings. The method minimizes the impacts of the dischargers included in a group on checkpoints associated with other groups of dischargers. The method is illustrated using data for several river basins, viz., the Lower Fox River in Wisconsin, the Willamette River in Oregon, and the Mohawk River in N...