Streamlined Project Closeout for Construction at KYTC

Project closeout is the period between the end of construction and when a contract is finalized. During closeout, resources are held in encumbered funds intended for the project and in the contractor’s bonding capacity. Although the Kentucky Transportation Cabinet’s (KYTC) stated goal is to close out projects within 240 days of their ending, in 2016 the average duration of project closeout was 366 days. This report analyzes the Cabinet’s project closeout procedures, summarizes project closeout best practices adopted by other state transportation agencies, and recommends ways to improve KYTC’s practices. Streamlining project closeouts would free up sufficient funds to resurface approximately 2,000 to 7,000 total lane miles that would otherwise not be rehabilitated. To begin reforming project closeout, the Cabinet may benefit from 1) investigating ways to improve the preparation of final documentation and 2) reducing the amount of time allocated for development and completion of the materials check. Other recommendations for revamping project closeout include establishing a KYTC task force to conduct high-level analysis of the project closeout process; thoroughly implementing e-Construction methodologies, which can reduce paperwork and centralize record-keeping within tightly controlled and monitored databases; revising project closeout checklists to standardize the process and eliminate all steps that are unneeded or outdated; and optimizing project closeout processes at the district level to help personnel adopt best practices. More efficient project closeouts will benefit the public because of their potential to increase the amount of funding that can be dedicated to critical transportation projects that would otherwise remain unaddressed. As the Cabinet investigates ways to begin this process, it is important to keep in mind that strategies or methods for streamlining project closeout should be implemented by KYTC personnel, as this increases the likelihood that staff buy-in across the agency

Respiratory symptoms in people living with HIV and the effect of antiretroviral therapy: a systematic review and meta-analysis

BACKGROUND: Antiretroviral therapy (ART) has significantly altered the pattern of acute and chronic HIV-related disease. However, it is not clear what this means in terms of respiratory symptoms. We sought to investigate the association between HIV status and respiratory symptoms and how these have changed with the availability of ART. METHODS: We searched Cochrane, Medline and Embase databases for studies published between 1946 and August 2015 comparing the prevalence of respiratory symptoms in populations with and without HIV infection. We undertook random effects meta-analysis of the main symptoms reported. We studied heterogeneity and completed sensitivity analyses and funnel plots. RESULTS: From 5788 unique references identified, 24 papers provided relevant data: 18 documented the prevalence of cough and 11 examined the prevalence of breathlessness among other symptoms reported. Compared with the HIV negative, people living with HIV (PLWH) were more likely to have respiratory symptoms with pooled ORs for the prevalence of cough of 3.05 (95% CI 2.24 to 4.16) in resource-limited populations without access to ART; 2.18 (1.56 to 3.18) in resource-rich populations without access to ART and 1.11 (0.99 to 1.24) in resource-rich populations with access to ART. In resource-rich settings, although the availability of ART was associated with a reduction in the difference between HIV-positive and HIV-negative individuals, PLWH were more likely to report breathlessness, OR 1.39 (95% CI 1.11 to 1.73). CONCLUSIONS: Respiratory symptoms are more common in PLWH than controls. This association persists although at a reduced level in populations with access to ART

Measurement of gut permeability using fluorescent tracer agent technology

Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use

Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need

Sea anemones may thrive in a high CO2 world

Increased seawater pCO 2, and in turn 'ocean acidification' (OA), is predicted to profoundly impact marine ecosystem diversity and function this century. Much research has already focussed on calcifying reef-forming corals (Class: Anthozoa) that appear particularly susceptible to OA via reduced net calcification. However, here we show that OA-like conditions can simultaneously enhance the ecological success of non-calcifying anthozoans, which not only play key ecological and biogeochemical roles in present day benthic ecosystems but also represent a model organism should calcifying anthozoans exist as less calcified (soft-bodied) forms in future oceans. Increased growth (abundance and size) of the sea anemone (Anemonia viridis) population was observed along a natural CO 2 gradient at Vulcano, Italy. Both gross photosynthesis (P G) and respiration (R) increased with pCO 2 indicating that the increased growth was, at least in part, fuelled by bottom up (CO 2 stimulation) of metabolism. The increase of P G outweighed that of R and the genetic identity of the symbiotic microalgae (Symbiodinium spp.) remained unchanged (type A19) suggesting proximity to the vent site relieved CO 2 limitation of the anemones' symbiotic microalgal population. Our observations of enhanced productivity with pCO 2, which are consistent with previous reports for some calcifying corals, convey an increase in fitness that may enable non-calcifying anthozoans to thrive in future environments, i.e. higher seawater pCO 2. Understanding how CO 2-enhanced productivity of non- (and less-) calcifying anthozoans applies more widely to tropical ecosystems is a priority where such organisms can dominate benthic ecosystems, in particular following localized anthropogenic stress. © 2012 Blackwell Publishing Ltd

Application of ¹⁴C analyses to source apportionment of carbonaceous PM_2.5 in the UK

Determination of the radiocarbon (<sup>14</sup>C) content of airborne particulate matter yields insight into the proportion of the carbonaceous material derived from fossil and contemporary carbon sources. Daily samples of PM<sub>2.5</sub> were collected by high-volume sampler at an urban background site in Birmingham, UK, and the fraction of <sup>14</sup>C in both the total carbon, and in the organic and elemental carbon fractions, determined by two-stage combustion to CO<sub>2</sub>, graphitisation and quantification by accelerator mass spectrometry. OC and EC content was also determined by Sunset Analyzer. The mean fraction contemporary TC in the PM<sub>2.5</sub> samples was 0.50 (range 0.27–0.66, n = 26). There was no seasonality to the data, but there was a positive trend between fraction contemporary TC and magnitude of SOC/TC ratio and for the high values of these two parameters to be associated with air-mass back trajectories arriving in Birmingham from over land. Using a five-compartment mass balance model on fraction contemporary carbon in OC and EC, the following average source apportionment for the TC in these PM<sub>2.5</sub> samples was derived: 27% fossil EC; 20% fossil OC; 2% biomass EC; 10% biomass OC; and 41% biogenic OC. The latter category will comprise, in addition to BVOC-derived SOC, other non-combustion contemporary carbon sources such as biological particles, vegetative detritus, humic material and tyre wear. The proportion of total PM<sub>2.5</sub> at this location estimated to derive from BVOC-derived secondary organic aerosol was 9–29%. The findings from this work are consistent with those from elsewhere in Europe and support the conclusion of a significant and ubiquitous contribution from non-fossil biogenic sources to the carbon in terrestrial aerosol

Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria

4-hydroxy-2-oxoglutarate (HOG) aldolase is a unique enzyme in the hydroxyproline degradation pathway catalyzing the cleavage of HOG to pyruvate and glyoxylate. Mutations in this enzyme are believed to be associated with the excessive production of oxalate in primary hyperoxaluria type 3 (PH3), although no experimental data is available to support this hypothesis. Moreover, the identity, oligomeric state, enzymatic activity, and crystal structure of human HOGA have not been experimentally determined.In this study human HOGA (hHOGA) was identified by mass spectrometry of the mitochondrial enzyme purified from bovine kidney. hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases. Sequence comparisons, however, show that HOGA is related to the tetrameric, bacterial dihydrodipicolinate synthases, but the reaction direction is reversed. The 1.97 Å resolution crystal structure of hHOGA bound to pyruvate was determined and enabled the modeling of the HOG-Schiff base intermediate and the identification of active site residues. Kinetic analyses of site-directed mutants support the importance of Lys196 as the nucleophile, Tyr168 and Ser77 as components of a proton relay, and Asn78 and Ser198 as unique residues that facilitate substrate binding.The biochemical and structural data presented support that hHOGA utilizes a type I aldolase reaction mechanism, but employs novel residue interactions for substrate binding. A mapping of the PH3 mutations identifies potential rearrangements in either the active site or the tetrameric assembly that would likely cause a loss in activity. Altogether, these data establish a foundation to assess mutant forms of hHOGA and how their activity could be pharmacologically restored

Mallard Duckling Growth and Survival in Relation to Aquatic Invertebrates

Identification and assessment of the relative importance of factors affecting duckling growth and survival are essential for effective management of mallards on breeding areas. For each of 3 years (1993-95), we placed Fl-generation wild mallard (Anas platyrhynchos) females on experimental wetlands and allowed them to mate, nest, and rear broods for 17 days. We manipulated invertebrate densities by introducing fathead minnows (Pimephales promelas) at high densities in half of the wetlands on which broods were confined. Day- 17 body mass of surviving ducklings (n = 183) was greater for ducklings that were heavier at hatch; the difference averaged 1.7 g at day 17 for each 1.0 g at hatch (P = 0.047). Growth ratio (the proportion of body mass attained by ducklings when they were last measured relative to that predicted for wild female mallard ducklings) also was positively related to body mass at hatch (P = 0.004). Mean day-17 body mass and mean growth ratio of ducklings per brood (each adjusted for body mass at hatch) were positively related to numbers of aquatic invertebrates (Ps \u3c 0.001) and negatively related to variance in the daily minimum air temperature during the exposure period (Ps \u3c 0.020). Early growth of mallards was more sensitive to variation in numbers of invertebrates than to air temperature or biomass of invertebrates. Duckling survival was positively related to growth ratio (P \u3c 0.001). Our study provides parameter estimates that are essential for modeling growth and survival of mallard ducklings. We emphasize the need for conserving brood-rearing wetlands in the Prairie Pothole Region that are capable of supporting high densities of aquatic invertebrates