Tumor Heterogeneity on FDG PET/CT and Immunotherapy: An Imaging Biomarker for Predicting Treatment Response in Patients With Metastatic Melanoma.

OBJECTIVE. The purpose of this study is to evaluate the ability of quantitative 18F-FDG PET parameters to predict outcomes of patients with malignant melanoma who have been treated with immune modulation therapy. MATERIALS AND METHODS. We retrospectively investigated 34 patients with malignant melanoma. Twenty-three patients received immunotherapy as first-line therapy, and 11 patients received it as second-line therapy. The maximum standardized uptake value (SUVmax), metabolic tumor volume, tumor lesion glycolysis, and intratumoral metabolic heterogeneity (as measured by the tumor heterogeneity [TH] index) were measured for the primary tumors and metastatic sites associated with up to five of the most FDG-avid lesions per patient. The TH index was calculated as the AUC value of a cumulative SUV volume histogram curve for all patients. The median follow-up was 29.5 months (range, 3-288 months). Outcome endpoints were progression-free survival and overall survival. Kaplan-Meier survival plots were used, and Cox regression analysis was performed for predictors of survival. RESULTS. A total of 101 lesions were analyzed. Five lesions were analyzed in 12 patients, four lesions in three patients, three lesions in three patients, two lesions in four patients, and one lesion in 12 patients. Of the 34 patients included in the study, 15 (44.1%) had disease progression and 11 (32.3%) had died by the time the last follow-up occurred. The mean (± SD) SUVmax, peak SUV, metabolic tumor volume, tumor lesion glycolysis, and TH values for all lesions were 9.68 ± 6.6, 7.82 ± 5.83, 81.96 ± 146.87 mL, 543.65 ± 1022.92 g, and 5841.36 ± 1249.85, respectively. TH had a negative correlation with SUVmax, peak SUV, and tumor lesion glycolysis (p < 0.0001 for all). CONCLUSION. The TH index is significantly associated with overall survival in patients with metastatic melanoma treated with immune modulation therapy as first-line or second-line therapy.

Soil surface temperatures reveal moderation of the urban heat island effect by trees and shrubs.

Urban areas are major contributors to air pollution and climate change, causing impacts on human health that are amplified by the microclimatological effects of buildings and grey infrastructure through the urban heat island (UHI) effect. Urban greenspaces may be important in reducing surface temperature extremes, but their effects have not been investigated at a city-wide scale. Across a mid-sized UK city we buried temperature loggers at the surface of greenspace soils at 100 sites, stratified by proximity to city centre, vegetation cover and land-use. Mean daily soil surface temperature over 11 months increased by 0.6 °C over the 5 km from the city outskirts to the centre. Trees and shrubs in non-domestic greenspace reduced mean maximum daily soil surface temperatures in the summer by 5.7 °C compared to herbaceous vegetation, but tended to maintain slightly higher temperatures in winter. Trees in domestic gardens, which tend to be smaller, were less effective at reducing summer soil surface temperatures. Our findings reveal that the UHI effects soil temperatures at a city-wide scale, and that in their moderating urban soil surface temperature extremes, trees and shrubs may help to reduce the adverse impacts of urbanization on microclimate, soil processes and human health.

Oxalate secretion by ectomycorrhizal Paxillus involutus is mineral-specific and controls calcium weathering from minerals.

Trees and their associated rhizosphere organisms play a major role in mineral weathering driving calcium fluxes from the continents to the oceans that ultimately control long-term atmospheric CO2 and climate through the geochemical carbon cycle. Photosynthate allocation to tree roots and their mycorrhizal fungi is hypothesized to fuel the active secretion of protons and organic chelators that enhance calcium dissolution at fungal-mineral interfaces. This was tested using (14)CO2 supplied to shoots of Pinus sylvestris ectomycorrhizal with the widespread fungus Paxillus involutus in monoxenic microcosms, revealing preferential allocation by the fungus of plant photoassimilate to weather grains of limestone and silicates each with a combined calcium and magnesium content of over 10 wt.%. Hyphae had acidic surfaces and linear accumulation of weathered calcium with secreted oxalate, increasing significantly in sequence: quartz, granite < basalt, olivine, limestone < gabbro. These findings confirmed the role of mineral-specific oxalate exudation in ectomycorrhizal weathering to dissolve calcium bearing minerals, thus contributing to the geochemical carbon cycle.

Untangling above- and belowground mycorrhizal fungal networks in tropical orchids.

Orchids typically depend on fungi for establishment from seeds, forming mycorrhizal associations with basidiomycete fungal partners in the polyphyletic group rhizoctonia from early stages of germination, sometimes with very high specificity. This has raised important questions about the roles of plant and fungal phylogenetics, and their habitat preferences, in controlling which fungi associate with which plants. In this issue of Molecular Ecology, Martos et al. (2012) report the largest network analysis to date for orchids and their mycorrhizal fungi, sampling a total of over 450 plants from nearly half the 150 tropical orchid species on Reunion Island, encompassing its main terrestrial and epiphytic orchid genera. The authors found a total of 95 operational taxonomic units of mycorrhizal fungi and investigated the architecture and nestedness of their bipartite networks with 73 orchid species. The most striking finding was a major ecological barrier between above- and belowground mycorrhizal fungal networks, despite both epiphytic and terrestrial orchids often associating with closely related taxa across all three major lineages of rhizoctonia fungi. The fungal partnerships of the epiphytes and terrestrial species involved a diversity of fungal taxa in a modular network architecture, with only about one in ten mycorrhizal fungi partnering orchids in both groups. In contrast, plant and fungal phylogenetics had weak or no effects on the network. This highlights the power of recently developed ecological network analyses to give new insights into controls on plant-fungal symbioses and raises exciting new hypotheses about the differences in properties and functioning of mycorrhiza in epiphytic and terrestrial orchids.

Plant-driven weathering of apatite--the role of an ectomycorrhizal fungus.

Ectomycorrhizal (EcM) fungi are increasingly recognized as important agents of mineral weathering and soil development, with far-reaching impacts on biogeochemical cycles. Because EcM fungi live in a symbiotic relationship with trees and in close contact with bacteria and archaea, it is difficult to distinguish between the weathering effects of the fungus, host tree and other micro-organisms. Here, we quantified mineral weathering by the fungus Paxillus involutus, growing in symbiosis with Pinus sylvestris under sterile conditions. The mycorrhizal trees were grown in specially designed sterile microcosms in which the supply of soluble phosphorus (P) in the bulk media was varied and grains of the calcium phosphate mineral apatite mixed with quartz, or quartz alone, were provided in plastic wells that were only accessed by their fungal partner. Under P limitation, pulse labelling of plants with (14)CO(2) revealed plant-to-fungus allocation of photosynthates, with 17 times more (14)C transferred into the apatite wells compared with wells with only quartz. Fungal colonization increased the release of P from apatite by almost a factor of three, from 7.5 (±1.1) × 10(-10) mol m(-2) s(-1) to 2.2 (±0.52) × 10(-9) mol m(-2) s(-1). On increasing the P supply in the microcosms from no added P, through apatite alone, to both apatite and orthophosphate, the proportion of biomass in roots progressively increased at the expense of the fungus. These three observations, (i) proportionately more plant energy investment in the fungal partner under P limitation, (ii) preferential fungal transport of photosynthate-derived carbon towards patches of apatite grains and (iii) fungal enhancement of weathering rate, reveal the tightly coupled plant-fungal interactions underpinning enhanced EcM weathering of apatite and its utilization as P source.

Twelve testable hypotheses on the geobiology of weathering.

Critical Zone (CZ) research investigates the chemical, physical, and biological processes that modulate the Earth's surface. Here, we advance 12 hypotheses that must be tested to improve our understanding of the CZ: (1) Solar-to-chemical conversion of energy by plants regulates flows of carbon, water, and nutrients through plant-microbe soil networks, thereby controlling the location and extent of biological weathering. (2) Biological stoichiometry drives changes in mineral stoichiometry and distribution through weathering. (3) On landscapes experiencing little erosion, biology drives weathering during initial succession, whereas weathering drives biology over the long term. (4) In eroding landscapes, weathering-front advance at depth is coupled to surface denudation via biotic processes. (5) Biology shapes the topography of the Critical Zone. (6) The impact of climate forcing on denudation rates in natural systems can be predicted from models incorporating biogeochemical reaction rates and geomorphological transport laws. (7) Rising global temperatures will increase carbon losses from the Critical Zone. (8) Rising atmospheric P(CO2) will increase rates and extents of mineral weathering in soils. (9) Riverine solute fluxes will respond to changes in climate primarily due to changes in water fluxes and secondarily through changes in biologically mediated weathering. (10) Land use change will impact Critical Zone processes and exports more than climate change. (11) In many severely altered settings, restoration of hydrological processes is possible in decades or less, whereas restoration of biodiversity and biogeochemical processes requires longer timescales. (12) Biogeochemical properties impart thresholds or tipping points beyond which rapid and irreversible losses of ecosystem health, function, and services can occur.

Demographic, institutional and obstetrical risk factors for postpartum haemorrhage mortality.

This study, initially presented at the SMFM Annual Conference in San Diego on 29 January 2009, sought to explore the risk factors for mortality from postpartum haemorrhage (PPH). A total of 138,316 cases of PPH from 1991 to 2000 were identified using the California Health Discharge Database. Data analysed included demographic information and clinical risk factors. PPH increased from 1.9% to 2.8%, while mortality rate decreased during the study period (1991-2000). Logistic regression showed that hysterectomy, hypertensive disorders, abruption, transverse caesarean delivery, and classical caesarean delivery, increased risk for PPH mortality, while manual placental extraction, episiotomy, and laceration repairs decreased risk. Two geographical regions, Inland Empire and Orange County, were associated with increased PPH mortality, despite having lower incidence of PPH. Teaching status and investor ownership of hospitals increased the risk of PPH mortality. There was no associated change in mortality based on hospital quality rating.

Biological weathering and the long-term carbon cycle: integrating mycorrhizal evolution and function into the current paradigm.

The dramatic decline in atmospheric CO2 evidenced by proxy data during the Devonian (416.0-359.2 Ma) and the gradual decline from the Cretaceous (145.5-65.5 Ma) onwards have been linked to the spread of deeply rooted trees and the rise of angiosperms, respectively. But this paradigm overlooks the coevolution of roots with the major groups of symbiotic fungal partners that have dominated terrestrial ecosystems throughout Earth history. The colonization of land by plants was coincident with the rise of arbuscular mycorrhizal fungi (AMF),while the Cenozoic (c. 65.5-0 Ma) witnessed the rise of ectomycorrhizal fungi (EMF) that associate with both gymnosperm and angiosperm tree roots. Here, we critically review evidence for the influence of AMF and EMF on mineral weathering processes. We show that the key weathering processes underpinning the current paradigm and ascribed to plants are actually driven by the combined activities of roots and mycorrhizal fungi. Fuelled by substantial amounts of recent photosynthate transported from shoots to roots, these fungi form extensive mycelial networks which extend into soil actively foraging for nutrients by altering minerals through the acidification of the immediate root environment. EMF aggressively weather minerals through the additional mechanism of releasing low molecular weight organic chelators. Rates of biotic weathering might therefore be more usefully conceptualized as being fundamentally controlled by the biomass, surface area of contact, and capacity of roots and their mycorrhizal fungal partners to interact physically and chemically with minerals. All of these activities are ultimately controlled by rates of carbon-energy supply from photosynthetic organisms. The weathering functions in leading carbon cycle models require experiments and field studies of evolutionary grades of plants with appropriate mycorrhizal associations. Representation of the coevolution of roots and fungi in geochemical carbon cycle models is required to further our understanding of the role of the biota in Earth's CO2 and climate history.

Identification of yeast in chronic wounds using new pathogen-detection technologies.

OBJECTIVE: To evaluate the ability of two new diagnostic methods to detect and accurately identify yeast associated with chronic wound infections. METHOD: Fungal tag-encoded FLX amplicon pyrosequencing (fTEFAP), a universal fungal identification method, bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP), a universal bacterial identification method, and a new quantitative polymerase chain reaction (qPCR) wound pathogen panel were used to evaluate three chronic wounds suspected to contain yeast. RESULTS: Forty wound samples were analysed in addition to the three samples suspected of containing yeast. The qPCR panel, which targets Candida albicans, detected this yeast in two of the three wound samples. In contrast, fTEFAP detected yeast in each of the three samples: two showed Candida albicans and the third Candida parapsilosis. fTEFAP also identified a lower level of Candida tropicalis in one of the wounds that was positive for Candida albicans. The qPCR wound panel results were returned within two hours, while the fTEFAP results were returned within 24 hours. CONCLUSION: Two new molecular methods have been developed to aid wound pathogen diagnostics. The quantitative PCR wound panel is rapid but is limited to major wound-associated bacteria and yeasts. The universal fTEFAP and bTEFAP methods take 24 hours to return results but are able to detect the relative contribution of any bacteria of yeast in a chronic wound diagnostic sample. DECLARATION OF INTEREST: Southwest Regional Wound Care Center is a clinical wound-care provider seeking to improve the ability of wound care practitioners to help patients. The Research and Testing Laboratory develops molecular methods including fTEFAP, bTEFAP and the quantitative PCR wound panel.

Public policy and the market for dental services.

Social inequality in access to oral health care is a feature of countries with predominantly privately funded markets for dental services. Private markets for health care have inherent inefficiencies whereby sick and poor people have restricted access compared to their healthy and more affluent compatriots. In the future, access to dental care may worsen as trends in demography, disease and development come to bear on national oral healthcare systems. However, increasing public subsidies for the poor may not increase their access unless availability issues are resolved. Further, increasing public funding runs counter to policies that feature less government involvement in the economy, tax policy on private insurance premiums, tax reductions and, in some instances, free-trade agreements. We discuss these issues and provide international examples to illustrate the consequences of the differing public policies in oral health care. Subsidization of the poor by inclusion of dental care in social health insurance models appears to offer the most potential for equitable access. We further suggest that nations need to develop national systems capable of the surveillance of disease and human resources, and of the monitoring of appropriateness and efficiency of their oral healthcare delivery systems.

Leptospirosis among patients presenting with dengue-like illness in Puerto Rico.

Leptospirosis is difficult to distinguish from dengue fever without laboratory confirmation. Sporadic cases/clusters of leptospirosis occur in Puerto Rico, but surveillance is passive and laboratory confirmation is rare. We tested for leptospirosis using an IgM ELISA on sera testing negative for dengue virus IgM antibody and conducted a case-control study assessing risk factors for leptospirosis, comparing clinical/laboratory findings between leptospirosis (case-patients) and dengue patients (controls). Among 730 dengue-negative sera, 36 (5%) were positive for leptospirosis. We performed post mortem testing for leptospirosis on 12 available specimens from suspected dengue-related fatalities; 10 (83%) tested positive. Among these 10 fatal cases, pulmonary hemorrhage and renal failure were the most common causes of death. We enrolled 42 case-patients and 84 controls. Jaundice, elevated BUN, hyperbilirubinemia, anemia, and leukocytosis were associated with leptospirosis (p < .01 for all). Male sex, walking in puddles, rural habitation, and owning horses were independently associated with leptospirosis. Epidemiological, clinical, and laboratory criteria may help distinguish leptospirosis from dengue and identify patients who would benefit from early antibiotic treatment.

Lectin receptors for endometrial H-type 1 antigen on goat conceptuses.

PROBLEM: The goal of this study was to determine if caprine conceptuses express lectin-like receptors for endometrial H-type 1 (HT1) antigen. METHOD OF STUDY: Conceptus tissues were collected during the apposition, adhesion and attachment phases of placentation and evaluated using immunofluorescence microscopy. RESULTS: Conceptus staining for the trisaccharide lacto-N-fucopentaose-1 was strong and uniform during apposition of fetal and maternal tissues but changed by day 25 of pregnancy when large aggregates of intense staining were observed. Monoclonal antibodies to galectin-3 did not stain conceptus tissue during the apposition phase but intense punctate staining was observed after day 25. Strong uniform staining for Lewis Y antigen was detected only on day 17 of pregnancy. CONCLUSION: Conceptus tissue expresses potential receptors for endometrial HT1 antigen. Carbohydrate-lectin interactions may facilitate attachment of the apical surfaces of uterine epithelial cells and trophectoderm during the early stages of placentation.

Prevalence of early childhood caries among First Nations children, District of Manitoulin, Ontario.

BACKGROUND: Epidemiological studies of Aboriginal communities in Canada and Native American populations in the United States have reported that early childhood caries (ECC) is highly prevalent. The purpose of this study was to determine the prevalence of ECC and dental caries in the First Nations population of 3- and 5-year-old children in the District of Manitoulin, Ontario to assist in developing effective dental health promotion strategies. METHODS: All 3- and 5-year-old children in elementary schools and day-care centres in seven First Nation communities were eligible for the survey examination. Three-year-old children at home and 5-year-old children attending school off-reserve in six of the communities were also eligible for epidemiological survey examination of oral health status including caries, gingival and soft tissue conditions. Cases of ECC were defined as children with caries or restorations on two or more primary maxillary incisors or canines or those having a total decayed, missing, filled primary teeth (dmft) score of 4 or greater. RESULTS: A total of 87 children (59% 5 years old, 54% females) were examined. Seventy-four per cent of children had one or more carious lesions. Forty-five cases of ECC were found, a prevalence of 52%. The mean dmft score for cases was 7.5 (95% CI 6.5-8.4) and 0.8 (95% CI 0.5-1.1) for non-cases (P < 0.001). Boys in both age groups were more likely to be affected by ECC than girls. CONCLUSION: Our results indicate that dental caries and ECC are highly prevalent in this population, with ECC cases having 6.7 more dmft than non-cases.

Symbiotic germination and development of the myco-heterotroph Monotropa hypopitys in nature and its requirement for locally distributed Tricholoma spp.

• Germination and symbiotic development of the myco-heterotrophic plant Monotropa hypopitys were studied by sequential recovery of packets of seed buried in dune slacks in relation to distance from mature M. hypopitys and presence and absence of shoots of its autotrophic coassociate Salix repens. • Fungal associates of M. hypopitys growing under S. repens in the dune slacks, and under S. caprea and Pinus sylvestris at two other locations in the UK, were identified by molecular analysis. • While the earliest stage of germination could be found in the absence both of mature M. hypopitys, and S. repens, further development was dependent upon mycorrhizal colonisation, which was most common close to these plants. Molecular analysis showed that when growing with Salix, M. hypopitys associated with the Salix-specific ectomycorrhizal fungus Tricholoma cingulatum, whereas under Pinus it was colonised by the closely related, Pinaceae-specific, T. terreum. • We establish the first definitive chronology of development of M. hypopitys and highlight its critical dependence upon, and specificity for, locally distributed Tricholoma species that link the myco-heterotroph to its autotrophic coassociates.

Observer agreement in the grading of oral epithelial dysplasia.

OBJECTIVES: To determine the extent of observer agreement in diagnosis of oral epithelial dysplasia (OED). Published studies of OED examiner agreement report relatively low agreement levels; however, these studies were limited by the methodologies employed. METHODS: For this study, 64 slides were each independently examined twice by three oral pathologists. Consistency was assessed by determining intra- and interexaminer agreement. Conformity was assessed by using the modal diagnosis as a gold standard. RESULTS: The group showed moderate interobserver agreement when grading the presence or absence of OED with a group-simple kappa (Ks) of 0.51 (95% CI = 0.42-0.61), and substantial agreement when using a 5-point ordinal scale with a group-weighted kappa (Kw) of 0.74 (95% CI = 0.64-0.85). The group showed fair to substantial intraexaminer agreement when assessing the presence or absence of OED, with Ks ranging from 0.22 to 0.78, and showing almost a perfect agreement using a 5-point ordinal scale, with Kw ranging from 0.82-0.96. Conformity with the comparison standard modal diagnosis was almost perfect, with pairwise Kw ranging from 0.81 to 0.92. CONCLUSION: Overall, there was substantial intra- and interobserver consistency and almost perfect conformity in the grading of OED. Appropriate statistical methods are necessary to determine the degree of observer agreement.

Early detection and response to meningococcal disease epidemics in sub-Saharan Africa: appraisal of the WHO strategy.

OBJECTIVE: To assess the sensitivity, specificity and predictive value positive of the WHO threshold strategy for detecting meningococcal disease epidemics in sub-Saharan Africa and to estimate the impact of the strategy on an epidemic at district level. METHODS: Data on meningitis cases at the district level were collected weekly from health ministries, WHO country and regional offices, and nongovernmental organizations in countries where there were epidemics of meningococcal disease in 1997. An epidemic was defined as a cumulative district attack rate of at least 100 cases per 100,000 population from January to May, the period of epidemic risk. The sensitivity, specificity and predictive value positive of the WHO threshold rate were calculated, and curves of sensitivity against (1 - specificity) were compared with alternatively defined threshold rates and epidemic sizes. The impact of the WHO strategy on a district epidemic was estimated by comparing the numbers of epidemic cases with cases estimated to have been prevented by vaccination. FINDINGS: An analysis was made of 48 198 cases reported in 174 districts in Benin, Burkina Faso, the Gambia, Ghana, Mali, Niger, and Togo. These cases were 80.3% of those reported from Africa to WHO during the 1997 epidemic period. District populations ranged from 10,298 to 573,908. The threshold rate was crossed during two consecutive weeks in 69 districts (39.7%) and there were epidemics in 66 districts (37.9%). Overall, the sensitivity of the threshold rate for predicting epidemics was 97%, the specificity was 95%, and the predictive value positive was 93%. Taken together, these values were equivalent or better than the sensitivity, specificity and predictive value positive of alternatively defined threshold rates and epidemics, and remained high regardless of district size. The estimated number of potential epidemic cases decreased by nearly 60% in the age group targeted for vaccination in one district where the guidelines were followed in a timely manner. CONCLUSION: The use of the WHO strategy was sensitive and specific for the early detection of meningococcal disease epidemics in countries of sub-Saharan Africa during 1997 and had a substantial impact on a district epidemic. Nevertheless, the burden of meningococcal disease in these countries remains formidable and additional control measures are needed.

The U.S. Surgeon General's report on oral health in America: A Canadian perspective.

This paper provides an overview of last year's U.S. Surgeon General's report on oral health, describes the burden of oral diseases and craniofacial disorders in the United States, and draws parallels with the state of dental health in Canada and in the province of Ontario. It concludes by focusing on the report's recommendations for future action and briefly notes some of the lessons that Canadians can learn from these findings. The goal of this paper is to stimulate further discussion of the issues raised in the report, in an effort to encourage public-private partnerships dedicated to the creation and support of programs to make oral health a more integral component of general health.

Clinical decision-making for caries management in root surfaces.

This report presents the results of an evidence-based approach to obtaining the best available information on the natural history, prevalence, incidence, diagnosis, and treatment of root caries. Searches of electronic databases produced 807 references; from these and from citations in the selected articles, a final 161 references were used. We found that the information on the natural history of the disease does not provide practitioners with probabilities of, or time estimates for, progression of the disease through stages. For patients aged thirty and older, the prevalence of root caries is roughly 20 to 22 percent less than a person's age. Severity reaches over one lesion by age fifty, two lesions by age seventy, and just over three lesions for those seventy-five and older. About 8 percent (odds of 1:11) of the population would be expected to acquire one or more new root caries lesions in one year. The accuracy of current systems of diagnosis is unknown, although color has been shown to have little validity. Using the criteria of "softness" to define active lesions has been validated by the presence of microbes in the lesion. One strong study and other studies with weaker design or shorter duration add consistent support for the use of fluorides in the remineralization of root caries. Every three-month application of chlorhexidine varnish was shown to be efficacious in one arm of one study. Evidence for restoration of root caries is tentative since the studies were of limited design and duration.