Ports' criticality in international trade and global supply-chains.

We quantify the criticality of the world's 1300 most important ports for global supply chains by predicting the allocation of trade flows on the global maritime transport network, which we link to a global supply-chain database to evaluate the importance of ports for the economy. We find that 50% of global trade in value terms is maritime, with low-income countries and small islands being 1.5 and 2.0 times more reliant on their ports compared to the global average. The five largest ports globally handle goods that embody >1.4% of global output, while 40 ports add >10% of domestic output of the economies they serve, predominantly small islands. We identify critical cross-border infrastructure dependencies for some landlocked and island countries that rely on specific ports outside their jurisdiction. Our results pave the way for developing new strategies to enhance the resilience and sustainability of port infrastructure and maritime trade.

A global multi-hazard risk analysis of road and railway infrastructure assets.

Transport infrastructure is exposed to natural hazards all around the world. Here we present the first global estimates of multi-hazard exposure and risk to road and rail infrastructure. Results reveal that ~27% of all global road and railway assets are exposed to at least one hazard and ~7.5% of all assets are exposed to a 1/100 year flood event. Global Expected Annual Damages (EAD) due to direct damage to road and railway assets range from 3.1 to 22 billion US dollars, of which ~73% is caused by surface and river flooding. Global EAD are small relative to global GDP (~0.02%). However, in some countries EAD reach 0.5 to 1% of GDP annually, which is the same order of magnitude as national transport infrastructure budgets. A cost-benefit analysis suggests that increasing flood protection would have positive returns on ~60% of roads exposed to a 1/100 year flood event.

A systems-based assessment of Palestine's current and future infrastructure requirements.

The occupied Palestinian territories of West Bank and Gaza Strip are currently experiencing many challenges in the provision of infrastructure services for their inhabitants. This includes an undersupply of infrastructure services across multiple sectors - an issue exacerbated by population growth, increasing urbanisation, economic growth and climate change. We address this challenge by providing a systems-based assessment of Palestine's infrastructure requirements and identifying broad strategies for how those needs might be met. This assessment involved four key components including: 1) defining and assessing the current system and planned infrastructure investments; 2) assessing potential future demand for infrastructure services; 3) identifying alternative strategies for future infrastructure provision beyond planned investments; and 4) analysing the performance of each strategy against a series of key performance indicators. Results from the assessment highlight the magnitude of the current and future need for urgent infrastructure investment in Palestine. The most immediate need is to alleviate the water crises in Gaza Strip, which will require at least twice as much water infrastructure investment over the coming decade than is currently in the pipeline, even if the goal is only to achieve the most basic World Health Organisation water availability requirements. To move beyond this protracted state of crises will then require a doubling of investments across all sectors to bring Palestine up to the standards of services already enjoyed by its neighbours. Such investments can have even greater impact on delivery of infrastructure services through the strategic use of interdependencies between infrastructure sectors, such as water re-use and energy-from-waste. In the pursuit of global sustainable development, the systems-based approach presented here provides an important first step in the assessment of infrastructure needs and opportunities for any country. It is particularly important for states like Palestine where key resources, such as water and energy, are so acutely constrained.

Fracture incidence in a large cohort of men age 30 years and older with osteoporosis.

UNLABELLED: In this large retrospective study of men with presumed osteoporosis, we estimate the rate of osteoporosis-related fractures in men age ≥30 years. Our results suggest that spine and hip fractures continue to be a considerable disease burden for osteoporotic men of all ages. INTRODUCTION: The purposes of this study were to describe a cohort of men with presumed osteoporosis and estimate the incidence rates of fractures by age. METHODS: Using US administrative claims data, we identified 43,813 men ≥30 years old with an osteoporosis diagnosis or use of an osteoporosis medication. Men were followed for a minimum of 12 months after diagnosis or treatment of osteoporosis (index date), until the earliest of fracture (hip, spine, pelvis, distal femur, humerus, wrist, forearm), disenrollment, or study end date. RESULTS: During the study period, there were 3834 first fractures following the index date and 3303 fractures in the 6-month period prior to the diagnosis/treatment of osteoporosis. Incidence rates of osteoporosis-related fracture, estimated from the index date onward, increased with age, although did not significantly differ from one another in younger age groups (30-49 and 50-64 years). Spine fractures had the highest incidence rate in men across all age groups, increasing from 10.8 per 100,000 person-years (p-yrs) (95% confidence interval (CI) 9.1, 12.7), 12.2 per 100,000 p-yrs (95% CI 11.2, 13.3), and 15.3 per 100,000 p-yrs (95% CI 13.8, 16.9) in men 30-49, 50-64, and 65-74 years to 33.4 per 100,000 p-yrs (95% CI 31.5, 35.4) in men ≥75 years. Hip fractures were the second most common, with the incidence rate reaching 16.2 per 100,000 (95% CI 14.9, 17.6) in the ≥75-year group. CONCLUSION: These incidence rates suggest that spine and hip fractures are a considerable disease burden for men of all ages diagnosed and/or treated for osteoporosis.

The energy-water-food nexus: strategic analysis of technologies for transforming the urban metabolism.

Urban areas are considered net consumers of materials and energy, attracting these from the surrounding hinterland and other parts of the planet. The way these flows are transformed and returned to the environment by the city is important for addressing questions of sustainability and the effect of human behavior on the metabolism of the city. The present work explores these questions with the use of systems analysis, specifically in the form of a Multi-sectoral Systems Analysis (MSA), a tool for research and for supporting decision-making for policy and investment. The application of MSA is illustrated in the context of Greater London, with these three objectives: (a) estimating resource fluxes (nutrients, water and energy) entering, leaving and circulating within the city-watershed system; (b) revealing the synergies and antagonisms resulting from various combinations of water-sector innovations; and (c) estimating the economic benefits associated with implementing these technologies, from the point of view of production of fertilizer and energy, and the reduction of greenhouse gases. Results show that the selection of the best technological innovation depends on which resource is the focus for improvement. Urine separation can potentially recover 47% of the nitrogen in the food consumed in London, with revenue of $33 M per annum from fertilizer production. Collecting food waste in sewers together with growing algae in wastewater treatment plants could beneficially increase the amount of carbon release from renewable energy by 66%, with potential annual revenues of $58 M from fuel production.

Noise and age-related hearing loss: a study of 40 123 gold miners in South Africa.

OBJECTIVE AND DESIGN: This retrospective cohort study aimed to describe the differential effect of noise exposure and age-related hearing loss in a large sample of gold miners in South Africa. STUDY SAMPLE: Audiological data of 40 123 South African mine workers were investigated. Data of a non-noise-exposed control group (n = 6162) and group exposed to underground noise (≥ 85 dB A (TWA) (n = 33 961) were included. Within these two larger noise-exposed groups two homogenous exposure groups (HEG) were also selected for analyses, namely the driller group (n = 4399) and the administration group (administrative workers) (n = 2211). Participants were categorized in terms of noise exposure, age, and race. RESULTS: Significantly different thresholds (worse for underground noise group) with respect to the median for all frequencies after adjusting for age was evident between the noise-exposed and control groups (ANCOVA). The largest differences in hearing thresholds between the noise-exposed and control groups were observed at 3 and 4 kHz in the age group 36 to 45 years. Administration and driller group differed significantly (driller group worse results) with respect to the mean LFA512 and HFA346 after adjusting for age (ANCOVA). Black males had significantly better high-frequency hearing compared with white male counterparts but significantly worse low-frequency hearing. CONCLUSION: Age was the most important influence on hearing thresholds for the noise and control groups. Race was shown to be a very significant factor determining susceptibility to NIHL and ARHL.

Evidence of hearing loss in a 'normally-hearing' college-student population.

We report pure-tone hearing threshold findings in 56 college students. All subjects reported normal hearing during telephone interviews, yet not all subjects had normal sensitivity as defined by well-accepted criteria. At one or more test frequencies (0.25-8 kHz), 7% of ears had thresholds ≥25 dB HL and 12% had thresholds ≥20 dB HL. The proportion of ears with abnormal findings decreased when three-frequency pure-tone-averages were used. Low-frequency PTA hearing loss was detected in 2.7% of ears and high-frequency PTA hearing loss was detected in 7.1% of ears; however, there was little evidence for 'notched' audiograms. There was a statistically reliable relationship in which personal music player use was correlated with decreased hearing status in male subjects. Routine screening and education regarding hearing loss risk factors are critical as college students do not always self-identify early changes in hearing. Large-scale systematic investigations of college students' hearing status appear to be warranted; the current sample size was not adequate to precisely measure potential contributions of different sound sources to the elevated thresholds measured in some subjects.

Structural and functional characterization of human CXCR4 as a chemokine receptor and HIV-1 co-receptor by mutagenesis and molecular modeling studies.

The human CXC chemokine receptor 4 (CXCR4) is a receptor for the chemokine stromal cell-derived factor (SDF-1alpha) and a co-receptor for the entry of specific strains of human immunodeficiency virus type I (HIV-1). CXCR4 is also recognized by an antagonistic chemokine, the viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus type VIII. SDF-1alpha or vMIP-II binding to CXCR4 can inhibit HIV-1 entry via this co-receptor. An approach combining protein structural modeling and site-directed mutagenesis was used to probe the structure-function relationship of CXCR4, and interactions with its ligands SDF-1alpha and vMIP-II and HIV-1 envelope protein gp120. Hypothetical three-dimensional structures were proposed by molecular modeling studies of the CXCR4.SDF-1alpha complex, which rationalize extensive biological information on the role of CXCR4 in its interactions with HIV-1 envelope protein gp120. With site-directed mutagenesis, we have identified that the amino acid residues Asp (D20A) and Tyr (Y21A) in the N-terminal domain and the residue Glu (E268A) in extracellular loop 3 (ECL3) are involved in ligand binding, whereas the mutation Y190A in extracellular loop 2 (ECL2) impairs the signaling mediated by SDF-1alpha. As an HIV-1 co-receptor, we found that the N-terminal domain, ECL2, and ECL3 of CXCR4 are involved in HIV-1 entry. These structural and mutational studies provide valuable information regarding the structural basis for CXCR4 activity in chemokine binding and HIV-1 viral entry, and could guide the design of novel targeted inhibitors.

Gap detection for similar and dissimilar gap markers.

Detection thresholds for temporal gaps between markers of dissimilar frequency are usually elevated with respect to thresholds for gaps between markers of similar frequency. Because gaps between markers of dissimilar frequency represent both a spectrally based perceptual discontinuity as well as a temporal discontinuity, it is not clear what factors underlie the threshold elevation. This study sought to examine the effects of perceptual dissimilarities on gap detection. The first experiment measured gap detection for configurations of narrow-band gap markers comprised of pure tones, frequency-modulated tones, and amplitude-modulated tones. The results showed that gap thresholds for frequency-disparate pure-tone markers were elevated with respect to isofrequency tonal markers, but that perceptual discontinuities between markers restricted to the same frequency region did not uniformly elevate threshold. The second experiment measured gap detection for configurations of markers where the leading and trailing markers could differ along the dimensions of bandwidth, duration, and pitch. The results showed that, in most cases, gap detection deteriorated when the bandwidth of the two markers differed, even when the spectral content of the narrower-band marker was completely subsumed by the spectral content of the wider-band marker. This finding suggests that gap detection is sensitive to spectral dissimilarity between markers in addition to spectral discontinuity. The effects of marker duration depended on the marker bandwidth. Pitch differences across spectrally similar markers had no effect.

A comparison of threshold estimation methods in children 6-11 years of age.

Estimating detection threshold for auditory stimuli in children can be problematic because of lapses in attention and the time limits usually imposed by scheduling restrictions or fatigue. Data reported here were collected to compare the stability of threshold estimation procedures in testing children ages 6 to 11 in a three-alternative, forced-choice paradigm. Stimuli consisted of a 1-kHz tonal signal and a Gaussian noise masker, bandpass filtered between 500-2,000 Hz and presented at 25-dB spectrum level. The signal was either presented for 400 ms in the presence of a continuous masker (simultaneous masking) or for 10 ms just prior to a 400-ms masker (backward masking). For each masking paradigm the 79% correct threshold was assessed via each of three procedures: 3-down, 1-up adaptive staircase (Levitt), maximum likelihood estimation (MLE), and method of constant stimuli. Percent correct was measured at the end of the study for a signal 10 dB above the previously determined threshold in order to estimate the most appropriate psychometric function asymptote for fitting data collected via the method of constant stimuli. Both the MLE and Levitt procedures produced equally stable threshold estimates for both conditions and age groups. This was the case despite considerable variability in backward-masking thresholds.

Gap duration discrimination in listeners with cochlear hearing loss: effects of gap and marker duration, frequency separation, and mode of presentation.

This study examined the effects of cochlear hearing loss on gap duration discrimination (GDD), with particular interest in whether cochlear hearing loss results in increased difficulty for across-channel temporal judgments. The hypothesis being tested was that listeners with cochlear loss would perform as well as normal-hearing listeners for all within-channel conditions but would exhibit relatively greater performance deficits in the across-channel conditions. A subsidiary aim was to determine whether, in normal-hearing listeners, the across-channel effects previously observed for minimal-duration standard gaps also existed for relatively long standard gaps. Two experiments were undertaken, one dealing with monaural conditions and one dealing with dichotic conditions. The monaural results indicated that across-frequency GDD was poorer than isofrequency GDD, even for the longer gap durations of 35 and 250 ms examined here. However, the results showed no effect of hearing loss on GDD. Rather, GDD appeared to be sensitive to listener age, with younger listeners showing better performance in both within-channel and across-channel conditions. In addition, both within-channel and across-channel performance was sensitive to the duration of the leading gap marker. Finally, the pattern of dichotic "across-ear" performance was similar, but not equivalent, to that of monaural across-frequency performance.

A novel peptide antagonist of CXCR4 derived from the N-terminus of viral chemokine vMIP-II.

The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi's sarcoma-associated herpesvirus is unique among all known chemokines in that vMIP-II shows a broad-spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cell entry of human immunodeficiency virus type 1 (HIV-1). To elucidate the mechanism of the promiscuous receptor interaction of vMIP-II, synthetic peptides derived from the N-terminus of vMIP-II were studied. In contrast to the full-length protein that recognizes both CXCR4 and CCR5, a peptide corresponding to residues 1-21 of vMIP-II (LGASWHRPDKCCLGYQKRPLP) was shown to strongly bind CXCR4, but not CCR5. The IC(50) of this peptide in competing with CXCR4 binding of (125)I-SDF-1alpha is 190 nM as compared to the IC(50) of 14.8 nM of native vMIP-II in the same assay. The peptide selectively prevented CXCR4 signal transduction and coreceptor function in mediating the entry of T- and dual-tropic HIV-1 isolates, but not those of CCR5. Further analysis of truncated peptide analogues revealed the importance of the first five residues for the activity with CXCR4. These results suggest that the N-terminus of vMIP-II is essential for its function via CXCR4. In addition, they reveal a possible mechanism for the distinctive interactions of vMIP-II with different chemokine receptors, a notion that may be further exploited to dissect the structural basis of its promiscuous biological function. Finally, the potent CXCR4 peptide antagonist shown here could serve as a lead for the development of new therapeutic agents for HIV infection and other immune system diseases.

Screening for and assessment of infant hearing impairment.

With the identification of hearing loss at birth and appropriate intervention within 6 months after birth, language can develop normally, even in children with severe hearing impairment. Universal newborn hearing screening (UNHS) is now endorsed by numerous national groups, including the American Academy of Pediatrics. Two electrophysiologic techniques--automated auditory brainstem response (ABR) and otoacoustic emissions (OAEs)--are used for the identification of communicatively significant hearing loss in newborn infants. UNHS is legislatively supported by more than one half of the United States, including the most populous. Successful hearing screening and intervention programs require the support and expertise of pediatricians, including perinatologists.

Development of the ear and hearing.

Knowledge of the development of the peripheral auditory system, especially the middle ear and inner ear (cochlea), contributes to meaningful interpretation of audiologic measures infants, including newborn screening outcome. An understanding of the effects of noise on neonatal auditory system and hearing function is also dependent on maturational factors. This paper is a brief overview of principles and trends in the development of the middle and inner ear. The emphasis is on maturation of human peripheral auditory system structure and function, although reference is also made to animal research.

Universal newborn hearing screening with automated auditory brainstem response: a multisite investigation.

OBJECTIVE: The purpose of the study was to assess the feasibility of performing universal newborn hearing screening in different clinical settings and tracking the infants who did not pass initial screening through their confirmatory testing. STUDY DESIGN: Between December 1996 and December 1997, a total of 11,711 infants were enrolled from five clinically different study sites. Universal newborn hearing screening was performed using automated auditory brainstem response (AABR) testing. Infants who did not pass the initial screening were tested again prior to discharge. Data regarding the rate of referral for follow-up testing, age of infant at screening, the duration of time required for screening, and type of personnel performing the test were collected. Formal audiology appointments were made prior to discharge for infants who required follow-up testing, and letters were sent with phone calls made to those who failed to keep their appointments for repeat testing. Outpatient testing consisted of a repeat AABR and, if necessary, a diagnostic auditory brainstem-evoked response, otoacoustic emission testing, and tympanometry. RESULTS: At the time of hospital discharge, the refer rate was < 2% (215 of 11,711 newborns) using AABR screening. Sensorineural hearing loss (SNHL) was confirmed in 32 of these infants, resulting in an overall incidence of confirmed SNHL of 2.7 per thousand newborns. The false-positive rate ranged from 0.3% to 2.5%, with a cumulative false-positive rate of 0.9% (1.5% if all infants lost to follow-up are included as false-positives). No false-negatives were identified. The average time of testing was 7.1 minutes independent of the personnel performing the testing and the age of testing was < 24 hours in 70% of the infants tested. The total number of infants lost to follow-up was 61 (29% of patients referred or 0.5% of the study population). CONCLUSION: This study demonstrated that the refer rate for universal hearing screening with the AABR was acceptably low when performed by a variety of personnel in typical nursery settings within the first 24 hours after birth. A low rate of screening failures with the AABR minimizes costs associated with subsequent follow-up assessments and lessens any potential impact of false-positive screening on the parent-newborn relationship.

Proficiency Testing in a Laboratory Accreditation Program for the Bacterial Ring Rot Pathogen of Potato.

Variability of enzyme-linked immunosorbent assay (ELISA) and immunofluorescence tests for the detection of Clavibacter michiganensis subsp. sepedonicus in potato tissue was analyzed to determine the magnitude of repeatability (within analyst variation) and reproducibility (among analyst variation) components. The analysis was based on data generated by analysts in eight laboratories testing proficiency panel samples distributed under a laboratory accreditation program. The standard deviation for repeatability of the ELISA test was small but increased at higher absorbance readings, while the standard deviation for reproducibility was larger and also increased at high absorbances. For immunofluorescence, the standard deviation for repeatability and reproducibility were similar to one another and increased with increasing bacterial concentration, as might be expected for count data and the inherent subjectivity of the test. The reproducibility standard deviation provided the basis for calculating "z-scores" by the Association of Official Analytical Chemists' procedure to evaluate proficiency of chemical analyses. More than 90 and 80% of the z-scores for samples tested in this study by ELISA and immunofluorescence, respectively, were in the acceptable range. The rescaled sums of z-scores for individual analysts were used as single combination scores to evaluate each analyst's results over all samples of a proficiency panel. This measure may be useful for tracking analyst performance on process control charts as part of a quality control system.

Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction.

The CC chemokine receptor CCR5 is the receptor for several chemokines and coreceptor for the entry of HIV-1. Whereas many studies focus on CCR5 interaction with HIV-1, residues in CCR5 important for chemokine binding and subsequent signal transduction remain poorly understood. Here we use an approach combining protein structure modeling and site-directed mutagenesis to probe the structure of CCR5 and its interactions with chemokine ligands and HIV-1. Structural models of CCR5 rationalize extensive biological data about the role of CCR5 in HIV-1 envelope glycoprotein gp120 binding and HIV-1 entry. Furthermore, we carry out site-directed mutagenesis guided by structural analysis of the complex of CCR5 and a chemokine. This leads to the novel observation that certain residues, such as Tyr10 and Lys26, in the N terminus of CCR5 play a critical structural role for ligand binding and signaling. Single glycine substitution of these residues significantly decreases chemokine binding and signal transduction. These results provide new insight into the structural basis for CCR5 receptor-ligand interaction and may guide the design of novel inhibitors.

Attachment of C-terminus of SDF-1 enhances the biological activity of its N-terminal peptide.

The N-terminus of stromal cell-derived factor 1 (SDF-1) is known to be a critical site for CXCR4 receptor binding and signaling. However, the functional role of other regions, in particular the C-terminal helix of SDF-1, has yet to be defined. In this study, we designed and synthesized a peptide model of SDF-1 containing its N- and C-terminal regions. The attachment of the C-terminus of SDF-1, which by itself had no activity in receptor binding and signaling, dramatically increased the effect of the N-terminal fragment in inducing chemotaxis and intracellular Ca(2+) influx in sup T1 cells compared with the peptide containing only the N-terminal sequence. The enhancement in activity was not due to the increase in receptor affinity as the N,C-terminal peptide did not show higher CXCR4 binding than the N-terminal peptide. On the other hand, the intracellular Ca(2+) influx activated by the N,C-terminal peptide, but not the N-terminal peptide, was completely abolished by the addition of heparin, suggesting that the C-terminal fragment of the peptide binds glycosaminoglycans (GAGs) and exerts an effect to modulate biological activity. These data raise the possibility that the C-terminus in native SDF-1 is one of interaction sites with GAGs and may be associated with biological function of SDF-1. Furthermore, this study demonstrates an approach for the design of novel agonists or antagonists of other chemokine receptors that possess enhanced biological activity.

The role of positively charged residues in CXCR4 recognition probed with synthetic peptides.

A high positive charge is the common characteristic shared by the beta-sheet region of stromal cell-derived factor-1 (SDF-1) and CXCR4 antagonists such as ALX40-4C consisting of nine D-arginines. This raises the question that the positively charged residues may play a role in recognition of CXCR4. To test this hypothesis, two studies were carried out using synthetic peptides. In the first study, peptide analogs possessing amino acid sequences from both the N-terminus and the beta-sheet region of SDF-1 were used as models to study the functional role of the beta-sheet region of SDF-1. The attachment of positively charged residues to the N-terminal peptide sequence of SDF-1 was found to enhance the ability of the peptides in CXCR4 binding and inhibiting CXCR4-mediated T-tropic HIV-1 entry. In the second study, two peptides containing nine arginines and the N-terminal signal sequence of SDF-1 were used as models to study the receptor binding mechanism of CXCR4 antagonists of high positive charges such as ALX40-4C. One peptide did not show signaling activity as indicated by the lack of calcium influx while another peptide induced unusual calcium influx distinct from that induced by the SDF-1 N-terminal peptide. In addition, the signal induced by the SDF-1 N-terminal peptide was inhibited by ALX40-4C. Therefore, the first study provides experimental support for the role of the highly positive beta-sheet region of SDF-1 in CXCR4 binding. The second study suggests that the binding site of ALX40-4C in CXCR4 may partially overlap with that of the SDF-1 N-terminal peptide. Both findings should be valuable for the design of SDF-1 agonists and antagonists.