Epidemiology of systematic reviews in imaging journals: evaluation of publication trends and sustainability?

PURPOSE: To evaluate the epidemiology of systematic reviews (SRs) published in imaging journals. METHODS: A MEDLINE search identified SRs published in imaging journals from 1 January 2000-31 December 2016. Articles retrieved were screened against inclusion criteria. Demographic and methodological characteristics were extracted from studies. Temporal trends were evaluated using linear regression and Pearson's correlation coefficients. RESULTS: 921 SRs were included that reported on 27,435 primary studies, 85,276,484 patients and were cited 26,961 times. The SR publication rate increased 23-fold (r=0.92, p<0.001) while the proportion of SRs to non-SRs increased 13-fold (r = 0.94, p<0.001) from 2000 (0.10%) to 2016 (1.33%). Diagnostic test accuracy (DTA) SRs were most frequent (46.5%) followed by therapeutic SRs (16.6%). Most SRs did not report funding status (54.2%). The median author team size was five; this increased over time (r=0.20, p<0.001). Of the studies, 67.3% included an imaging specialist co-author; this decreased over time (r=-0.57, p=0.017). Most SRs included a meta-analysis (69.6%). Journal impact factor positively correlated with SR publication rates (r=0.54, p<0.001). Magnetic resonance imaging (MRI) and 'vascular and interventional radiology' were the most frequently studied imaging modality and subspecialty, respectively. The USA, UK, China, Netherlands and Canada were the top five publishing countries. CONCLUSIONS: The SR publication rate is increasing rapidly compared with the rate of growth of non-SRs; however, they still make up just over 1% of all studies. Authors, reviewers and editors should be aware of methodological and reporting standards specific to imaging systematic reviews including those for DTA and individual patient data. KEY POINTS: • Systematic review publication rate has increased 23-fold from 2000-2016. • The proportion of systematic reviews to non-systematic reviews has increased 13-fold. • The USA, UK and China are the most frequent published countries; those from the USA and China are increasing the most rapidly.

Reporting bias in imaging: higher accuracy is linked to faster publication.

OBJECTIVES: The objective of this study was to evaluate whether higher reported accuracy estimates are associated with shorter time to publication among imaging diagnostic accuracy studies. METHODS: We included primary imaging diagnostic accuracy studies, included in meta-analyses from systematic reviews published in 2015. For each primary study, we extracted accuracy estimates, participant recruitment periods and publication dates. Our primary outcome was the association between Youden's index (sensitivity + specificity - 1, a single measure of diagnostic accuracy) and time to publication. RESULTS: We included 55 systematic reviews and 781 primary studies. Study completion dates were missing for 238 (30%) studies. The median time from completion to publication in the remaining 543 studies was 20 months (IQR 14-29). Youden's index was negatively correlated with time from completion to publication (rho = -0.11, p = 0.009). This association remained significant in multivariable Cox regression analyses after adjusting for seven study characteristics: hazard ratio of publication was 1.09 (95% CI 1.03-1.16, p = 0.004) per unit increase for logit-transformed estimates of Youden's index. When dichotomizing Youden's index by a median split, time from completion to publication was 20 months (IQR 13-33) for studies with a Youden's index below the median, and 19 months (14-27) for studies with a Youden's index above the median (p = 0.104). CONCLUSION: Imaging diagnostic accuracy studies with higher accuracy estimates were weakly associated with a shorter time to publication. KEY POINTS: • Higher accuracy estimates are weakly associated with shorter time to publication. • Lag in time to publication remained significant in multivariate Cox regression analyses. • No correlation between accuracy and time from submission to publication was identified.

Application of the Target Lipid Model and Passive Samplers to Characterize the Toxicity of Bioavailable Organics in Oil Sands Process-Affected Water.

Oil sand operations in Alberta, Canada will eventually include returning treated process-affected waters to the environment. Organic constituents in oil sand process-affected water (OSPW) represent complex mixtures of nonionic and ionic (e.g., naphthenic acids) compounds, and compositions can vary spatially and temporally, which has impeded development of water quality benchmarks. To address this challenge, it was hypothesized that solid phase microextraction fibers coated with polydimethylsiloxane (PDMS) could be used as a biomimetic extraction (BE) to measure bioavailable organics in OSPW. Organic constituents of OSPW were assumed to contribute additively to toxicity, and partitioning to PDMS was assumed to be predictive of accumulation in target lipids, which were the presumed site of action. This method was tested using toxicity data for individual model compounds, defined mixtures, and organic mixtures extracted from OSPW. Toxicity was correlated with BE data, which supports the use of this method in hazard assessments of acute lethality to aquatic organisms. A species sensitivity distribution (SSD), based on target lipid model and BE values, was similar to SSDs based on residues in tissues for both nonionic and ionic organics. BE was shown to be an analytical tool that accounts for bioaccumulation of organic compound mixtures from which toxicity can be predicted, with the potential to aid in the development of water quality guidelines.

Comparison of clinical tests of olfactory function.

To assess olfactory function, various measures are used in clinical routine. In this study, the Sniff Magnitude Test (SMT), a test considering the sniff response to an odor, was applied to patients with olfactory dysfunction (n = 49) and to a control group without subjective olfaction disorder (n = 21). For comparison, the validated "Sniffin' Sticks" test battery, a psychophysical olfactory test consisting of tests for phenyl ethyl alcohol odor threshold, odor discrimination, and odor identification was performed. Analyses indicated that the SMT showed significant differences between patients and controls (p = 0.003). Furthermore, results from the SMT and the "Sniffin' Sticks" correlated significantly (p < 0.001). In conclusion, the SMT appears to be a useful addition to the battery of available clinical tests to assess olfactory function.

Mass spectral characterisation of a polar, esterified fraction of an organic extract of an oil sands process water.

RATIONALE: Characterising complex mixtures of organic compounds in polar fractions of heavy petroleum is challenging, but is important for pollution studies and for exploration and production geochemistry. Oil sands process-affected water (OSPW) stored in large tailings ponds by Canadian oil sands industries contains such mixtures. METHODS: A polar OSPW fraction was obtained by silver ion solid-phase extraction with methanol elution. This was examined by numerous methods, including electrospray ionisation (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) and ultra-high-pressure liquid chromatography (uHPLC)/Orbitrap MS, in multiple ionisation and MS/MS modes. Compounds were also synthesised for comparison. RESULTS: The major ESI ionisable compounds detected (+ion mode) were C15-28 SO3 species with 3-7 double bond equivalents (DBE) and C27-28 SO5 species with 5 DBE. ESI-MS/MS collision-induced losses were due to water, methanol, water plus methanol and water plus methyl formate, typical of methyl esters of hydroxy acids. Once the fraction was re-saponified, species originally detected by positive ion MS, could be detected only by negative ion MS, consistent with their assignment as sulphur-containing hydroxy carboxylic acids. The free acid of a keto dibenzothiophene alkanoic acid was added to an unesterified acid extract of OSPW in known concentrations as a putative internal standard, but attempted quantification in this way proved unreliable. CONCLUSIONS: The results suggest the more polar acidic organic SO3 constituents of OSPW include C15-28 S-containing, alicyclic and aromatic hydroxy carboxylic acids. SO5 species are possibly sulphone analogues of these. The origin of such compounds is probably via further biotransformation (hydroxylation) of the related S-containing carboxylic acids identified previously in a less polar OSPW fraction. The environmental risks, corrosivity and oil flow assurance effects should be easier to assess, given that partial structures are now known, although further identification is still needed.

Long-term effects of an early-life exposure of fathead minnows to sediments containing bitumen. Part II: Behaviour, reproduction, and gonad histopathology.

The oil sands area of northern Alberta has river sediments that contain natural bitumen. Eggs and fish in these rivers may be exposed to bitumen-related chemicals early in life. This paper assesses a short embryo-larval fish exposure to oil sands sediment and follows the fish behaviour as they mature in clean water and examines their breeding success as adults (5 months afterwards). The three different oil sands river sediments tested were: a sediment collected outside of the bitumen deposit (tested at 3 g/L, Reference sediment from upstream Steepbank River site), and two sediments collected within the deposit (each tested at low (1 g/L) and high (3 g/L) concentrations). The sediments within the bitumen deposit were from the Ells and Steepbank (Stp) Rivers, and both contained significant total PAHs (>170 ng/g wet weight sediment) and alkylated PAHs (>4480 ng/g). Fish were exposed to these sediments for 21 days (as eggs and larval fish), and then transferred permanently to clean water to mature and breed. There was a significant decrease in the number of egg clutches produced by fish exposed early in life to Stp downstream high sediment (compared to Reference sediment). There was also a decrease in overall cumulative egg production, with fish from Stp downstream high sediment producing just over 1000 eggs in total while fish exposed to Ref sediment produced nearly 6900 eggs. The fish with reduced egg production were also less social than expected as they matured, and they had a lower % of early vitellogenic eggs in their ovaries. Overall, the exposure shows that a single, brief exposure during early life stages to natural bitumen can affect fish in adulthood. Naturally occurring bitumen-derived PAHs can reduce fish reproductive output by complex mechanisms, measurable as lower ovary maturity and changes in social behaviour.

Chemical fingerprinting of naphthenic acids and oil sands process waters-A review of analytical methods for environmental samples.

This article provides a review of the routine methods currently utilized for total naphthenic acid analyses. There is a growing need to develop chemical methods that can selectively distinguish compounds found within industrially derived oil sands process affected waters (OSPW) from those derived from the natural weathering of oil sands deposits. Attention is thus given to the characterization of other OSPW components such as oil sands polar organic compounds, PAHs, and heavy metals along with characterization of chemical additives such as polyacrylamide polymers and trace levels of boron species. Environmental samples discussed cover the following matrices: OSPW containments, on-lease interceptor well systems, on- and off-lease groundwater, and river and lake surface waters. There are diverse ranges of methods available for analyses of total naphthenic acids. However, there is a need for inter-laboratory studies to compare their accuracy and precision for routine analyses. Recent advances in high- and medium-resolution mass spectrometry, concomitant with comprehensive mass spectrometry techniques following multi-dimensional chromatography or ion-mobility separations, have allowed for the speciation of monocarboxylic naphthenic acids along with a wide range of other species including humics. The distributions of oil sands polar organic compounds, particularly the sulphur containing species (i.e., OxS and OxS2) may allow for distinguishing sources of OSPW. The ratios of oxygen- (i.e., Ox) and nitrogen-containing species (i.e., NOx, and N2Ox) are useful for differentiating organic components derived from OSPW from natural components found within receiving waters. Synchronous fluorescence spectroscopy also provides a powerful screening technique capable of quickly detecting the presence of aromatic organic acids contained within oil sands naphthenic acid mixtures. Synchronous fluorescence spectroscopy provides diagnostic profiles for OSPW and potentially impacted groundwater that can be compared against reference groundwater and surface water samples. Novel applications of X-ray absorption near edge spectroscopy (XANES) are emerging for speciation of sulphur-containing species (both organic and inorganic components) as well as industrially derived boron-containing species. There is strong potential for an environmental forensics application of XANES for chemical fingerprinting of weathered sulphur-containing species and industrial additives in OSPW.

Short-term functional outcome after hip resurfacing surgery.

Hip resurfacing arthroplasty is a popular method for treating late stage osteoarthritis, especially in young and active patients. Most studies presenting short-term follow-up after hip resurfacing present radiographic or dual clinician-patient-related outcome. These kinds of outcomes are influenced by interpretation of the clinician and do not tell us much about functional outcome from the patients perspective. Today, functional outcome is often measured using patient-reported outcome instruments. We used the patient-reported 'Hip Disability and osteoarthritis Outcome Score' questionnaire, which has good measurement properties, to assess short-term functional outcome in 160 patients (mean follow-up of 2.6 years) after hip resurfacing surgery. Furthermore, we focused on pain, range of motion, subjective improvement and complications. The majority (86.9%) of patients was free of pain after surgery and range of motion improved significantly. Subjective improvement was indicated in 95% of the patients. Mean HOOS in 149 patients was 87.5. In total, there were 11 complications (6%), and deep infections contributed the most (3.4%). In general, short-term follow-up after hip resurfacing in this cohort showed good clinical and patient-reported functional outcome. When assessing the results of medical interventions, a good PRO instrument can give reliable and valuable information from the patients perspective.

Naphthenic acid fraction compounds reduce the reproductive success of wood frogs (Rana sylvatica) by affecting offspring viability.

Understanding the toxicity of organic compounds in oil sands process-affected water (OSPW) is necessary to inform the development of environmental guidelines related to wastewater management in Canada's oil sands region. In the present study, we investigated the effects of naphthenic acid fraction compounds (NAFCs), one of the most toxic components of OSPW, on mating behaviour, fertility, and offspring viability in the wood frog (Rana sylvatica). Wild adult wood frogs were exposed separately from the opposite sex to 0, 5, or 10 mg/L of OSPW-derived NAFCs for 24 h and then combined in outdoor lake water mesocosms containing the same NAFC concentrations (n = 2 males and 1 female per mesocosm, n = 3 mesocosms per treatment). Mating events were recorded for 48 h and egg masses were measured to determine adult fertility. NAFC exposure had no significant effect on mating behaviour (probability of amplexus and oviposition, amplexus and oviposition latency, total duration of amplexus and number of amplectic events) or fertility (fertilization success and clutch size). Tadpoles (50 individuals per mesocosm at hatching, and 15 individuals per mesocosm from 42 d post-hatch) were reared in the same mesocosms under chronic NAFC exposure until metamorphic climax (61-85 d after hatching). Offspring exposed to 10 mg/L NAFCs during development were less likely to survive and complete metamorphosis, grew at a reduced rate, and displayed more frequent morphological abnormalities. These abnormalities included limb anomalies at metamorphosis, described for the first time after NAFC exposure. The results of this study suggest that NAFCs reduce wood frog reproductive success through declines in offspring viability and therefore raise the concern that exposure to NAFCs during reproduction and development may affect the recruitment of native amphibian populations in the oil sands region.

Preliminary fingerprinting of Athabasca oil sands polar organics in environmental samples using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry.

There is a growing need to develop analytical methods that can distinguish compounds found within industrially derived oil sands process water (OSPW) from those derived from natural weathering of oil sands deposits. This is a difficult challenge as possible leakage beyond tailings pond containments will probably be in the form of mixtures of water-soluble organics that may be similar to those leaching naturally into aquatic environments. We have evaluated the potential of negative ion electrospray ionization high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) for comparing oil sands polar organics from tailing ponds, interceptor wells, groundwater, river and lake surface waters. Principal component analysis was performed for all species observed. which included the O(2) class (often assumed to be monocarbxoylic naphthenic acids) along with a wide range of other species including humic substances in the river and lake samples: O(n) where n=1-16; NO(n) and N(2)O(n) where n=1-13; and O(n)S and O(n)S(2) where n=1-10 and 1-8, respectively. A broad range of species was investigated because classical naphthenic acids can be a small fraction of the 'organics' detected in the polar fraction of OSPW, river water and groundwater. Aquatic toxicity and environmental chemistry are attributed to the total organics (not only the classical naphthenic acids). The distributions of the oil sands polar organics, particularly the sulfur-containing species, O(n)S and O(n)S(2), may have potential for distinguishing sources of OSPW. The ratios of species containing O(n) along with nitrogen-containing species: NO(n), and N(2)O(n), were useful for differentiating organic components derived from OSPW from those found in river and lake waters. Further application of the FTICRMS technique for a diverse range of OSPW of varying ages and composition, as well as the surrounding groundwater wells, may be critical in assessing whether leakage from industrial sources to natural waters is occurring.

Incidence of low-grade infection in aseptic loosening of total hip arthroplasty.

PURPOSE: We investigated the hypothesis that many total hip arthroplasty revisions that are classified as aseptic are in fact low-grade infections missed with routine diagnostics. METHODS: In 7 Dutch hospitals, 176 consecutive patients with the preoperative diagnosis of aseptic loosening of their total hip arthroplasty were enrolled. During surgery, between 14 and 20 tissue samples were obtained for culture, pathology, and broad-range 16S rRNA PCR with reverse line blot hybridization. Patients were classified as either not being infected, suspected of having infection, or infected according to strict, predefined criteria. Each patient had a follow-up visit after 1 year. RESULTS: 7 patients were classified as infected, 4 of whom were not identified by routine culture. 15 additional patients were suspected of having infection. 20 of these 22 patients received a cemented prosthesis, fixated with antibiotic-loaded bone cement. All 22 patients received prophylactic systemic antibiotics. 7 of them reported complaints one year after surgery, but only one showed signs of early loosening. However, additional surgery was not performed in any of the patients. INTERPRETATION: Although the proportions were not as high as previously reported in the literature, between 4% and 13% of patients with the preoperative diagnosis of aseptic loosening were infected. However, as thorough debridement was performed during surgery and prophylactic antibiotics were used, the diagnosis of infection did not have any obvious clinical consequences, as most patients performed well at the 1-year follow-up. Whether this observation has implications for long-term implant survival remains to be seen.

A preparative method for the isolation and fractionation of dissolved organic acids from bitumen-influenced waters.

The surface mining of oil sands north of Fort McMurray, Alberta produces considerable tailings waste that is stored in large tailings ponds on industrial lease sites. Viable strategies for the detoxification of oil sands process affected water (OSPW) are under investigation. In order to assess the toxic potential of the suite of dissolved organics in OSPW, a method for their extraction and fractionation was developed using solid phase extraction. The method successfully isolated organic compounds from 180 L of an aged OSPW source. Using acidic- or alkaline-conditioned non-polar ENV+ resin and soxhlet extraction with ethyl acetate and methanol, three fractions (F1-F3) were generated. Chemical characterization of the generated fractions included infusion to electrospray ionization ultrahigh-resolution mass spectrometry (ESI-UHRMS), liquid chromatography quadrupole time-of-flight mass spectrometry, gas chromatography triple quadrupole time-of-flight mass spectrometry, and synchronous fluorescence spectroscopy (SFS). Additionally, ESI-UHRMS class distribution data and SFS identified an increased degree of oxygenation and aromaticity, associated with increased polarity. Method validation, which included method and matrix spikes with surrogate and labelled organic mono carboxylic acid standards, confirmed separation according to acidity and polarity with generally good recoveries (average 76%). Because this method is capable of extracting large sample volumes, it is amenable to thorough chemical characterization and toxicological assessments with a suite of bioassays. As such, this protocol will facilitate effects-directed analysis of toxic components within bitumen-influenced waters from a variety of sources.

Long-term effects of an early-life exposure of fathead minnows to sediments containing bitumen. Part I: Survival, deformities, and growth.

The aim of this study was to investigate the long-term effects of a short exposure to natural sediments within the Athabasca oil sand formation to critical stages of embryo-larval development in fathead minnows (Pimephales promelas). Three different sediments were used: Ref sediment from the upper Steepbank River tested at 3 g/L (containing 12.2 ng/g ∑PAHs), and two bitumen-rich sediments tested at 1 and 3 g/L; one from the Ells River (Ells downstream, 6480 ng/g ∑PAHs) and one from the Steepbank River (Stp downstream, 4660 ng/g ∑PAHs). Eggs and larvae were exposed to sediments for 21 days, then transferred to clean water for a 5-month grow-out and recovery period. Larval fish had significantly decreased survival after exposure to 3 g/L sediment from Stp downstream, and decreased growth (length and weight at 16 days post hatch) in Ells and Stp downstream sediments at both 1 and 3 g/L. Decreased tail length was a sensitive endpoint in larval fish exposed to Ells and Stp downstream sediments for 21 days compared to Ref sediment. After the grow-out in clean water, all growth effects from the bitumen-containing sediments recovered, but adult fish from Stp downstream 3 g/L sediment had significant increases in jaw deformities. The study shows the potential for fish to recover from the decreased growth effects caused by sediments containing oil sands-related compounds, but that some effects of the early-life sediment exposure occur later on in adult fish.

The toxicity of organic fractions from aged oil sands process-affected water to aquatic species.

The process of surface mining and extracting bitumen from oil sand produces large quantities of tailings and oil sands process-affected water (OSPW). The industry is currently storing OSPW on-site while investigating strategies for their detoxification. One such strategy relies on the biodegradation of organic compounds by indigenous microbes, resulting in aged tailings waters with reduced toxicity. This study assessed the toxicity of OSPW aged statically for approximately 18 years. Dissolved organics in aged OSPW were fractionated using a preparative solid-phase extraction method that generated three organic fractions (F1-F3) of increasing polarity. Eight aquatic species from different trophic levels were exposed to whole OSPW (WW) and the derived OSPW organic fractions to assess toxicity: Pimephales promelas, Oryzias latipes, Vibrio fischeri, Daphnia magna, Lampsilis cardium, Hyalella azteca, Ceriodaphnia dubia, and Hexagenia spp. Broad comparisons revealed that P. promelas and H. azteca were most sensitive to dissolved organics within aged OSPW, while WW was most toxic to L. cardium and H. azteca. Three cases of possible contaminant interactions occurred within whole OSPW treatments, as toxicity was higher than organic fractions for H. azteca and L. cardium, and lower for P. promelas. As such, the drivers of toxicity appeared to be dependent on the species exposed. Of the organic fractions assessed, F3 (most polar) was the most toxic overall while F2 (intermediate polarity) displayed little toxicity to all species evaluated. This presents strong evidence that classical mono-carboxylic naphthenic acids, mostly present in F1 (least polar), are not primarily responsible for the toxicity in aged tailings. The current study indicates that although the aged tailings source (≥18 years) did not display acute toxicity to the majority of organisms assessed, inorganic components and polyoxygenated organics may pose a persistent concern to some aquatic organisms.

Meltwater from snow contaminated by oil sands emissions is toxic to larval fish, but not spring river water.

To assess the toxicity of winter-time atmospheric deposition in the oil sands mining area of Northern Alberta, embryo-larval fathead minnow (Pimephales promelas) were exposed to snowmelt samples. Snow was collected in 2011-2014 near (<7km) oil sands open pit mining operations in the Athabasca River watershed and at sites far from (>25km) oil sands mining. Snow was shipped frozen back to the laboratory, melted, and amended with essential ions prior to testing. Fertilized fathead minnow eggs were exposed (<24h post-fertilization to 7-16days post-hatch) to a range of 25%-100% snowmelt. Snow samples far from (25-277km away) surface mining operations and upgrading facilities did not affect larval fathead minnow survival at 100%. Snow samples from sites near surface mining and refining activities (<7km) showed reduced larval minnow survival. There was some variability in the potencies of snow year-to-year from 2011 to 2014, and there were increases in deformities in minnows exposed to snow from 1 site on the Steepbank River. Although exposure to snowmelt from sites near oil sands surface mining operations caused effects in larval fish, spring melt water from these same sites in late March-May of 2010, 2013 and 2014 showed no effects on larval survival when tested at 100%. Snow was analyzed for metals, total naphthenic acid concentrations, parent PAHs and alkylated PAHs. Naphthenic acid concentrations in snow were below those known to affect fish larvae. Concentrations of metals in ion-amended snow were below published water quality guideline concentrations. Compared to other sites, the snowmelt samples collected close to mining and upgrading activities had higher concentrations of PAHs and alkylated PAHs associated with airborne deposition of fugitive dusts from mining and coke piles, and in aerosols and particles from stack emissions. CAPSULE: Snow collected close to oil sands surface mining sites is toxic to larval fathead minnows in the lab; however spring melt water samples from the same sites do not reduce larval fish survival.

Assessing Risks of Shallow Riparian Groundwater Quality Near an Oil Sands Tailings Pond.

The potential discharge of groundwater contaminated by oil sands process-affected water (OSPW) is a concern for aquatic ecosystems near tailings ponds. Groundwater in the area, but unaffected by OSPW, may contain similar compounds, complicating the assessment of potential ecological impacts. In this study, 177 shallow groundwater samples were collected from riparian areas along the Athabasca River and tributaries proximate to oil sands developments. For "pond-site" samples (71; adjacent to study tailings pond), Canadian aquatic life guidelines were exceeded for 11 of 20 assessed compounds. However, "non-pond" samples (54; not near any tailings pond) provided similar exceedances. Statistical analyses indicate that pond-site and non-pond samples were indistinguishable for all but seven parameters assessed, including salts, many trace metals, and fluorescence profiles of aromatic naphthenic acids (ANA). This suggests that, regarding the tested parameters, groundwater adjacent to the study tailings pond generally poses no greater ecological risk than other nearby groundwaters at this time. Multivariate analyses applied to the groundwater data set separated into 11 smaller zones support this conclusion, but show some variation between zones. Geological and potential OSPW influences could not be distinguished based on major ions and metals concentrations. However, similarities in indicator parameters, namely ANA, F, Mo, Se, and Na-Cl ratio, were noted between a small subset of samples from two pond-site zones and two OSPW samples and two shallow groundwater samples documented as likely OSPW affected. This indicator-based screening suggests that OSPW-affected groundwater may be reaching Athabasca River sediments at a few locations.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.

BACKGROUND: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. METHODS: Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. RESULTS: Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. CONCLUSIONS: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

Psychosocial concomitants of biological maturation in preadolescence.

The authors studied 8 sets of healthy twins, ranging in physical maturity from prepubertal to late pubertal, and their parents to assess psychological changes in early adolescence. Interview and questionnaire data suggested that self-doubt, avoidance of responsiblity, resentment of parents, and anxiety about social relationships peaked in early puberty; emotional upset peaked in early puberty to mid-puberty. The results support a hypothesis of phase-specific psychosocial regression correlated with the biological onset of puberty. Children in all pubertal stages were shifting their interests away from parents and toward peers.

A systematic evaluation of the properties of self-stimulation train-duration response functions.

A series of experiments examined the characteristics of train-duration response functions and two statistics derived from these functions: train-duration thresholds and maximum rates. Train-duration response functions exhibited a steplike appearance. The slope of the train-duration curves was not influenced by either reward or performance manipulations, which suggests that the animals were not matching their response rates to changes in these factors along the steep part of the function. Substantial shifts in train-duration thresholds were observed following changes in the reward value of the brain stimulation, whereas maximum rates were affected by changes in factors such as response effort. The results of Experiments 1 through 6 demonstrate several similarities and differences between train-duration response functions and the reward summation functions generated with manipulations of stimulation frequency. The experiments described in this report provide convergent evidence for the validity of both of these approaches.