NO) potentially detects airway inflammation related to air pollution exposure. Existing studies have not yet provided conclusive evidence on the association of FeNO with traffic-related pollution (TRP).Background: The fractional concentration of nitric oxide in exhaled air  who participated in the Southern California Children’s Health Study (CHS) to five classes of metrics of residential TRP: distances to freeways and major roads; length of all and local roads within circular buffers around the home; traffic densities within buffers; annual average line source dispersion modeled nitrogen oxides (NOx) from freeways and nonfreeway roads; and predicted annual average nitrogen oxide, nitrogen dioxide, and NOx from a model based on intracommunity sampling in the CHS.Methods: We related FeNO, with stronger associations in smaller buffers , 12.4% , and 4.1%  higher FeNO for 100-, 300-, and 1,000-m increases in the length of all roads in 50-, 100-, and 200-m buffers, respectively. Other TRP metrics were not significantly associated with FeNO, even though the study design was powered to detect exposures explaining as little as 0.4% of the variation in natural log-transformed FeNO (R2 = 0.004).Results: In children with asthma, length of roads was positively associated with FeNO.Conclusion: Length of road was the only indicator of residential TRP exposure associated with airway inflammation in children with asthma, as measured by Fe NO) is a noninvasive marker of aspects of airway inflammation , and ozone (O3) were associated with elevated FeNO  is an ongoing prospective cohort study designed to study the chronic effects of air pollution on children’s respiratory health. Traffic plays an important role in Southern California air pollution. TRP has been associated previously with respiratory health in the CHS. Residential proximity to freeways was associated with substantial deficits in lung function growth, independent of regional pollutant effects ; residented FeNO , and elet asthma .NO with five classes of metrics of residential TRP exposure in a large cohort of children.The objective of this study was to evaluate the association of FeStudy population. Study participants were children from a CHS cohort enrolled from kindergarten or first-grade classrooms in 2002–2003 in 12 communities in Southern California , using a protocol approved by the University of Southern California Institutional Review Board. Informed consent was obtained from a parent or guardian, who completed baseline and annual follow-up written questionnaires, and informed assent was obtained from each child. More information on the study design is available elsewhere (lsewhere .NO assessment.Fe Detailed descriptions of FeNO collection in the CHS have been reported previously (NO was collected at schools from October to June during the 2005–2006 school year using an offline breath collection technique according to American Thoracic Society (ATS) guidelines . Collection occurred primarily in the mid to late morning to minimize possible effects of early morning traffic-related peaks in ambient nitrogen oxide (NO) and recent food intake. Participants with acute respiratory infection in the preceding 3 days were rescheduled or excluded. To differentiate seasonal and spatial effects, each CHS community was visited at least twice in different seasons. In subsequent study years, online FeNO collection, which allows real-time flow monitoring and is not subject to NO measurement errors related to analysis delay or bagged sample contamination, became feasible in a large study population. A pilot study with collection of offline (100 mL/sec flow) FeNO and measurement of online  FeNO within 4 hr of each other in 2006–2007 was used to develop a model that reliably predicted online values of FeNO (R2 = 0.94) using measured offline FeNO, concurrent ambient NO, and offline sample analysis interval  (in parts per billion) from freeway and nonfreeway roads at participant residence locations were obtained via the California Line-Source Dispersion Model (CALINE4) using information on roadway geometry, traffic volumes, wind speed and direction, atmospheric stability, mixing heights and vehicle emission rates, as described elsewhere (2) at 942 CHS participant resident locations, schools, and central sites across the same 12 CHS communities considered here for 2 weeks in the summer and 2 weeks in the winter of 2005 (R2 = 0.75), NO2 (adjusted R2 = 0.67), and NOx (adjusted R2 = 0.75) at CHS participants’ homes, with the following information as model inputs: CALINE4 NOx estimates from freeways and nonfreeways, distances to freeways and nonfreeway major roads, population density, elevation, and whether the community was inside the Los Angeles basin.eviously . The toteviously . Local reviously . Predictlsewhere . The Int of 2005 . As partCovariate information. Parent/guardian responses to a written questionnaire during the 2005–2006 school year provided information on race/ethnicity, highest attained parental education, physician diagnosis of asthma, rhinitis, asthma medication use in the previous 12 months, and exposure to secondhand smoke. Height and weight measured on the day of the FeNO test were used to calculate age- and sex-specific body mass index (BMI) percentiles from Centers for Disease Control and Prevention (CDC) growth charts  medication is known to acutely affect FeNO levels . We calculated within-community correlations of the exposures by subtracting community-specific means from each exposure and then calculating the Pearson’s correlation of the resultant deviations from community-specific means. We used multiple linear regression models to relate natural log (ln)-transformed FeNO to exposures because FeNO has a right-skewed distribution. After careful consideration of potential confounders and effect modifiers, all models were adjusted for child’s race/ethnicity, sex, asthma status, use of asthma medication (controller and/or rescue) in the previous 12 months, rhinitis history , age at FeNO collection, BMI percentile, secondhand tobacco smoke, parental education, month and hour of FeNO collection, whether the FeNO test was performed outdoors, and community of residence . We investigated potential effect modification by asthma status by fitting models with an appropriate interaction term and by fitting separate models for children with and without asthma. Because many of the exposures were correlated, we fit single-pollutant models.NO), using a procedure that estimates the degrees of freedom of the smooth relationship as part of the model-fitting process . Our results were not sensitive to this approach, because complete case or multiple imputation analyses produced similar results (data not shown).a) testing for heterogeneity in TRP effects by race/ethnicity; b) additionally adjusting for recent pollution: ambient NO at the time of test at the testing location, daily community-specific central site 24-hr cumulative lagged average of PM2.5 (over 1–8 days)  restricting the analysis to the subset of children reporting no change of residence since November 2004.We performed additional sensitivity analyses by –8 days) , or centhttp://dx.doi.org/10.1289/ehp.1103516)] using information from this study on sample size, the distribution of FeNO and its association with adjustment covariates, and the distributions of the TRP variables.To determine the lower bound of effects detectable at 80% power with our study design, we performed a power simulation study . Within communities, distances to freeway and major road were moderately correlated (0.42), traffic densities within 150-m and 300-m buffers were highly correlated (0.90), the lengths of all and local roads had correlations of 0.61 to 0.72, CALINE4 predictions of freeway and nonfreeway NOx had low correlation (0.05), and ICV predictions of NO, NO2, and NOx were highly correlated (0.91 to 0.98) (tributed . Approxito 0.98) . Length NO associations.TRP–Fe Length of road was the only class of TRP exposure metric that had any statistically significant associations with FeNO in all children . The maximum R2 of a model that included an additional linear effect of a single TRP metric was 0.130 (0.273 for children with asthma). For children with asthma, there was a positive association of length of road with FeNO, with a stronger and statistically significant association in the 50-m buffer , 14.3 to 88.4], 12.4 , and 4.1 , respectively, for children with asthma and –0.2 , 4.6 , and 4.7 , respectively, for children without asthma.children , with slchildren . A largem buffer . For chiNO associations.Nonlinear TRP–Fe For children with asthma, FeNO had a nonlinear association with the length of local roads in a 50-m buffer. There was no evidence for an association of length of road with FeNO for shorter lengths of road, but a strong positive association when the length of road was longer than 100 m , more than twice the estimated effect for a 50-m increase when we assume the relationship is linear over the range of the data . There was no evidence of other biologically relevant nonlinear exposure–response relationships between the other TRP metrics and FeNO (data not shown).an 100 m . Using aSensitivity analyses. There was no evidence of heterogeneity in TRP effects by race/ethnicity or community. The associations of length of road with FeNO were generally stronger in the subgroup of 1,937 children who had not reported a move since November 2004 (data not shown) and not sensitive to adjustment for recent pollution, including ambient NO at the time of the test.Power simulation study. A study with our design has 80% power to detect an exposure that explains as little as 0.4% of the variation in ln(FeNO) (R2 = 0.004) after controlling for the adjustment covariates. The minimum detectable effect sizes for the given exposure contrasts ranged from a percent difference in FeNO of 1.15 for a 5-ppb increase in CALINE4 estimated annual average freeway NOx to 7.66 for a 100-m increase in the length of local roads in a 50-m buffer . As expected  land-use regression–modeled annual averages of NO2, SO2, coarse PM, PM2.5, and black smoke at the residential postal code; b) distance to a single major truck transportation route; and c) length of all or local roadways within 200 m of the residence  and local (p < 0.05) roadways. In our study, we had no metric analogous to distance to truck route, but FeNO was highest in Long Beach, California, a community with more truck traffic. We had finer spatial resolution and a wider range for annual average NO2 but comparable distributions of lengths of roads in a 200-m buffer. The estimated percent difference in FeNO associated with a 1,000-m increase in the length of local roads in a 200-m buffer in our study  was similar to the estimate in Windsor . In Windsor, the length of all roads in a 200-m buffer was statistically significantly associated with FeNO. We observed smaller, nonsignificant associations .The largest comparable study related Feesidence . FeNO waNO with length of road and traffic densities within 50-m, 100-m, 200-m, 300-m, 400-m, 500-m, and 750-m buffers around schools and homes ]. For example, in a residential 50-m buffer, the percent difference in FeNO associated with a 100-m increase in the length of all roads for children with asthma was 46.7  in our study and 47.9  in Mexico.A study of 200 children in Mexico, half with asthma, examined the association of Fend homes . StatistNO to be 8.8% higher  in urban children compared with suburban children, a difference possibly related to TRP exposure but potentially confounded by the lack of adjustment for ambient NO at the time of the test  but not with distance from a motorway or with traffic counts, although a larger positive association (not significant) was observed for children with asthma (x (n = 19) (2 (n = 45)   and pers(n = 45)  to be ash asthma . Fourteea tunnel .This study has several strengths. It is a large, ongoing, prospective cohort study that included ethnically diverse children—with and without asthma—in 12 communities in Southern California, an area with a uniquely broad range of air pollution exposures in which TRP plays an important role. Multiple metrics were available to measure different features of TRP exposure. Distance, total length of road, and traffic density offered straightforward, although somewhat crude, measures of the effects of proximity to roadways and may be indicators of short- or long-term exposure. CALINE4 predictions accounted for key factors that determine exposure, such as wind speed and direction, and the CHS ICV study predictions offered a further refinement of the exposure surface. However, both predictions focused only on annual averages of specific TRP components that have been considered as representative surrogates for products of traffic-related combustion  and did NO association. We had information only on parent report of asthma medication use in the previous 12 months, so we excluded participants taking ICS medication. Information on recent food intake or exercise was not available, but we adjusted for time of day of collection. We adjusted for parent education, but because socioeconomic status (SES) may be related to TRP exposure, there is a potential for residual confounding by SES. However, results were similar when we additionally adjusted for household income and whether the child had health insurance. We conducted thorough exploration during model building and sensitivity analyses, but as in any analysis of observational data, we may have lacked data on or been unaware of other potentially important confounding variables. Asthma is an important susceptibility factor; our determination of asthma status by parent report of doctor diagnosis has limitations but is widely used in epidemiologic studies (http://dx.doi.org/10.1289/ehp.1103516)].This study also has several limitations. We were unable to disentangle the effects of asthma medication use on the TRP–Fe studies . We had NO in our study population. For other metrics, we can compare minimum detectable effect sizes based on our study design with effect sizes observed in other studies. For example, NO associated with a 10-ppb increase in land-use regression–modeled annual average NO2. Our study design had 80% power to detect an association of similar magnitude , assuming similarity in these metrics across studies. However, in our study—with larger sample size and greater exposure contrast—we observed an effect that was smaller and negative . This result, along with our other findings, is consistent with the null hypotheses that local, long-term average NO2, NO, NOx exposures; local traffic densities; and distance to freeway and major road are not associated with FeNO in our study population. Similarly, in a previous study, we found evidence of short-term but not long-term effects of community-level ambient PM2.5 on FeNO  PDFClick here for additional data file.


The size and diversity of this artistic ceramic assemblage indicate the emergence of a social tradition, rather than more ephemeral experimentation with a new material. Vela Spila ceramics offer compelling technological and stylistic comparisons with the only other evidence of a developed Palaeolithic ceramic tradition found at the sites of Pavlov I and Dolní Věstonice I, in the Czech Republic, c. 31,000–27,000 cal BP. Because of the 10,000-year gap between the two assemblages, the Vela Spila ceramics are interpreted as evidence of an independent invention of this technology. Consequently, these artifacts provide evidence of a new social context in which ceramics developed and were used to make art in the Upper Palaeolithic.Recent finds of 36 ceramic artifacts from the archaeological site of Vela Spila, Croatia, offer the first evidence of ceramic figurative art in late Upper Palaeolithic Europe,  The size, diversity, and complexity of this ceramic art assemblage indicate the emergence of a social tradition rather than more ephemeral experimentation with a new material. On morphological, technological and stylistic grounds, Vela Spila ceramics offer compelling comparisons with the only other evidence of a developed Palaeolithic ceramic tradition, found at Pavlovian sites, such as Pavlov I and Dolní Věstonice I, in the Czech Republic. The new finds from Vela Spila, like the Pavlovian ceramics, provide insight into how socio-technical innovations developed, were adopted, and were sometimes rejected from Upper Palaeolithic socio-technical and artistic repertoires. On current evidence, ceramic technologies seem to have been independently invented c. 17,500 years ago, and were subsequently lost from the socio-technical tradition at this site between about 2,000 and 3,000 years later. Consequently, these artifacts provide evidence of a new location and context in which ceramics developed and were used to make art in the Upper Palaeolithic. They encourage consideration of broader archaeological concerns such as the social role of experimentation and innovation and the impact of technological innovations on artistic expression.The Upper Palaeolithic preserves a rich and diverse record of early technological innovations, including textiles and weaving Vela Spila is a cave on the western end of Korčula island, in the central Dalmatian archipelago, Croatia  & 2. TheVela Spila consists of a single, large chamber approximately 50 m long, 30 wide, and 17 m high . The cavc. 20,000 cal BP, probably at the time of the Last Glacial Maximum. Overlying it is a series of layers with abundant archaeological remains; radiocarbon assays on charcoal and bone date these deposits from c. 19,500–14,500 cal BP. These contain abundant lithic and organic Upper Palaeolithic remains that are typologically similar to those from well-known Epigravettian sites in the wider region . Large vertebrate faunal remains are extremely frequent and are dominated by red deer (Cervus elaphus), followed by the extinct half-ass (Equus cf. hydruntinus); other taxa either are relatively rare  or are represented by only a few specimens  Pleistocene sediments have been systematically excavated in an area of about 20 square meters . Sedimenc. 17,500 and c. 15,000 years ago. These dates confirm the Epigravettian attribution suggested by material culture in these horizons.The ceramics were found during wet-sieving of finds post-excavation in 2001 and 2006. All ceramics are attributable to one of the Late Upper Palaeolithic (LUP) horizons: LUP-D, E, F, or G. As noted above, artifacts and faunal remains found in LUP-D, E, F and G are broadly consistent with nearby regional Epigravettian sites These Late Upper Palaeolithic horizons did not contain any clearly intrusive material from later deposits  which were also excavated in this area of the cave. The Epigravettian horizons are more than 1.5 m beneath Neolithic contexts with ceramics, and this part of the cave contains no evidence of later prehistoric pits or postholes dug into underlying sediments. Therefore, we can be confident that the Epigravettian ceramics come from secure contexts and are not intrusive from younger deposits.One ceramic zoomorphic figurine was identified in 2004 during post-excavation analysis of material recovered during the 2001 excavations. The figurine may have been overlooked during the initial sorting of materials in 2001 due to the incongruity of finding a ceramic artifact in Upper Palaeolithic horizons. Owing to this discovery, assemblages excavated in 2006 were carefully examined with the intent of recovering more ceramic fragments; that year, 45 additional fragments were excavated from Epigravettian horizons and identified as potential ceramic figurines and portions of figurines. These artifacts were arbitrarily numbered C1–C46. Beginning in 2010, these objects were analyzed macroscopically, using a hand lens with 10× magnification, looking for evidence of human modification, such as finger pinches, surface engravings, or marks of smoothing, to determine whether fragments are ceramics demonstrating evidence of human modification. All artifacts were measured in three dimensions using digital calibers, and their dimensions were recorded to the nearest 0.5 mm. They were subsequently weighed using jewelers scales, with weight recorded to the nearest 0.1 g. The general shape  and color  were recorded for each object. The presence of surface incisions, puncture marks, irregularities of the surface, impressions, and breaks was noted. Evidence of modeling, for instance joins, pinch marks, or rolling, was recorded. An overall, qualitative description was also recorded. Finally, each artifact was photographed from all angles, using a tripod-mounted digital SLR camera.From this assemblage of potential ceramic artifacts, ten fragments were removed from the assemblage and reclassified as: ochre or other pigmented mineral (n = 2), calcite accumulation (n = 3), and unintentionally burned or hardened earth that lacks evidence of intentional human modification (n = 5). Thus, 36 objects from the site are accepted as human-made ceramic artifacts . ThirteeThe objects were distinguished based on overall color. This is similar to classifications made by Soffer and Vandiver Tests of durability similar to those described by Soffer and Vandiver The most complete artifact, designated C1, was identified in 2004 during analysis of artifacts that were excavated during the 2001 season. C1 preserves the torso and foreleg of an animal, perhaps a horse or deer  and 6. TThe figurine preserves no engravings such as facial features, fur or hair, or another decorative marks or patterns. The few faint marks on the torso were likely made unintentionally with a fingernail while the object was being modeled. A hole perforates the animal’s rear, in the anatomical position of the anus. The smooth-edged and uniform hole, measuring 1.67×1.78 mm, was probably made with a tool such as a small bone point. One bone point fragment, VS 06.99, which was excavated in 2006 from Square 12, Layer 20 (within the LUP-G horizon), measures 34.24 mm long and its rounded point tapers to less than 1.1 mm across . This toThe surviving foreleg on C1 represents both forelimbs as a single appendage. The artist modeled the two forelegs  as a single limb. This convention allows the artist to make fewer potentially fragile limbs, thus minimizing the number of joins and imparting more structural strength to the figurine with resulting limbs that are thicker near the join with the torso.c. 17,300 cal BP. The piece is fragmented and broken at two extremities, making it difficult to discern the original shape. The fragment is relatively large in comparison to the rest of the assemblage, measuring 25.0×21.0×8.0 mm and weighing 5.0 grams. The dark brown-orange color and smooth texture of this piece are consistent with firing at a reasonably high temperature.A second figurative fragment, C2  and 9, wThis piece is heavily engraved with bands of incisions which resemble punctures and short hatches. Microscopically, these incisions are visibly V-shaped, suggesting they were made with a burin or the corner of a lithic blade or flake fragment. There is also one shallow engraving or scraping which is internally striated (visible under 10× magnification) extending down one side of the fragment   and 5 suTwo fragments offer primary evidence of human manipulation of ceramics at Vela Spila (C34 and C18). Small impressions or striations are visible with a hand lens on the smoothed surfaces of both objects . The sizOther ceramic fragments excavated from Epigravettian horizons at Vela Spila include: C5, an orange, flattened, oval-shaped ceramic; C7, a spherical, orange-brown artifact with one pinched point, with a maximum dimension of 15.0 mm; C8, a tabular, orange-brown artifact with a maximum dimension of 23.0 mm; C9, an orange-brown, dome-shaped artifact with a maximum dimension of 21.0 mm, comprised of two fragments that refit together; C13, a cylindrical, tan-brown artifact with a worked, rounded extremity and a maximum dimension of 21.0 mm; C19, a rounded tabular, orange-brown artifact that appears to have been pinched into shape; C22, an irregularly shaped, tan-brown ceramic with a maximum dimension of 19.0 mm; C23, a brown, cylindrical artifact shaped by rolling and pinching; C25, a cylindrical, dark-brown artifact with one broken extremity and evidence of smoothing across its surfaces; C26, a flattened, triangular shaped fragment with several striations on one surface; C27, a small, tan, tabular shaped artifact, with a maximum dimension of 15.0 mm; C28, a conical, orange-tan artifact with a maximum dimension of 21.0 mm; C29, an orange-tan, cylindrical artifact with one extremity that has been pinched into shape; C30, an orange-brown, irregularly-shaped artifact with a maximum dimension of 23.0 mm; C32, a dome-shaped, orange-tan artifact; C33, a round, tan-brown artifact with round and smoothed surfaces and one broken edge; C35, a small, orange-tan, cylindrical artifact without any breaks at its extremities; C36, a small, conical, brown fragment with a break at one end and a group of incisions near the tapered point; C40, a tabular, tan-brown artifact with a maximum dimension of 15.0 mm; C41, a regular, smoothed, spherical, tan-brown artifact; C42, an orange-brown, cylindrical artifact, seemingly shaped by rolling, featuring one incised mark on its surface; and C44, a flattened, semi-circular shaped artifact with smoothed surfaces .Cyclope sp., Luria sp., and Lucinidae sp. were excavated from LUP horizons D-G. Eleven perforated red deer canines, one engraved with six linear incisions, were also excavated from Epigravettian layers. One perforated bone fragment, possibly an ornament or pendant, and two decorated bone tools were also found The ceramic artifacts are important components of the classifiable Epigravettian “art” from Vela Spila. To date, 29 other symbolic or ornamental artifacts have also been found. Perforated shells of c. 31,000–27,000 cal BP The most immediate points of comparison to the Vela Spila ceramics are Pavlovian ceramic assemblages from Moravia, Czech Republic, particularly Dolní Věstonice I and Pavlov I, dated to The Vela Spila ceramics, like many Pavlovian ceramics However, the Vela Spila assemblage is distinguishable from the Pavlovian assemblage in several ways. Many ceramic leg fragments from Pavlov I depict a schematic foot in situ hearths. Furthermore, because all of the ceramics were recovered in wet-sieved residues rather than in the trench, it is impossible to associate them with any features that might have been present. In contast, Pavlovian ceramics are strongly spatially associated with hearths and purported “kilns” Vela Spila ceramics do not cluster near settlement features, hearths or concentrations of burned material. Combustion features, including hearths, were excavated in Horizon LUP-H, but this horizon did not contain ceramics. Combustion features were not identified in any of the horizons with ceramics, although all of these horizons yielded both wood charcoal and burned faunal remains (13.9–31.1% of fragments). Dispersed ash was found in some layers where ceramics were also found, but this ash was not associated with rubified sediment which would suggest the presence of BP Ceramic artifacts from Upper Palaeolithic levels are rare but not unknown beyond the Moravian Gravettian record. A small number of Gravettian ceramics were discovered at Krems-Wachtberg in Austria In other Palaeolithic contexts, ceramic technologies distinguishable from an art tradition have been uncovered. Ceramic hearths found in late Aurignacian levels at Klisoura cave in Greece c. 7,000–6,400 uncal BP. Impressed-ware vessels feature the use of shells, fingernails, or other implements to create patterned incisions and marks Cardium sp. shells), indicating the development of distinct cultural and technical traditions. Finally, the marks are not regularly arranged on C2, whereas Impressed-ware pottery features marks which are often evenly distributed or grouped in patterns. The similarities between the incisions covering C2 and those noted on Pavlovian ceramics reinforce the differences between the Palaeolithic and Neolithic ceramic traditions.No ceramics have been found in Mesolithic horizons at Vela Spila, so more than 8,000 years separate the Palaeolithic ceramics from the site’s earliest Neolithic ceramic pottery. The earliest Neolithic, or Impressed-ware ceramics at Vela Spila date to between Early Neolithic ceramic figurines are rare in the Balkans. Only one such statuette is currently known from Croatia, which was found in Vela Spila in 2004. This Neolithic statuette, which might depict a pig, is somewhat larger than most of the Pleistocene ceramics (33.0×18.0×15.0 mm). One key techno-stylistic difference relates to the way legs were formed. Palaeolithic ceramicists combined zoomorphic legs in both C1 and C2 so that only two limbs were modeled, rather than four. However, the Neolithic figurine preserves four breaks, where four separate limbs were joined to the body. The Palaeolithic tradition of combining four legs into two is not expressed here, illustrating a different stylistic and technical convention in the Neolithic. Thus, the stratigraphic evidence and stylistic and technological differences between the Palaeolithic and Neolithic figurines reinforce the authencity of the new finds from Vela Spila as securely Palaeolithic. Furthermore, it suggests that the Palaeolithic ceramic tradition may have been considerably different from the later Neolithic ones that developed in this area, with no evidence of continuity between these two time periods. Indeed, Palaeolithic and Neolithic craftspeople and artists seem to have independently invented ceramics in two very different social contexts.c. 27,000 cal BP, when the Pavlovian technocomplex either transformed into or was replaced by a later Gravettian culture . The geographic, chronological, and techno-cultural differences between Gravettian Moravia and Epigravettian Croatia make it reasonable to purport an independent invention of this technology and tradition in the western Balkans almost 10,000 years later. Without destructive technological analysis of the materials used to make the ceramics at Vela Spila, it remains impossible to determine if the ceramics were made in situ at Vela Spila or if they were imported from elsewhere in the region. However, the lack of Pleistocene ceramics at contemporaneous sites in the region, such as Crvena Stijena (Montenegro), Kopačina (Croatia), Badanj (Bosnia and Herzegovina), and Grotta Paglicci , suggests the tradition may have developed at Vela Spila.Despite some technological and stylistic similarities between the Pavlovian and Vela Spila ceramic assemblages, the technocomplexes share little other material culture suggesting cultural continuity spanning thousands of kilometers and 10,000 years. Pavlovian ceramic technology seems to have remained a geographically circumscribed tradition within Central Europe. Furthermore, Pavlovian ceramic artifacts disappear from the archaeological record only a few millennia after their first appearance, The stratigraphic sequence at Vela Spila demonstrates Upper Palaeolithic occupation as much as 2,000 years before the emergence of ceramics and also slightly after the ceramic figurines disappear from the record. Interestingly, charcoal and faunal remains are most abundant in horizons where ceramics were found . This peThe ornaments and decorated bones from Vela Spila suggest that a symbolic tradition existed here throughout much of the late Upper Palaeolithic. Perforated marine shells and red deer canine ornaments at the site are similar in form throughout the late Upper Palaeolithic sequence, indicating a stable decorative or symbolic tradition. The raw materials were minimally modified to make the ornaments; in most instances, a single perforation was made in the material. The stratigraphic sequence demonstrates that the ornaments predate the ceramic technologies; when ceramics begin to appear in the record, they are often found associated with these ornaments in the same layers. After the ceramics disappear from the record, shell and tooth ornaments continue to be found. Figurative engravings or sculptures made in bone, antler, or stone, similar to those found in post-LGM contexts elsewhere in Europe  have not been found at Vela Spila. Consequently, the two ceramic figurines discussed above and the purported leg fragments are the only evidence of Epigravettian figurative art at Vela Spila. Indeed, at Vela Spila, figurative art directly and exclusively correlates with the use of ceramics. Moreover, the exclusive use of ceramics for the production of figurative art at Vela Spila suggests artistic motivation for this innovation. The development of a new material and innovative technologies may have been a catalyst for transformation in artistic expression and the earliest figurative art at the site. Although Palaeolithic archaeologists often focus on “functional” or “utilitarian” innovations as important moments of social transformation , the ceramics from Vela Spila offer a glimpse into the ways a symbolic innovation can significantly alter the scope of artistic expression within a culture.c. 17,500 years ago.The ceramic figurines and fragments from Vela Spila are the first evidence of a developed artistic ceramic technology and tradition in Europe after the LGM. These new finds encourage reconsideration of the conventional conception of ceramics as a primarily Neolithic technology. Furthermore, they offer support for the notion that ceramics were first used to make art rather than functional or utilitarian material culture such as vessels. This association of the earliest iteration of the innovative material with ornamental or decorative artifacts echoes the development of metallurgy, which also often emerged first in non-utilitarian contexts c. 17,500-15,000 cal BP. This new evidence indicates that the Pavlovian ceramics are not a unique Palaeolithic technology. Rather, a variety of social, geographic, environmental, and chronological contexts over extended periods of time in Europe supported experimentation with ceramic to make art well before societies became more sedentary at the beginning of the Neolithic. Broadening our understanding and awareness of these materials in Palaeolithic contexts may increase the recovery of these idiosyncratic, but significant, artifacts during future excavations.Both stylistically and technologically, the figurines from Vela Spila recall the Pavlovian ceramic figurines from Moravia. Some similarities between Pavlovian figurative art and the Vela Spila ceramics may suggest that inherent qualities of this material contributed to the stylistic character of figurines made in ceramic. Compressed legs and the fragmentation of limbs and extremities in accordance with the additive method of production are found in figurines from both assemblages. However, differences in their spatial distribution pattern, as well as the geographic and chronological distance between southern Dalmatia and Moravia, suggest the emergence of a distinct socio-technical tradition during the Epigravettian in Croatia,


Physical activity (PA) for older adults has well-documented physical and cognitive benefits, but most seniors do not meet recommended guidelines for PA, and interventions are lacking.This study evaluated the efficacy of a 12-week Internet intervention to help sedentary older adults over 55 years of age adopt and maintain an exercise regimen.A total of 368 sedentary men and women  were recruited, screened, and assessed online. They were randomized into treatment and control groups and assessed at pretest, at 12 weeks, and at 6 months. After treatment group participants rated their fitness level, activity goals, and barriers to exercise, the Internet intervention program helped them select exercise activities in the areas of endurance, flexibility, strengthening, and balance enhancement. They returned to the program weekly for automated video and text support and education, with the option to change or increase their exercise plan. The program also included ongoing problem solving to overcome user-identified barriers to exercise.P=.001; large effect size) and at 6 months . At posttest, intervention participation showed significant improvement on 13 of 14 outcome measures compared to the control participants. At 6 months, treatment participants maintained large gains compared to the control participants on all 14 outcome measures.The multivariate model indicated significant treatment effects at posttest (These results suggest that an online PA program has the potential to positively impact the physical activity of sedentary older adult participants. More research is needed to replicate the study results, which were based on self-report measures. Research is also needed on intervention effects with older populations. Physical activity (PA) for older adults increases active life expectancy while limiting the development and progression of disabling conditions and chronic disease . PA is aAlthough the most effective PA intervention mediators are yet to be determined, theory-based behavioral interventions promoting adoption of exercise as a lifetime habit are recommended ,14-16. SComputer-technology with multimedia interfaces has the potential to provide cost-effective personalized home PA interventions ,24,25. EShaping a PA intervention to an older adult audience requires a thoughtful approach because seniors may have decade-old habits and attitudes to change, and they may have functional limitations due to age or medical conditions. Further, based on rates of Internet adoption, seniors may be less prone than younger age groups to adopt new technological approaches, but the tide is changing as baby boomers age and use of the Internet becomes more commonplace. While seniors have been the slowest age group to use the Internet, they have been the fastest growing population segment in recent years, and as of April 2012, 53% of American adults aged 65 and older use the Internet or email, and 70% of them use the Internet daily . Thus, uThe intervention in this research was based on the theory of planned behavior ,49, whicConsequently, the program was designed to provide information and support that would enhance knowledge, attitudes, self-efficacy, and behavioral intentions to participate in exercise activities on a regular basis. Using the criteria recommended for theoretically driven web exercise programs by Doshi and colleagues , the intStage of change theory ,63 suggeIn this study, we developed and tested a stand-alone 12-week Internet intervention designed to improve self-reported PA of sedentary older adults. The randomized design  evaluated self-reported changes in exercise across four domains: endurance, stretching, strengthening, and balance. We hypothesized that the intervention would be linked to improvement in the above PA domains and to theoretically relevant mediators of behavior change  and that user acceptance would be positive. This was a “real-world” effectiveness trial  in the pActive After 55, was a multiple-visit Internet program to enhance functional ability, mobility, and physical activity of older adults. Using text and video messages integrated with interactive values clarification and goal-setting activities, it helped users develop a self-tailored exercise plan  consisting of four activities: endurance, stretching, strengthening, and balance enhancement. Our rationale for a self-tailored approach was based on formative research in this and a previous Web PA study with sedentary individuals [The intervention, entitled ividuals  and on tividuals -52. We aThe interactive framework was developed in consultation with professionals experienced in the design and implementation of research-based exercise programs for older adults. Care was taken to include only exercises that the participants could do safely on their own with minimal equipment.Active After 55 was designed as a browser format, and it did not control the participants’ actions with mandatory linear pathways. The home page had links to Personal Activity Planning , The Health Value of Exercise, Overcoming Obstacles , Tracking Progress , Staying Motivated , Safety Tips , Disease Specific Recommendations , and a library with additional related articles and tip sheets. After logging in, participants were encouraged to visit the section on Personal Activity Planning, but they were not required or later prompted to do so.Active After 55 assisted users in designing a personalized PA program. With 11 subsequent weekly sessions, lasting at least 10-15 minutes or more in length, the content logically built on the previous session, with new exercises or advanced challenges of the same exercise added over time. A narrator and personal coach presented video-based educational content with bulleted text teaching points and interactive knowledge-building content. Onscreen titles, bullets, and printable text articles were written at a grade 6-8 reading level. Each exercise was introduced with text instruction and offered optional video demonstrations employing a diverse cast of older adults.At the initial 1-hour start-up session, During the first visit, participants were asked to identify their personal goals and their perceived benefits of increased exercise. Users provided information on their recent exercise history and then categorized themselves  for each of the four activity types. Next, the program helped the user build a tailored weekly exercise plan for each activity type . Given the sedentary target population, the program was not designed to provide aerobic exercise. Since we could not control for inaccurate self-categorization of fitness level , the activities were designed conservatively. That is, Advanced levels were slight increases in frequency or duration from Intermediate levels, and participants were encouraged by text on their printouts to postpone finishing an activity if it seemed too difficult.For each activity type, users committed to exercises  and scheduled the days of the week when they would do each one. For each of the four activity types, users responded to multiple-choice questions about their confidence in achieving their exercise plan for the following week. If they were not confident, they were interactively asked to adjust either the intensity or duration of that exercise , and they were queried until they interactively expressed confidence that they could meet their weekly commitment. Users also were encouraged to print the schedule for their reference. The printout included personal goals, next week’s exercise plan and blank exercise tracking sheets, guidelines, and safety tips for each activity type. Finally, the session was summarized by the video narrator who extolled the benefits of following the exercise plan and invited the user back in a week for the next session. While participants could visit the website as often as they liked , the next program session was available no sooner than 1 week after the completion of the previous session.th visit, users were encouraged to maintain their exercise program into the future, making it a habit.At return visits, users were welcomed back and given video and text support for returning. Based on an interactive self-report about success in adhering to exercise commitments from the previous session, users were appropriately praised and encouraged to continue their efforts. For those who reported no progress, the coach’s message was upbeat, offering praise for coming back, and encouragement to try again. At each visit, the user was offered tailored video support on overcoming self-identified exercise barriers . Each week, new educational material was presented to engage users and enhance their knowledge about how to make exercise a habit over time. Based on the user’s self-reported progress and motivation, changes to the exercise plan from the previous week were recommended, if appropriate. As before, the users selected exercise amounts and schedules for each activity and affirmed their confidence to meet the commitments. At the 12The study was a randomized controlled trial on the Internet with three assessments: pretest (T1), postintervention at 12 weeks after pretest (T2), and 6-month follow-up T3; see . After sAfter approval by an Institutional Review Board for protection of human subjects (IRB), the study was conducted entirely on the Internet. Participants were recruited via a mixture of online recruitment strategies , flyers, newsletters, and announcements supported by service agencies, senior centers, and worksites. Interested individuals linked to an information website, which offered a link to an online screening questionnaire to determine eligibility . Page viThe online screening questionnaire asked respondents a total of 14 questions about current PA levels , desire to exercise more , demographics , a working email address, and access to a computer Internet connection. Participants were required to be at least 55 years of age, with a reported desired to engage in more PA. Maximum self-reported exercise levels were: (1) no more than 60 minutes per week of moderate exercise, defined as exercise that increases heart rate, with (2) no bouts of continuous exercise lasting 35 minutes or more. Each respondent answered questions from the 7-item Par-Q , which iIndividuals who qualified for the study read and agreed to an online informed consent. They then provided contact information, which was checked for fraud before they were randomized by the database into Tx and Ctrl groups. Blinding of the research team to the participants’ research condition was unnecessary.Our previous Internet research has found a few applicants who attempted to screen-in to a study by providing false information. Consequently, in this study, participant data were checked against our database of about 6000 records from previous Internet study applicants, for fraudulent information . Screened-in participants providing suspicious data were telephoned, and if the inconsistencies were not resolved, the individual was excluded from the study. A total of 38 were dropped from the study, including 19 before T1, who were not randomized, and 19 after randomization  who were discovered between T1-T3 and were then dropped from the study. Personal privacy was protected with unique user ID and passwords once a participant was accepted into the study and provided contact information. Only passwords provided to Tx participants could link to the intervention.Active After 55 intervention website. Use of the WECD was designed to provide broadband quality video, even from computers with dial-up Internet connections. The WECD, played from the CD-ROM drive of the participant’s computer, contained video with necessary programming code so that specific video elements  were seamlessly integrated into the program presentation, while being controlled by Internet commands from the research host.After completing T1, Tx group participants were mailed a web-enabled CD-ROM (WECD) and emailed log-in information to the Active After 55, an email was sent informing the participant that the next session was now available. The email prompts continued weekly thereafter until the 12 sessions were complete. Twelve weeks after submitting the T1 assessment, all Tx participants who had completed at least Session 1, and all Ctrl participants were emailed a link to the T2 survey. Individuals who had not submitted the T1 assessment or who asked to discontinue participation were dropped from the study. After completion of T2, any Tx participants still in the process of completing the 12 weekly sessions were encouraged to continue using the program until they had completed all sessions.Tx group members were asked by a flyer in the WECD mailer to visit the website within a week. One week after a visit to Active After 55 website. They were given free access for 6 months.Twelve weeks after T2, and 6 months after T1, all participants still enrolled in the study were emailed a link to the T3 assessment. After completion of T3, Ctrl participants and individuals who initially were screened out of the study, but who expressed interest in using the site, were emailed a link to access the The protocol for prompting individuals who failed to submit surveys or to complete intervention visits included up to 5 emails over a 1-month time period. They were followed by a single phone call attempting to verify that technical difficulties were not responsible for the lack of participant communication. The individual was then dropped from the study if participation was not re-established. This protocol was developed with the approval of our IRB in other studies. We believe that it allowed for contentious follow-up of consented participants without undo harassments.All participants were mailed a $25 check after submitting each survey. Participants in the Tx group did not receive a financial incentive to use the intervention website.The T1, T2, and T3 assessments were adapted from our previous Internet research on sedentary factory workers , which hEach participant’s self-reported current activity level was measured with 2-item sets addressing the frequency and duration of intentional physical activities that included: (1) cardiovascular activities to increase heart rate , (2) stretching activities to improve flexibility, (3) strength building activities, and (4) balance enhancement activities. For each category, one item asked “In a typical week, how many days do you intentionally…?”, and a pull-down menu offered choices between 0-7 days a week. The second statement asked “How many minutes do you typically … on each of those days?” and a pull-down menu offered choices of from 5-60+ minutes in 5-minute increments. Items were scored to reflect minutes per week of each activity. Scores showed substantial skew, so a log to base 10 transformation was applied.For a sedentary individual, an increase in the number of physical activities, even if they were not categorized as intentional exercise, would indicate an improvement over a sedentary lifestyle. Participants were asked to report on activities they engaged in during the previous week. They were presented with a list of 16 typical physical activities of older adults: yard work, housework, doing exercises, toe raises or stretches, dancing alone as a physical activity, going for a walk for 10 minutes or more, using the stairs instead of an elevator, parking farther away from the store, exercising with others, playing with children, attending activity classes, dancing/square dancing, bowling or other active games, going to a museum, park, or mall, playing golf, and other physical activities. A count of the number of activities engaged in during the previous week was computed for analysis.The SF-12 is a 12-item survey that has proven useful in monitoring health outcomes . The SF-The Body Mass Index (BMI) has been used as a way to classify sedentary  individuals with an average body composition by the World Health Organization (WHO) . An indiThe theory of planned behavior suggests that an individual’s attitude and knowledge will shape self-efficacy and intention ,49. The The importance of behavioral self-efficacy to exercise adherence is supported by both social cognitive theory ,51 and tThe theory of planned behavior suggests that behavioral intentions can predict exercise behavior . Five itWe found no research to adequately measure the motivation of sedentary individuals to exercise, but improvement on this variable should be linked with an increase in PA. Consequently, we adapted the motivation item used by Irvine et al  in InterA positive change in perceived ability of an individual to perform day-to-day activities was hypothesized to be a measure of improved physical fitness. To assess these capabilities, scales from previous research, eg, -79 were One goal of the intervention was to change perceptions about possible barriers to participating in physical activity, which research suggests are the reasons many individuals fail to adopt and/or maintain exercise habits, eg, ,81. Our If the research intervention was successful, a progression of participants along the continuum of change would be expected. Stage of change (SOC), ie, precontemplation, contemplation, action, maintenance, which assesses an individual’s readiness to adopt new behavior, was measured using four items developed by Marcus, Rossi, Selby, Niaura, and Abrams . A definActive After 55 program, including satisfaction, ease of use, helpfulness of the overall information, helpfulness of the articles, and willingness to recommend the program to a friend. For each item, participants were asked to rate their opinions on a 7-point rating scale . A final item asked for opinions on the number of sessions, with a 5-point Likert scale from 1 “Needed many more” to 5 “Far too many”.User acceptance of the intervention was measured with ratings of perceived satisfaction. Tx group participants responded to additional items relating to their subjective opinions of the A total of 405 participants, including 200 Tx and 205 Ctrl group participants were randomized into the study after consenting, and a total of 368 participants completed the T1 assessment including Tx (n=178) and Ctrl n=190;  conditioP=.035. Given this significant difference, the main outcome analysis included race/ethnicity as a between-subjects factor. The two conditions did not differ significantly on any of the 13 numeric outcome measures or the Stage of Change groups.The two experimental groups were compared on baseline characteristics and pretest outcome measures. With respect to baseline characteristics, the only significant difference was obtained for race/ethnicity: compared to the Ctrl participants, Tx participants were less likely to be Caucasian, ie, 53% vs. 64%; chi-square  = 4.46, Over the course of the study, a total of 84  of the 405 randomized participants were unresponsive to repeated prompts and were dropped from the study, and 19 participants  were removed as fraudulent during the 6-month period between T1-T3 assessments. Of the Tx group participants, only 145 of the 178 who submitted the T1 assessment logged on to initially use the intervention, and 6 of those participants did not complete Visit 1. A total of 92 (73.6%) of those completing T3 assessments  from the T1 Tx group completed all 12 sessions.Thus, out of the 178 Tx Group participants at T1, 125 (70.2%) eventually remained in the study to T3. A total of 305 participants  submitted a T2 assessment, and 302  submitted a T3 assessment. Overall, T1-T3 attrition was (368-302)/368 = 17.9%.P<.001. In addition, significantly higher rates of attrition were obtained for male vs. female participants with 25% vs. 15%; chi-square  = 4.51, P=.034, race/ethnic minority vs. Caucasian participants at 26% vs. 12%; chi-square  = 32.84, P<.001, and those who reported less frequent baseline computer usage, ie, 1-2 times per week = 46%, 3-4 times per week = 44%, 5-6 times per week = 12%, 7 times per week = 14%, 8 or more times per week = 15%; chi-square  = 20.83, P<.001. Participants who dropped out of the study after T1 (n=65) were also compared to those who continued participating (n=302) on the pretest outcome measures. Compared to the participants who completed either T2 or T3 assessments, those who dropped out had significantly lower means on the attitudes/knowledge scale at 3.8 vs. 4.1; t (365) = 3.26, P=.001, ie, attriters had poorer attitudes/knowledge at T1 and significantly higher mean levels for the barriers to exercise scale at 2.7 vs. 2.4; t (365) = 2.86, P=.005. However, no condition-by-attrition interactions were found to be significant for any of the T1 measures, ie, attriters did not differ across experimental condition on the T1 measures.A significantly higher attrition rate was obtained for the Tx condition compared to the Ctrl condition with 30% vs. 7%; chi-square  = 32.84, Rates of missing study outcomes ranged from 0-1% at T1, 18-21% at T2, and 19-22% at T3. The full-information maximum likelihood estimators assume data are at least missing at random (MAR). It is not possible to know for sure that data are MAR because information about the value of the missing data is not available. However, given the abovementioned significant associations between attrition and study outcomes at baseline, the MAR assumption appears less tenable. Therefore, the main outcome analyses were conducted with (1) available data , and (2) one fully-imputed dataset that included all 368 study participants. Since the inclusion of additional predictors in the imputation model can reduce bias and make the MAR assumption more plausible -89, in aSequential regression multiple imputation (SRMI ) was useResults indicate that the available data approach and imputed data approach resulted in a similar pattern of results. Following the intent-to-treat approach, results from the imputed model are reported below.As mentioned, 125 (70%) of the original Tx group remained in the 12-week study. The mean number of visits to the website for these individuals was 15.2 visits (SD 9.02). The mean total time spent using the program summed across all visits was 123.4 minutes (SD 185.98), and the mean time spent per visit was 9.66 minutes (SD 10.48). Participants each accessed an average of 2.92 (SD 4.30) program segments designed to help overcome specific perceived barriers to exercise.A 2 x 2 (condition by race/ethnic minority status) MANCOVA was conducted on the posttest outcome measures in which the pretest outcome measures were included as covariates. The dependent measures included: (1) physical activity measures, (2) SF-12 physical and mental composite measures, (3) BMI, and (4) psychosocial measures .F  = 4.81, P= .001, eta-square = .17  = 3.08, P<.001, eta-square = .11. The Tx group differed significantly from the Ctrl participants on all of the 14 outcome measures  = 1.96, P=.020, eta-square = .08, the condition-by-race/ethnicity interaction effect was not significant. Compared to race/ethnic minority participants, Caucasian participants reported significantly lower follow-up mean scores for self-efficacy at 3.6 vs. 3.9; F  = 5.05, P=.025, eta-square = .01, behavioral intentions at 3.6 vs. 4.0; F  = 5.39, P=.021, eta-square = .02, and motivation at 3.3 vs. 3.8; F  = 12.05, P<.001, eta-square = .03.To examine the maintenance of program effects at follow-up, an overall 2 x 2 MANCOVA model was tested comparing the two conditions on the follow-up outcome measures, controlling for pretest measures, followed by univariate ANCOVA models. The multivariate model at follow-up was significant in which the Tx participants were found to maintain large gains compared to the Ctrl participants, ures see . The outStage of change groupings are compared in r=.22, P=.014. Thus, a higher level of program utilization was associated with significantly greater change in outcome, which provides further support for the internal validity of the study.A dose-response analysis was conducted to examine whether the level of exposure to the program was significantly associated with pretest-posttest change in the outcome measures for the participants assigned to the treatment condition. A composite dose measure was created by standardizing the total time spent across all sessions, the number of page views, and the number of sessions, and computing the mean value of the three standardized scores . A composite outcome measure was created by calculating pretest-posttest gain scores for each of the 13 outcome measures, standardizing each gain score, and computing the mean value of the standardized gain scores . The correlation between the composite dose measure and the composite gain score was significant, On a 7-point scale , participants reported they were quite satisfied with the program , the program was very easy to use , the overall information was very helpful , the articles provided by the program were very helpful , and they would be very likely to recommend the program to a friend or family member . On a 5-point scale to determine opinions about the number of sessions, 89 participants (70%) rated “Just Right,” and 27 (21%) rated “A few too many”.Active After 55 Web program indicates that the intervention positively impacted the physical activity of sedentary older adults, and it was well received. The hypotheses were that the intervention would be linked to changes in the exercise domains of endurance, stretching, strengthening, and balance and that it would be linked to theoretically relevant mediators of behavior change. The findings were very consistent across an array of measures, with a large multivariate effect size at posttest and a medium multivariate effect size at 6-month follow-up. The Tx group showed significant improvement on 13 of 14 outcomes at posttest and on all 14 outcomes at follow-up  for the participants  who completed Visit 1 finished all 12 sessions without payment to do so, suggests that the PA intervention was engaging enough for a majority to follow through for 12 weeks. This is a very positive sign, but we found no attrition results from comparable Web research against which to measure our results. As indicated by the dose-response analysis, greater program utilization resulted in greater change in outcomes, which has been reported by other ,96, but e-attainer [one hit wonders [Dropouts in this study had lower attitude/knowledge scores about the benefits of exercise, and they had higher perceptions of barriers to exercise. While the results presented here must be viewed cautiously until validated by other research, they might offer a hint as to why sedentary individuals fail to start to engage in a Web PA program. Other research attributes attrition from PA programs to unrealistic participants’ expectation , demograattainer  or one h wonders , benefit wonders . More re wonders ,105, whi wonders .This research also presents data on recruitment success using an informational website and automated online screening . While 3Also of potential interest to other researchers is the incidence of fraud reported here. Of the 424 individuals who screened in and agreed to the informed consent, 19 were dropped because of fraudulent information before being randomized, and another 19 subjects were discovered to be fraudulent and were dropped between T1-T3. Thus, 9% of those who screened in provided false information. We have experienced roughly similar numbers in other Internet studies, causing us to set up our fraud database to cross-check participant information. Some individuals are repeat offenders, and we even had one fraudulent participant in another study complain to us when confronted on the telephone that removal from a study constituted mistreatment by us because she said, “I’m only trying to make a living.” We believe that the potential for fraudulent participation in research studies on the Internet is an important issue, but we are aware of no research into the frequency of occurrence or steps to minimize it.The current results must be viewed cautiously because we have no evidence that the participants actually engaged in PA or provided accurate information. Additionally, some of the measures were not validated in other research, physical functionality was not measured beyond the SF-12 physical sub-scale, and the follow-up period was somewhat limited . Follow-up studies of 1-2 years, using participant exercise logs and verifiable measures of PA , and functionality , and they tended to be employed, educated, and frequent computer users with at least a middle-class income. Less educated, lower income, rural, and ethnic populations might be less likely to have Internet in their homes , and thiThe higher attrition rate among treatment participants compared to control participants is another limitation that may have biased the study findings. However, because experimental conditions did not interact significantly with any of the baseline participant characteristics in predicting study attrition, the potential confounding due to differential attrition would appear to be minimal. Furthermore, the use of maximum likelihood estimation for missing data would help to reduce potential biases associated with study attrition.Despite limitations, this research demonstrates that a theoretically based stand-alone Internet exercise program that tailors content according to users’ preferences and interests can increase self-reported PA and be well received by sedentary older adults. This type of intervention can be available to users 24/7 on the Internet, making it a potentially cost-effective PA tool that can reach large numbers of people. The results are impressive considering that the study was not conducted as part of a larger health promotion campaign, which might have provided additional support and encouragement for the participants and which might have decreased attrition. Still, more research is needed to understand factors associated with using Internet interventions to maintain engagement in PA over time.


Escherichia coli is a contaminant of food and water that in humans causes a diarrheal prodrome followed by more severe disease of the kidneys and an array of symptoms of the central nervous system. The systemic disease is a complex referred to as diarrhea-associated hemolytic uremic syndrome (D+HUS). D+HUS is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. This review focuses on the renal aspects of D+HUS. Current knowledge of this renal disease is derived from a combination of human samples, animal models of D+HUS, and interaction of Shiga toxin with isolated renal cell types. Shiga toxin is a multi-subunit protein complex that binds to a glycosphingolipid receptor, Gb3, on select eukaryotic cell types. Location of Gb3 in the kidney is predictive of the sites of action of Shiga toxin. However, the toxin is cytotoxic to some, but not all cell types that express Gb3. It also can cause apoptosis or generate an inflammatory response in some cells. Together, this myriad of results is responsible for D+HUS disease.Shiga toxin-producing  TMAThrombotic microangiopathic anemia+HUSDDiarrhea-associated hemolytic uremic syndrome -HUSDNon-diarrhea hemolytic uremic syndrome TTPThrombotic thrombocytopenic purpuraE. coliEscherichia coliSTECShiga toxin-producing E. coli EHECEnterohemorrhagic E. coliVTECVerotoxin-producing E. coliE. coli O157:H7+HUSThe most common type of STEC as a cause of DStxShiga toxin (a generic term in this paper), same as Verotoxin, previously Shiga-like toxin.Stx1Shiga toxin type 1Stx2Shiga toxin type 2, most common among clinical STEC isolatesVTVerotoxin, same as Shiga toxin HUVEChuman umbilical vein endothelial cellsPTCproximal tubule cellsIHCimmunohistochemistryVEGFVascular endothelial growth factor TNFTumor necrosis factorvWfvon Willebrand factorMCP-1Monocyte chemotactic protein type 1MIP-2Monocyte inflammatory protein+HUS). An attempt is made to relate the clinical course of D+HUS in humans with the experimental studies in vitro, and in vivo, i.e., with animal models of D+HUS. Brief descriptions are provided for the structure and function of the Shiga toxins  and its receptor (Gb3). More emphasis has been placed on the interaction of Stx1 and Stx2 with isolated renal cells and on kidney disease that develops in the animal models. In addition, the role of E. coli LPS in D+HUS is addressed. This review does not include details of how circulating cells types are involved in D+HUS, but rather centers on resident cells of the kidney. This review focuses on the kidney disease caused by Shiga toxin-producing E. coli, referred to as diarrhea-associated hemolytic uremic syndrome (DE. coli Shiga toxins with diarrhea-associated hemolytic uremic syndrome (D+HUS) was established in 1985 [+HUS is caused by the action of Stx on multiple cell types in the kidney whereas D-HUS  is caused by dysfunctional complement regulatory proteins, and TTP is initiated by deficient ADAMTS13 protease activity for degradation of platelet-activating ultra large von Willebrand factor (vWf) multimers. The association of  in 1985 ,11. Fort-HUS, or abnormal von Willebrand factor in TTP also have a role in predisposing some individuals to the action of Shiga toxin in D+HUS  [+HUS. Such genetic predisposition exists for complement regulatory factor proteins in D-HUS and for ADAMTS13 protein, a von Willebrand factor cleaving protease in TTP [Despite the distinct initial causes of each, there are hints of biological mechanisms that may overlap in the disease processes. For example, it is not entirely clear if altered complement activity, a key feature of Dcal HUS) ,13. Thise in TTP ,15,16,17Another very important component of these diseases is the neurological sequelae. The causes of the changes in CNS function are the least studied among of the TMAs. Although the endothelium remains a focal point here as it does for the corresponding renal disease, new findings in D+HUS indicate the neuron is a plausible target for Shiga toxin in the CNS ,19,20,21+HUS models, although some of these do not include a diarrheal phase. However, they all result in renal disease related to Shiga toxin action and exhibit aspects of D+HUS in humans.In this review, the animal models discussed are referred to a D+HUS was derived from a large prospective clinical patient referral study of children in the Pacific Northwest [+HUS is a toxemic rather than a bacteremic event. The toxemic period advances to acute renal failure in approximately 4 days after the hemorrhagic colitis phase. Fortunately, most patients resolve the systemic complications and do not progress to renal failure. Although the latter 4 days represent a potential ‘therapeutic window’, there is no therapeutic treatment other than fluid volume control and dialysis currently available to reduce or prevent renal failure in D+HUS. Another complicating factor in D+HUS is that antibiotics are not recommended in the earlier phases, i.e., prior to appearance of bloody diarrhea because STEC bacteria respond to some antibiotics by producing excess Shiga toxin [An accurate timeline for Dorthwest . Three dga toxin ,24. The Escherichia coli (E. coli) bacteria is a pathogen associated with contamination of food and water. Equivalent terms for this E. coli are Shiga toxin-producing E. coli (STEC), or Verotoxin-producing E. coli (VTEC). The primary virulence factor in systemic host responses produced by clinical isolates of STEC is Shiga toxin type 2 (Stx2), but some isolates produce both Stx1 and Stx2, or more rarely only Stx1 [+HUS [This form of nly Stx1 ,26,27. Nnly Stx1 ,29. It anly Stx1 . STEC isx1 [+HUS ,32. +HUS [vs. with a Stx-deficient strain of the pathogen. The intestinal hemorrhagic response was observed only with the wild-type bacteria. The following is an abbreviated description of structure and functions of the Shiga toxins. It is commonly accepted that Shiga toxin (Stx) is the primary virulence factor of pathogenic STEC bacteria in D+HUS ,33,34. E+HUS . In thisAll of the Shiga toxins comprise a single 30 kDa A-subunit and a pentamer of non-covalently attached identical 7 kDa B-subunits . Enzymat+HUS [Despite related primary amino acid sequences, Stx1 and Stx2 are immunologically distinct . In addi+HUS ,38,39. T+HUS . Howevervs. Stx is valuable knowledge for an understanding of D+HUS. Thus, it is important that Stx1 and Stx2 preparations be processed to remove contaminant proteins and residual LPS, and prior to use the final toxin preparation should be analyzed by silver staining following gel electrophoresis, by dose-response in a Vero cell cytotoxicity assay, and by neutralization of biological activity with toxin-specific monoclonal antibodies in the Vero cell assay. Interpretation of data should also take into account the amount of Stx employed in animal experiments. In some cases, there has been a 10 to 40-fold difference in the amount of Stx2 that has been used for murine experiments. The data derived from studies using 10 or 20-times the lethal dose of toxin is likely to be less useful for interpretation purposes. Unfortunately, there is no universal source of highly purified toxin available to all researchers that would eliminate the variability in experiments from different laboratories. Some commercial sources of these toxins are only 50% pure, yet results from experiments performed with such toxin are occasionally reported to be due to the toxin itself. This remains a problem and is one that actually provides a valid explanation for some disparate results among related experiments. LPS is a much more potent pro-inflammatory agent than Stx and results due to LPS Following binding to Gb3 on target eukaryotic cells, the Stx-receptor complex is internalized and locates within endosomes. Rather than moving to lysosomes for degradation, the complex is transported in a retrograde manner through the golgi to the endoplasmic reticulum (ER) . It is hThe Shiga toxins enzymatically inactivate the eukaryotic ribosome by removal of a single adenine base from 28S rRNA within the large (60S) ribosomal subunit . This isShiga toxin can exert its effects on eukaryotic cells by one of three known mechanisms. Firstly, inactivation of ribosomes and inhibition of cytoplasmic protein synthesis can result in cell death . SecondlThus, Stx can exert different responses in a cell type-specific manner. The end results of these events can be cell death  or inflammatory responses in cells that remain viable, and perhaps other intermediate responses.+HUS kidney disease [The Stx receptor is a major determinant and of central importance to D disease ,58,59,60 disease ,62. The  disease ,64.vs. Stx2. It is more difficult to accept that two molecules of Gb3, identical in all respects, may have differential preference for the toxins. However, as described above, different domains of plasma membranes being unique appear to influence the presentation of identical Gb3 molecules and reactivity with Stx1 or Stx2.There is a relationship between the amount of Gb3 in cells and their sensitivity to Stx, although this appears not to be stoichiometric. Other receptor-related determinants of Stx sensitivity of a cell are complex biochemical aspects of the Gb3 membrane microenvironment. In brief, much or perhaps most of the Gb3 in a plasma membrane may not be reactive with Stx. This cryptic Gb3 may be a function of direct interaction of the Gb3 ceramide moiety with other membrane components including cholesterol, other glycolipids, fatty acids, or proteins ,66,67,68+HUS kidney disease is that it remains important not only to determine where and how much Gb3 is localized to different renal cell types, but also if the Gb3 is reactive with Stx1 or Stx2. Finally, the host response to Stx should represent a change in physiology consistent with the known function of the cell type. What this means for DDifferential expression of Stx receptor (Gb3) by cell types of human and animal kidney is a reliable predictor of Stx site of action. Gb3 has been detected in homogenates of total kidney from human and animals. In these cases, detection methodologies include thin-layer chromatography with detection of Gb3 by Stx overlay, high-performance liquid chromatography, or mass spectrometry of extracted total neutral glycolipids ,74. In aHuman glomerular cell types that express Stx receptor include: endothelial, podocyte, and mesangial. It is likely that these cell types in baboon glomeruli also express the Stx receptor. Porcine glomerular endothelial cells are positive for Gb3 ,78,79. G+HUS, Gb3 is expressed by proximal tubules [in situ Gb3 localization in other epithelial cells of the nephron in human or animal kidneys has not been completed as this requires demonstration of co-localization of Gb3 with markers specific for each cell type along the nephron. It has been reported that in murine kidneys, Gb3 co-localizes with aquaporin-2, a marker of collecting duct cells [In humans, and most animal models of D tubules ,85,86,87 tubules ,79. Huma tubules . A systect cells . Unexpec+HUS have been employed for the salient reason that human studies are limited to analysis of blood and urine samples, a rare renal biopsy or autopsy sample. Prior to animal models, the discussions of mechanisms of D+HUS were based largely on the analysis of human renal tissue autopsy samples. However, autopsy samples represent late stage changes which are inherently less helpful for determining the mechanisms of pathogenesis. The ideal animal model of D+HUS would start with oral inoculation of fully virulent STEC and end with complete D+HUS. For a number of reasons, this ideal model does not exist. Nonetheless, much valuable information has been obtained from animal models of D+HUS that begin with either oral inoculation of the pathogen or with direct intraperitoneal or intravascular injection of the purified toxin. It is not the purpose of this review to provide details of animal models of D+HUS . Animal +HUS studies are the mouse, rabbit, pig, and baboon. The following are some generalities generated from the D+HUS animal studies of many different groups. Firstly, each animal model is distinct and different in response to either STEC bacteria or purified Stx1 or Stx2. Secondly, the animal models differ in location of the organ damage  which most closely represents that of human D+HUS. Thirdly, the mouse has been the most utilized D+HUS model for baseline knowledge, cost, availability of reagents, and genetic applications [+HUS model most closely represents D+HUS of humans and for this reason will continue to be important for validation of data derived from the small animal models of D+HUS [The most common animals utilized in Dications ,93,94,95of D+HUS ,99,100. +HUS have been instructive for kidney disease whether beginning from oral STEC or injected (i.p. or i.v.) Stx1 and Stx2 [+HUS model also has been useful for application of host gene-arrays in analysis of renal responses, something that is not yet available for rabbit, pigs, or baboons [+HUS is that mice, and perhaps all rodents, do not express Stx receptor on their endothelium [Results from the mouse model of Dand Stx2 ,103,104.and Stx2 ,94. The  baboons . The priothelium ,84. It aothelium ,105,106.othelium ,105. NeuThe Dutch Belted rabbit develops acute renal failure following exposure to STEC, but exhibits a low and variable rate of response ,81,82. AThe pig model of Stx-induced renal disease has not been described in detail, but it demonstrates tubular damage ,108,109.+HUS for kidney failure because the physiology most closely represents that of the human kidney [Finally, the baboon appears to be the ‘acid test’ model of Dn kidney ,100,111.+HUS. Although Stx from the intestine would traverse the lung prior to encountering the kidneys, damage to the lungs in D+HUS is secondary in severity to that of the kidneys. A plausible explanation is the kidney expresses the most abundant amount of biologically active Stx receptor and thus contains the most Stx-sensitive cell types. Another reason is the high volume of blood flow and filtration rate of blood in kidneys increase the chance of Stx interaction with cells of the renal microvasculature and the filtration barrier. Indeed, as described in more detail below, human renal endothelial and podocyte cells are very sensitive to the action of Stx2 [It is not totally clear why the kidney, aside from the CNS, is the most affected organ in D of Stx2 . In addivs. Stx2 on kidney has not been performed in animal models of D+HUS. Injection of animals with Stx1 or Stx2 results in preferential damage to organs including kidney and lung. Stx1 appears to target the lung while Stx2 prefers the kidney . A data-+HUS is to digest the large volume of data derived from human renal cells in vitro, and to connect these data in a meaningful way with information about renal damage in humans. A recent review describes the use of different renal cell types in the study of renal disease [+HUS disease process should they express Gb3, be sensitive to Stx in vitro, and are located within a part of the kidney identified with the pathological disease in D+HUS. To date, these include human podocyte, endothelial, mesangial, proximal tubule and collecting duct tubule cells. These are discussed in more detail below. An ongoing process in studies of D disease . There i+HUS, it is that the endothelium is a likely target of Stx [+HUS was provided in a Stx1 cytotoxicity assay with human umbilical vein endothelial cells, HUVEC [+HUS, this observation could possibly be related in terms of genetic predisposition to the similar percentage of individuals who progress to renal failure in D+HUS. Subsequent studies showed that most HUVEC express little Gb3 compared to human microvascular renal endothelial cells, thus providing an explanation of the generally poor sensitivity of large vessel vs. microvascular endothelial cells [in vitro, but in vivo HRMEC only become swollen and detached from the basement matrix in D+HUS. This suggests the presence of a mechanism that partially protects renal endothelium from Stx in vivo that does not exist in vitro. The biological cross-talk between the glomerular fenestrated endothelium and podocytes may be important to this phenomenon [+HUS.If there is any consensus among clinicians and researchers in the field of Dt of Stx . Examinas, HUVEC ,116. In s, HUVEC . This waal cells ,119. A cenomenon . As with+HUS differ in their response of glomerular endothelium to the direct action of Stx. Importantly, baboon, rabbit and pig express Stx receptor on their microvascular endothelial cells while mice do not [+HUS, all of the changes in biology and pathology of renal endothelium related to Stx must be indirect. Some insight into how this might occur is provided below, particularly for the observed coagulation and thrombosis [+HUS are associated with more complete occlusion of glomerular microcapillaries [Animal models of De do not ,98,121. rombosis ,93,105. illaries ,125,126.The glomerular endothelium, being part of the filtration barrier of the kidney, when damaged can become leaky and may, in part, be responsible for proteinuria and appearance in the urine of host cytokines, chemokines, and other biological markers of disease. However, some inflammatory mediators appear to be of renal origin in D+HUS. in vitro, as are human renal microvascular endothelial cells and they also express an ample amount of Stx receptor [+HUS pediatric kidney on autopsy revealed Stx binding to podocytes [Human podocytes  are almost as sensitive to Stx2, receptor . Analysiodocytes . As withodocytes . Howeverodocytes ,129. Pododocytes ,131,132 odocytes .+HUS [+HUS. However, biomarkers of podocyte damage have been detected in urine of D+HUS patients [in vitro [Alteration of podocytes is a feature of several well-known renal diseases including focal segmental glomerular sclerosis (FSGS), polycystic kidney disease (PKD), diabetic nephropathy (DN) ,135,136.+HUS ,138. Stx+HUS . Additiopatients ,141. Impin vitro . +HUS kidney includes mesangial expansion or proliferation [in vitro, with reported changes in mesangial physiology, but the relative role of mesangium in Stx-induced glomerular disease is less studied than for other renal cell types [+HUS model studies have reported changes in the rabbit mesangium, but not in the murine or baboon models [It is often reported that the pathology of human Dferation ,143,144.ll types ,146,147.n models ,92,93,96+HUS. Due to the availability of primary and immortalized cell lines, human PTCs are the most studied in D+HUS. Gb3 has been localized to PTCs from human and animal kidneys [Many reports place proximal tubular cells at the top of the list along with endothelial cells for renal cell types that respond to Stx and are of importance in D kidneys ,86,148.  kidneys , and tis kidneys , apoptos kidneys , necrosi kidneys ,101,150, kidneys . The nor kidneys . A compl kidneys ,154,155.+HUS as the collecting duct cell functions to maintain water balance of the body. In D+HUS patients , dehydration is a prominent feature, presenting as oliguria and anuria which must be treated. Initial data suggest that prevention of Stx2-dependent damage to these cells helps preserve renal function in the murine model of D+HUS [Collecting duct cells in human kidneys were reported to express Gb3 . In muriof D+HUS . +HUS is associated with young children although individuals of all ages can develop D+HUS. A simple explanation would be that more Gb3 is expressed in the kidneys of the young. However, this has proven not to be the case as there is more Gb3 extractable from kidneys of adults vs. children [+HUS. It is interesting that only pediatric kidney expressed Gb3 in glomeruli [+HUS in children [+HUS.Most Dchildren ,75. An alomeruli ,156,157.children ,159. It +HUS develop circulating antibodies to STEC LPS [+HUS [+HUS patients is needed. In the murine model of D+HUS, one of the three hallmarks of D+HUS was driven by LPS rather than be Stx2 [+HUS requires initial interaction with LPS [in vitro are not restricted to LPS from STEC, but appear to require the lipid A moiety (endotoxin) common to all E. coli LPS [+HUS [in vitro [in vivo [+HUS, a study of temporal renal responses demonstrated early (0–24 h) changes were due to LPS and later (24–96 h) changes were due to Stx2 [vs. Stx2 throughout the kidney and to determine the level of circulating LPS in D+HUS patients. Humans with DSTEC LPS ,161,162.STEC LPS . Due to PS [+HUS . This bePS [+HUS ,167,168. be Stx2 . In addi be Stx2 ,175,176.with LPS ,178,179.with LPS . Some accoli LPS . There iPS [+HUS ,187,188.in vitro , and in [in vivo . In the  to Stx2 . In addi+HUS. The more prominent aspects of this sub-topic are the following. Although controversial, circulating neutrophils have been implicated in binding and trafficking of Stx in humans and animals [+HUS. Monocytes and macrophages may be a source of cytokines and chemokines in D+HUS [+HUS not only because thrombocytopenia is one of the hallmarks of the disease, but for their active role as inflammatory mediators [Several cell types in the blood circulation have been implicated in different aspects of D animals ,192,193.in D+HUS ,197,198.ediators ,178,179.ediators ,184,199.+HUS are complex due to the numerous variables in primary, secondary, etc., targets of Stx and the timing of responses to both Stx and LPS. We now know considerably more about the biochemical mode of action of Stx than we do about the disease process it causes. However, much has been learned about the role of Shiga toxin and LPS in the renal physiology and disease in D+HUS. Most of the renal cell types involved in the disease have been identified and their respective contributions are being revealed. Strides have been made in equating the animal model data with D+HUS of humans. An active movement is on to determine the relative importance in D+HUS of factors known to function in D-HUS and TTP, such as complement regulatory proteins and vWf proteases. Finally, the field has advanced sufficiently so as to identify therapeutic targets in D+HUS with the hope of impeding or preventing renal failure itself.Renal aspects of D


Growing socioeconomic disparity is a global concern, as it could affect population health. The author and colleagues have investigated the health impacts of socioeconomic disparities as well as the pathways that underlie those disparities. Our meta-analysis found that a large population has risks of mortality and poor self-rated health that are attributable to income inequality. The study results also suggested the existence of threshold effects , period effects , and lag effects between income inequality and health outcomes. Our other studies using Japanese national representative survey data and a large-scale cohort study of Japanese older adults (AGES cohort) support the relative deprivation hypothesis, namely, that invidious social comparisons arising from relative deprivation in an unequal society adversely affect health. A study with a natural experiment design found that the socioeconomic gradient in self-rated health might actually have become shallower after the 1997–98 economic crisis in Japan, due to smaller health improvements among middle-class white-collar workers and middle/upper-income workers. In conclusion, income inequality might have adverse impacts on individual health, and psychosocial stress due to relative deprivation may partially explain those impacts. Any study of the effects of macroeconomic fluctuations on health disparities should also consider multiple potential pathways, including expanding income inequality, changes in the labor market, and erosion of social capital. Further studies are needed to attain a better understanding of the social determinants of health in a rapidly changing society. First, the existence of marked inequality in a society implies that a substantial segment of the population is impoverished, and poverty is bad for health. Second, and more contentiously, income inequality might affect the health of not just the poor, but also society’s more affluent individuals. The so-called spillover effects of inequality have in turn been attributed to psychosocial stress resulting from invidious social comparisons2,3 and the erosion of social cohesion  have experienced a growing gap between the rich and poor in the last 2 decades; in addition, growing socioeconomic disparity in the last 3 decades has become a global issue.4,9 To provide quantitative evidence regarding the income inequality hypothesis, my colleagues and I conducted a meta-analysis.5The income inequality hypothesis implies that income inequality is harmful to all persons, regardless of their absolute income level. This hypothesis has attracted many researchers, and it has been examined in hundreds of studies. Despite the existence of many systematic reviews on this topic, they provide only qualitative evaluations; the debate has thus not reached its conclusion.In a search of the online data resources PubMed, the ISI Web of Science, and the National Bureau for Economic Research database, we gathered peer-reviewed papers that used multilevel data. Nine cohort studies and 19 cross-sectional studies were eligible. The overall cohort relative risk and cross-sectional odds ratio (OR)  per 0.05-unit increase in Gini coefficient, a measure of income inequality, was 1.08 (1.06–1.10) and 1.04 1.02–1.06), respectively. Meta-regressions showed stronger associations between income inequality and each of 2 health outcomes among studies with higher Gini values (≥0.3) .12 The theory of social comparisons underlies this hypothesis.13 Empirical support for this hypothesis has been provided recently by studies in Nordic countries14,15 and the United States16,17; however, contrary and less-supportive findings have also been reported,18–20 and there have been no data from Asian countries. Using a large national representative survey dataset from Japan and a large-scale prospective cohort study sample of older adults in Aichi prefecture, Japan, we tested the relative deprivation hypothesis in Japanese populations of adults and older adults.2,3The relative deprivation hypothesis posits that increasing income inequality in a society will heighten an individual’s sense of relative deprivation, resulting in frustration, shame, stress, and maladaptive coping responses .21 This survey included a probability sample of 22 871 men and 24 243 women aged 25 to 64, from whom information was gathered on demographic variables, household income, occupation or employment status, and self-rated health. Our measure of relative deprivation was the Yitzhaki Index, which calculates deprivation suffered by each individual as a function of the aggregate income shortfall for each person relative to everyone else with higher incomes in that person’s reference group:i is the sum of the income gap between individuals i and j  divided by the total number of people in the reference group (N). Since we cannot know the reference group of each individual , our approach involves creating alternative definitions for the “reference group”: those with the same occupation, of the same age group, or living in the same geographic area (prefecture), as well as combinations of these. Generalized estimating equations showed that a higher relative deprivation level was associated with worse self-rated health. Even after controlling for absolute income and other sociodemographic factors, the OR (95% CI) for poor self-rated health ranged from 1.09 (1.02–1.16) to 1.18 (1.11–1.26) for men, and from 1.10 (1.04–1.16) to 1.16 (1.09–1.23) for women per 1 million Japanese yen unit increase in the Yitzhaki Index.In the first study, we used data from the 2001 Comprehensive Survey of the Living Conditions of People on Health and Welfare (CSLC), conducted by the Japanese government.22 Our study subjects returned the mail-in survey questionnaire, and we analyzed data from 7673 subjects (81%) who had submitted complete information. As a study outcome, we determined the onset of functional disability, based on a new certification for the use of public LTC insurance benefits.23 As in our previous approach, we used the Yitzhaki Index, with alternative definitions of “reference group”, namely, others living in the same geographical area , others in the same age group (65–74 or 75+ years) or of the same sex, others with the same educational attainment (0–9 or 9+ years of education), and combinations of these. A Cox regression analysis showed that after controlling for sociodemographic factors (including absolute income), the hazard ratio (95% CI) of incident physical/cognitive disability per 1 standard deviation increase in relative deprivation ranged from 1.13 (0.99–1.29) to 1.15 (1.01–1.31) in men and from 1.11 (0.94–1.31) to 1.18 (1.00–1.39) in women, depending on the definition of “reference group”. Additional adjustment for lifestyle factors attenuated the hazard ratios to statistical nonsignificance.In the second study, we used data from the Aichi Gerontological Evaluation Study (AGES), a prospective longitudinal study. In AGES, we conducted a baseline survey in November 2003, with a random sample of functionally independent individuals aged 65 or older residing in 15 municipalities across 3 prefectures in Japan. The sample was restricted to those who were not already receiving public long-term care insurance benefits. Subjects were included only if they reported no limitations in basic activities of daily living, including walking, bathing, and toilet use.In summary, relative deprivation may be a mechanism that underlies the link between income inequality and the health of Japanese adults and older adults. The selection of an unhealthy lifestyle due to stressful psychosocial conditions could in part explain the association between relative deprivation and incident disability.7 Using a natural experiment design, we examined whether socioeconomic-based inequality in self-rated health increased after the 1997–98 economic crisis.8,24 Data on perceived health status, occupation, income, and demographic factors were derived from the 1986, 1989, 1998, and 2001 CSLC. To increase statistical power, data from 1986 and 1989 and those from 1998 and 2001 were pooled. Because we focused on the working-age population, we investigated individuals aged 20 to 60 years. Thus, we used data from a total of 168 801 and 150 016 respondents who completed the income questionnaire for the 1998/2001 and 1986/1989 datasets, respectively. After the economic crisis, the absolute percentages of people reporting poor health declined across all socioeconomic statuses. However, after controlling for confounding factors, the OR (95% CI) for poor self-rated health among middle-class non-manual workers  as compared with the highest class of workers  was 1.02 (0.92–1.14) before the crisis, but increased to 1.14 (1.02–1.29) after the crisis . The association was stronger among men. Adjusted ORs among professional workers and young female homemakers also marginally increased over time. The results showed that self-rated health improved in absolute terms for all occupational groups, even after the economic recession. However, as compared with lower-income people, the self-rated health of people with middle to higher incomes deteriorated after the crisis; unemployed people, however, were twice as likely to report poor health than were the highest class of workers, throughout the period. Unlike commonly observed findings in other countries—namely, the worse the economy, the greater the health inequality25,26—in Japan, the health gradient became shallower after the economic crisis of 1997–98. It was not the health of blue-collar/low-income workers but that of middle-class white-collar workers that declined due to the economic crisis and dramatic changes in social and labor systems.Japan experienced an economic crisis precipitated by the collapse of the so-called bubble economy. This was followed by more than 2 decades of economic recession, which continues at this writing. Although issues relating to rapid changes in society, the labor market, and expanding socioeconomic disparities are attractive topics of research and debate among many researchers and policy-makers, little is known about the impact of economic fluctuations on health disparities.27,28 Biological mechanisms related to the link between socioeconomic disparities and health also deserve further study.29Society continues to change at a rapid pace in this era of globalization; a better understanding of the social determinants of health is therefore becoming increasingly important. The author and colleagues have investigated social determinants of health, with a special focus on the health impacts of macroeconomic conditions. They found that income inequality and macroeconomic shocks had adverse effects on population health. These effects might be attributable to psychosocial influences that stem from human nature in responding to interpersonal relationships within society. Theories concerning social comparisons and relative deprivation have the potential to explain the pathways that link socioeconomic disparities and health; however, further study is needed to evaluate the health effects of broader social factors. For example, studies on the association between economic fluctuations and society’s health gradient require strong theoretical and empirical underpinnings vis-à-vis pathways and mechanisms. Multiple social aspects could change in times of economic crisis, including labor-market policies, job security, levels of income inequality, and community and workplace social capital; indeed, any of these factors could independently affect health.