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Abstract Declining metabolic function with aging is a conserved phenotype across many species. While aging-associated changes in metabolic status have been investigated rigorously in humans, less is known about metabolic aging in dogs. In this cross-sectional study, we aimed to examine changes in metabolic health with age, and any associations with frailty and quality of life, in a diverse population of companion dogs. This cross-sectional study enrolled 451 mature, adult companion dogs. Serum adiponectin, ALP, ALT, AST, cholesterol, insulin, IGF-1 and glucose levels were quantified. Additionally, plasma FFA, SFA, PA, OA and LA were quantified in a 61 dog subpopulation. All analytes were significantly associated with age, with the exception of AST. Elevated ALP, ALT, cholesterol, insulin, FFA, PA and OA were correlated with increased frailty scores, while higher levels of glucose and adiponectin were correlated with reduced frailty scores. The strength of these associations increased with age. Higher ALP, ALT and insulin were associated with lower HRQL scores after adjusting for covariates. Our findings establish novel associations between deleterious aging-associated metabolic changes and validated measures of clinical well-being in companion dogs. Future research should investigate the causality of these associations to inform therapeutic strategies targeting age-associated changes to frailty and quality of life.

AimsEarly detection and management of sleep disturbances can improve postoperative outcomes given the high prevalence of sleep disturbances and unrecognized cognitive impairment in older surgical patients. There is an association between sleep disturbances and cognitive impairment in the general population. However, the relationship in older surgical patients has not been systematically investigated. The objective of this study was to assess the prevalence and trajectory of preoperative and postoperative sleep disturbances in older surgical participants with and without suspected cognitive impairment (sCI).MethodsTwo hundred and fifty-two participants aged ≥ 65 years undergoing non-cardiac surgery were recruited. The primary outcome was the prevalence and trajectory of sleep disturbances measured by the Pittsburgh Sleep Quality Index (PSQI) in participants with and without sCI preoperatively, 30, 90, and 180 days postoperatively. The main exposure, preoperative sCI, was operationalized as screening positive on one or more of the following cognitive screening tools: Centers for Disease Control and Prevention cognitive question (answered "yes"), Ascertain Dementia Eight-item Questionnaire (≥2), Telephone Montreal Cognitive Assessment (≤18), and Modified Telephone Interview for Cognitive Status (≤31). Sleep disturbances were defined as a PSQI score > 5. Mixed effects logistic regression models with random intercepts were used for the dichotomous outcome of sleep disturbances.ResultsOne hundred and eight participants (43%) screened positive for preoperative sCI. The prevalence of preoperative sleep disturbances was higher in participants with sCI versus without (63% vs 47%, P = 0.02). Postoperatively in both groups, the prevalence of sleep disturbances was lower at 30, 90, and 180 days, compared to the preoperative assessment and overall trajectories did not differ significantly. Female sex and depression were associated with poorer postoperative sleep, regardless of cognitive status.ConclusionSleep disturbances and suspected cognitive impairment are highly prevalent in surgical cohorts. Targeting conditions such as depression which affect sleep, may improve postoperative outcomes.

Abstract Accurate measurement of habitual sleep duration (HSD) is crucial for understanding the relationship between sleep and health. This study aimed to assess the bias and agreement limits between two commonly used short HSD self-report methods, considering sleep quality (SQ) and social jetlag (SJL) as potential predictors of bias. Data from 10,268 participants in the International COVID Sleep Study-II (ICOSS-II) were used. Method-Self and Method-MCTQ were compared. Method-Self involved a single question about average nightly sleep duration (HSDself), while Method-MCTQ estimated HSD from reported sleep times on workdays (HSDMCTQwork) and free days (HSDMCTQfree). Sleep quality was evaluated using a Likert scale and the Insomnia Severity Index (ISI) to explore its influence on estimation bias. HSDself was on average 42.41 ± 67.42 min lower than HSDMCTQweek, with an agreement range within ± 133 min. The bias and agreement range between methods increased with poorer SQ. HSDMCTQwork showed less bias and better agreement with HSDself compared to HSDMCTQfree. Sleep duration irregularity was − 43.35 ± 78.26 min on average. Subjective sleep quality predicted a significant proportion of variance in HSDself and estimation bias. The two methods showed very poor agreement and a significant systematic bias, both worsening with poorer SQ. Method-MCTQ considered sleep intervals without adjusting for SQ issues such as wakefulness after sleep onset but accounted for sleep irregularity and sleeping in on free days, while Method-Self reflected respondents’ interpretation of their sleep, focusing on their sleep on workdays. Including an SQ-related question in surveys may help bidirectionally adjust the possible bias and enhance the accuracy of sleep-health studies.

IntroductionDepression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied.MethodsFour databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias.ResultsOf the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias.ConclusionsFuture research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.

Seafloor hydrocarbon seepage is a natural fluid release process that occurs worldwide on continental shelves, slopes, and in deep oceanic basins. The Vestnesa sedimentary ridge in the eastern Fram Strait hosts a deep-water gas hydrate system that became charged with hydrocarbons ∼2.7 Ma and has experienced episodic seepage along the entire ridge until a few thousand years ago, when seepage activity apparently ceased in the west but persisted in the east. Although it has been documented that faults and fractures play a key role in feeding the seeps with thermogenic gases, the mechanisms controlling seepage periodicity remain poorly understood. Here we integrate high-resolution P-cable 3D seismic and Chirp data to investigate the spatial and temporal evolution of high-resolution fractures and fluid flow features in the west of the Vestnesa Ridge. We characterize sediment deformation using a fracture density seismic attribute workflow revealing two highly deformed stratigraphic intervals and associated small-scale pockmarks (

Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S. Food and Drug Administration (FDA). These findings were augmented with data from peer reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized following PRISMA guidelines. Meta-analysis was conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biologic were identified. Safety data including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00) across STPs, respectively. Immunogenicity data showed similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biologic and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients. This first systematic review using statistical methods to address the risk of switching patients between reference biologics and biosimilars finds no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or a biosimilar.

BackgroundThe Ascertain Dementia 8-item Questionnaire (AD8) is a screening tool for cognitive impairment that can be administered to older persons and/or their informants.ObjectivesTo evaluate the diagnostic accuracy and compare the predictive parameters of the informant and participant-completed Ascertain Dementia 8-item Questionnaire (iAD8 and pAD8, respectively) in older adults with cognitive impairment.Methods/designWe searched ten electronic databases (including MEDLINE (Ovid), Embase) from tool inception to March 2022. We included studies with patients ≥60 years old that were screened for cognitive impairment using AD8 in any healthcare setting. Predictive parameters were assessed against reference standards to estimate accuracy and diagnostic ability using bivariate random-effects meta-analyses. We used QUADAS-2 criteria to assess risk of bias.ResultsA cut-off of ≥2/8 was used to classify mild cognitive impairment (MCI), dementia, and cognitive impairment (MCI or dementia). Seven studies using the iAD8 (n = 794) showed a sensitivity of 80% and specificity of 79% to detect MCI. Nine studies using the iAD8 (n = 2393) established 91% sensitivity and 64% specificity to detect dementia. To detect MCI using the pAD8, four studies (n = 836) showed 57% sensitivity and 71% specificity. To detect dementia using the pAD8, four studies (n = 3015) demonstrated 82% sensitivity and 75% specificity. Recurring high or unclear risk of bias was noted in the domains of "Index test" and "reference standard".ConclusionsThe diagnostic accuracy of iAD8 is superior to that of pAD8 when screening for cognitive impairment. The AD8 may be an acceptable alternative to screen for cognitive impairment in older adults when there are limitations to formal testing.

Immune-checkpoint blockade has shown limited benefits in patients with glioblastoma. To understand how the composition of the tumor immune microenvironment might limit clinical responses, here the authors present a high dimensional profiling of the immune landscape in patients with glioblastoma following neoadjuvant PD-1 checkpoint blockade.

Abstract Many studies project that climate change is expected to cause a significant number of excess deaths. Yet, in integrated assessment models that determine the social cost of carbon (SCC), human mortality impacts do not reflect the latest scientific understanding. We address this issue by estimating country-level mortality damage functions for temperature-related mortality with global spatial coverage. We rely on projections from the most comprehensive published study in the epidemiology literature of future temperature impacts on mortality (Gasparrini et al. in Lancet Planet Health 1:e360–e367, 2017), which estimated changes in heat- and cold-related mortality for 23 countries over the twenty-first century. We model variation in these mortality projections as a function of baseline climate, future temperature change, and income variables and then project future changes in mortality for every country. We find significant spatial heterogeneity in projected mortality impacts, with hotter and poorer places more adversely affected than colder and richer places. In the absence of income-based adaptation, the global mortality rate in 2080–2099 is expected to increase by 1.8% [95% CI 0.8–2.8%] under a lower-emissions RCP 4.5 scenario and by 6.2% [95% CI 2.5–10.0%] in the very high-emissions RCP 8.5 scenario relative to 2001–2020. When the reduced sensitivity to heat associated with rising incomes, such as greater ability to invest in air conditioning, is accounted for, the expected end-of-century increase in the global mortality rate is 1.1% [95% CI 0.4–1.9%] in RCP 4.5 and 4.2% [95% CI 1.8–6.7%] in RCP 8.5. In addition, we compare recent estimates of climate-change induced excess mortality from diarrheal disease, malaria and dengue fever in 2030 and 2050 with current estimates used in SCC calculations and show these are likely underestimated in current SCC estimates, but are also small compared to more direct temperature effects.

Abstract Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

The symmetry of metal ions in inorganic nanofilms can be manipulated by the transfer of optical spin from a chiral light beam. Here the authors present a route to functional manipulation that does not require the application of extreme conditions.

RationaleDespite the high prevalence of obstructive sleep apnea (OSA) and concurrent use of opioid therapy, no large-scale population studies have investigated whether opioid use and pre-existing OSA may interact synergistically to increase the risk of adverse health consequences. To address this knowledge gap, we conducted a retrospective cohort study using provincial health administrative data to evaluate whether the combined presence of opioid use and OSA increases the risk of adverse health consequences, such as mortality, hospitalizations, and emergency department (ED) visits; and if it does, whether this co-occurrence has synergistic clinical relevance.MethodsWe included all adults who underwent a diagnostic sleep study in Ontario, Canada, between 2013 and 2016. Individuals were considered exposed to opioids if they filled a prescription that overlapped with the date of their sleep study (Opioid+). Individuals with at least a 50% probability of having a diagnosis of moderate to severe OSA (OSA+) were identified using a previously externally validated case-ascertainment model. The primary outcome was all-cause mortality; secondary outcomes were all-cause or ischemic heart disease hospitalizations, all-cause ED visits, and motor vehicle collisions (MVC) requiring hospital or ED visit. We used multivariable Cox regression models to compare hazards between four mutually exclusive groups: (1) Opioid+ OSA+; (2) Opioid+ OSA-; (3) Opioid- OSA+, and (4) OSA- Opioid- (reference for comparison). Relative excess risks due to interaction (RERI) were calculated to test for additive interaction.ResultsOf 300,663 adults who underwent a sleep study, 15,713 (5.2%) were considered as Opioid+ and 128,351 (42.7%) as OSA+. Over a median of two years, 6,223 (2.1%) died from any cause. Regardless of OSA status, opioid use at the date of the sleep study was associated with an increased hazard for all-cause mortality with the greatest hazard associated with Opioid+ OSA- (adjusted hazard ratio [aHR]: 1.75, 95% CI 1.57-1.94), but not Opioid+ OSA+ (aHR: 1.14, 95% CI 1.02-1.27) as hypothesized. Regardless of OSA status, opioid use at the date of the sleep study was associated with an increased hazard for all secondary outcomes. Opioid+ OSA+ was associated with the greatest hazards of all-cause hospitalizations (aHR 1.55, 95% CI 1.49-1.61) and MVC (aHR of 1.39; 95% CI 1.09-1.77); however, no statistically significant synergistic effects were observed.ConclusionsAdults referred for sleep disorder assessment who used opioids had a significantly increased hazard of adverse health outcomes than those who did not, regardless of whether they had a high probability of moderate to severe OSA. The use of opioids and OSA was associated with the greatest hazard of all-cause hospitalizations and MVC requiring hospital or ED visit. The interaction of opioids and OSA did not confer a synergistic risk for poor outcomes.

Extreme high temperature events are increasing in frequency and severity, threatening the capacity for crops and farmers alike to adapt. Here Sloat and colleagues track the movement of cereal crops over the past 40 years, finding a global migration away from warming climates.

The degree of flooding in a particular location depends sensitively on local topography and bathymetry. Here the authors used the remarkability of flood events to estimate county-specific flood thresholds for shoreline counties along the Atlantic and Gulf coasts of the United States and found that several areas experience noticeable flooding at a height lower than existing thresholds.

IntroductionIn adults with cardiovascular risk factors undergoing major noncardiac surgery, unrecognized obstructive sleep apnea (OSA) was associated with postoperative cardiovascular complications. There is a need for an easy and accessible home device in predicting sleep apnea. The objective of the study is to determine the predictive performance of the overnight pulse oximetry in predicting OSA in at-risk surgical patients.MethodsThis was a planned post-hoc analysis of multicenter prospective cohort study involving 1,218 at-risk surgical patients without prior diagnosis of sleep apnea. All patients underwent home sleep apnea testing (ApneaLink Plus, ResMed) simultaneously with pulse oximetry (PULSOX-300i, Konica Minolta Sensing, Inc). The predictive performance of the 4% oxygen desaturation index (ODI) versus apnea-hypopnea index (AHI) were determined.ResultsOf 1,218 patients, the mean age was 67.2 ± 9.2 years and body mass index (BMI) was 27.0 ± 5.3 kg/m2. The optimal cut-off for predicting moderate-to-severe and severe OSA was ODI ≥15 events/hour. For predicting moderate-to-severe OSA (AHI ≥15), the sensitivity and specificity of ODI ≥ 15 events per hour were 88.4% (95% confidence interval [CI], 85.7-90.6) and 95.4% (95% CI, 94.2-96.4). For severe OSA (AHI ≥30), the sensitivity and specificity were 97.2% (95% CI, 92.7-99.1) and 78.8% (95% CI, 78.2-79.0). The area under the curve (AUC) for moderate-to-severe and severe OSA was 0.983 (95% CI, 0.977-0.988) and 0.979 (95% CI, 0.97-0.909) respectively.DiscussionODI from oximetry is sensitive and specific in predicting moderate-to-severe or severe OSA in at-risk surgical population. It provides an easy, accurate, and accessible tool for at-risk surgical patients with suspected OSA.

Enhancement of X-ray emission was observed from a micro-jet of a nano-colloidal gold suspension in air under double-pulse excitation of ultrashort (40 fs) near-IR laser pulses. Temporal and spatial overlaps between the pre-pulse and the main pulse were optimized for the highest X-ray emission. The maximum X-ray intensity was obtained at a 1–7 ns delay of the main pulse irradiation after the pre-pulse irradiation with the micro-jet position shifted along the laser beam propagation. It was revealed that the volume around gold nanoparticles where the permittivity is near zero, ε ≈ 0, accounts for the strongest absorption, which leads to the effective enhancements of X-ray emission.

Amphibian skin microbe communities have been putatively associated with the severity of chytrid fungal disease. Here, the authors show that different types of disease dynamics (enzootic versus epizootic) are associated with different microbiota in the host populations.

Climate change impacts in models used to calculate the social cost of carbon (SCC) are either poorly documented or based on a small number of dated studies. Here, the authors estimate new damages for the agricultural sector and find that updating this sector alone causes the SCC to increase substantially.

“Variation in the noncoding regulatory sequences in the genome plays important roles in human disease and evolution. Here, the authors use F1 mouse hybrids to shed light on the regulatory mechanisms mediating transcription factor binding, chromatin state and gene expression in mammalian cells.”

Functional localizers allow the definition of regions of interest in the human brain that cannot be delineated by anatomical markers alone. To date, when localizing the body-selective areas of the visual cortex using fMRI, researchers have used static images of bodies and objects. However, there are other relevant brain areas involved in the processing of moving bodies and action interpretation that are missed by these techniques. Typically, these biological motion areas are localized separately using whole and scrambled point-light display stimuli. Currently, one can only localize either the static body-selective areas or the biological motion areas, but not both together. Here, for the first time, using motion-controlled dynamic body and object stimuli, we describe a method for localizing the full dynamic body-selective network of the human brain in one experimental run. • The method uses dynamic body and object stimuli. • Low-level local motion information is added as a covariate into the fMRI analysis. • This localizes the full dynamic body-selective network of the human brain.

PURPOSE:To evaluate whether the early identification of patients who may benefit from palliative care impacts on the use of palliative, community and acute-based care services. METHODS:Between 2014 and 2017, physicians from eight sites were encouraged to systematically identify patients who were likely to die within one year and would were thought to benefit from early palliative care. Patients in the INTEGRATE Intervention Group were 1:1 matched to controls selected from provincial healthcare administrative data using propensity score-matching. The use of palliative care, community-based care services (home care, physician home visit, and outpatient opioid use) and acute care (emergency department, hospitalization) was each evaluated within one year after the date of identification. The hazard ratio (HR) in the Intervention Group was calculated for each outcome. RESULTS:Of the 1,185 patients in the Intervention Group, 951 (80.3%) used palliative care services during follow-up, compared to 739 (62.4%) among 1,185 patients in the Control Group [HR of 1.69 (95% CI 1.56 to 1.82)]. The Intervention Group also had higher proportions of patients who used home care [81.4% vs. 55.2%; HR 2.07 (95% CI 1.89 to 2.27)], had physician home visits [35.5% vs. 23.7%; HR 1.63 (95% CI 1.46 to 1.92)] or had increased outpatient opioid use [64.3% vs. 52.1%); HR 1.43 (95% CI 1.30 to 1.57]. The Intervention Group was also more likely to have a hospitalization that was not primarily focused on palliative care (1.42 (95% CI 1.28 to 1.58)) and an unplanned emergency department visit for non-palliative care purpose (1.47 (95% CI 1.32 to 1.64)). CONCLUSION:Physicians actively identifying patients who would benefit from palliative care resulted in increased use of palliative and community-based care services, but also increased use of acute care services.

Climate change is expected to increase the scarcity and variability of fresh water supplies in some regions with important implications for irrigated agriculture. By allowing for increased flexibility in response to scarcity and by incentivizing the allocation of water to higher value use, markets can play an important role in limiting the economic losses associated with droughts. Using data on water demand, the seniority of water rights, county agricultural reports, high-resolution data on cropping patterns, and agronomic estimates of crop water requirements, we estimate the benefits of market-based allocations of surface water for California’s Central Valley. Specifically, we estimate the value of irrigation water and compare the agricultural costs of water shortages under the existing legal framework and under an alternate system that allows for trading of water. We find that a more efficient allocation of curtailments could reduce the costs of water shortages by as much as $362 million dollars per year or 4.4% of the net agricultural revenue in California in expectation, implying that institutional and market reform may offer important opportunities for adaptation.

The direct impacts of climate change on crop yields and human health are individually well-studied, but the interaction between the two have received little attention. Here we analyze the consequences of global warming for agricultural workers and the crops they cultivate using a global economic model (GTAP) with explicit treatment of the physiological impacts of heat stress on humans’ ability to work. Based on two metrics of heat stress and two labor functions, combined with a meta-analysis of crop yields, we provide an analysis of climate, impacts both on agricultural labor force, as well as on staple crop yields, thereby accounting for the interacting effect of climate change on both land and labor. Here we analyze the two sets of impacts on staple crops, while also expanding the labor impacts to highlight the potential importance on non-staple crops. We find, worldwide, labor and yield impacts within staple grains are equally important at +3 ^∘ C warming, relative to the 1986–2005 baseline. Furthermore, the widely overlooked labor impacts are dominant in two of the most vulnerable regions: sub-Saharan Africa and Southeast Asia. In those regions, heat stress with 3 ^∘ C global warming could reduce labor capacity in agriculture by 30%–50%, increasing food prices and requiring much higher levels of employment in the farm sector. The global welfare loss at this level of warming could reach $136 billion, with crop prices rising by 5%, relative to baseline.

Assimilable organic carbon (AOC) is known to correlate with microbial growth, which can consequently degrade drinking water quality. Despite this, there is no standardised AOC test that can be applied to drinking water distribution systems (DWDS). Herein we report the development of a quick, robust AOC that incorporates known strains Pseudomonas fluorescens strain P-17 and Spirillum strain NOX, a higher inoculum volume and enumeration using flow cytometry to generate a quicker (total test time reduced from 14 to 8 days), robust method. We apply the developed AOC test to twenty drinking water treatment works (WTW) to validate the method reproducibility and resolution across a wide range of AOC concentrations. Subsequently, AOC was quantified at 32 sample points, over four DWDS, for a year in order to identify sinks and sources of AOC in operative networks. Application of the developed AOC protocol provided a previously unavailable insight and novel evidence of pipes and service reservoirs exhibiting different AOC and regrowth behaviour. Observed correlations between AOC and microbial growth highlight the importance of monitoring AOC as an integral part of managing drinking water quality at the consumers tap.

ObjectiveActive surveillance (AS) represents a fundamental shift in managing select cancer patients that initiates treatment only upon disease progression to avoid overtreatment. Given uncertain outcomes, patient engagement could support decision-making about AS. Little is known about how to optimize patient engagement for AS decision-making. This scoping review aimed to characterize research on patient and provider communication about AS, and associated determinants and outcomes.MethodsMEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched from 2006 to October 2016. English language studies that evaluated cancer patient or provider AS views, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings.ResultsA total of 2,078 studies were identified, 1,587 were unique, and 1,243 were excluded based on titles/abstracts. Among 344 full-text articles, 73 studies were eligible: 2 ductal carcinoma in situ (DCIS), 4 chronic lymphocytic leukemia (CLL), 6 renal cell carcinoma (RCC) and 61 prostate cancer. The most influential determinant of initiating AS was physician recommendation. Others included higher socioeconomic status, smaller tumor size, comorbid disease, older age, and preference to avoid adverse treatment effects. AS patients desired more information about AS and reassurance about future treatment options, involvement in decision-making and assessment of illness uncertainty and supportive care needs during follow-up. Only three studies of prostate cancer evaluated interventions to improve AS communication or experience.ConclusionsThis study revealed a paucity of research on AS communication for DCIS, RCC and CLL, but generated insight on how to optimize AS discussions in the context of routine care or clinical trials from research on AS for prostate cancer. Further research is needed on AS for patients with DCIS, RCC and CLL, and to evaluate interventions aimed at patients and/or providers to improve AS communication, experience and associated outcomes.

BACKGROUND:Difficult airway management and obstructive sleep apnea may contribute to increased risk of perioperative morbidity and mortality. The objective of this systematic review and meta-analysis (SRMA) is to evaluate the evidence of a difficult airway being associated with obstructive sleep apnea (OSA) patients undergoing surgery. METHODS:The standard databases were searched from 1946 to April 2017 to identify the eligible articles. The studies which included adult surgical patients with either suspected or diagnosed obstructive sleep apnea must report at least one difficult airway event [either difficult intubation (DI), difficult mask ventilation (DMV), failed supraglottic airway insertion or difficult surgical airway] in sleep apnea and non-sleep apnea patients were included. RESULTS:Overall, DI was 3.46-fold higher in the sleep apnea vs non-sleep apnea patients (OSA vs. non-OSA: 13.5% vs 2.5%; OR 3.46; 95% CI: 2.32-5.16, p

Pathological response of breast cancer to chemotherapy is a prognostic indicator for long-term disease free and overall survival. Responses of locally advanced breast cancer in the neoadjuvant chemotherapy (NAC) settings are often variable, and the prediction of response is imperfect. The purpose of this study was to detect primary tumor responses early after the start of neoadjuvant chemotherapy using quantitative ultrasound (QUS), textural analysis and molecular features in patients with locally advanced breast cancer.The study included ninety six patients treated with neoadjuvant chemotherapy. Breast tumors were scanned with a clinical ultrasound system prior to chemotherapy treatment, during the first, fourth and eighth week of treatment, and prior to surgery. Quantitative ultrasound parameters and scatterer-based features were calculated from ultrasound radio frequency (RF) data within tumor regions of interest. Additionally, texture features were extracted from QUS parametric maps. Prior to therapy, all patients underwent a core needle biopsy and histological subtypes and biomarker ER, PR, and HER2 status were determined. Patients were classified into three treatment response groups based on combination of clinical and pathological analyses: complete responders (CR), partial responders (PR), and non-responders (NR). Response classifications from QUS parameters, receptors status and pathological were compared. Discriminant analysis was performed on extracted parameters using a support vector machine classifier to categorize subjects into CR, PR, and NR groups at all scan times.Of the 96 patients, the number of CR, PR and NR patients were 21, 52, and 23, respectively. The best prediction of treatment response was achieved with the combination mean QUS values, texture and molecular features with accuracies of 78%, 86% and 83% at weeks 1, 4, and 8, after treatment respectively. Mean QUS parameters or clinical receptors status alone predicted the three response groups with accuracies less than 60% at all scan time points. Recurrence free survival (RFS) of response groups determined based on combined features followed similar trend as determined based on clinical and pathology.This work demonstrates the potential of using QUS, texture and molecular features for predicting the response of primary breast tumors to chemotherapy early, and guiding the treatment planning of refractory patients.

Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg- 0.5mg/kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impact-acceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI.

Background: Human mast cells (MCs) are long-lived tissue-resident immune cells characterised by granules containing the proteases chymase and/or tryptase. Their phenotype is modulated by their tissue microenvironment. The human uterus has an outer muscular layer (the myometrium) surrounding the endometrium, both of which play an important role in supporting a pregnancy. The endometrium is a sex steroid target tissue consisting of epithelial cells (luminal, glandular) surrounded by a multicellular stroma, with the latter containing an extensive vascular compartment as well as fluctuating populations of immune cells that play an important role in regulating tissue function. The role of MCs in the human uterus is poorly understood with little known about their regulation or the impact of steroids on their differentiation status. The current study had two aims: 1) To investigate the spatial and temporal location of uterine MCs and determine their phenotype; 2) To determine whether MCs express receptors for steroids implicated in uterine function, including oestrogen (ERα, ERβ), progesterone (PR) and glucocorticoids (GR). Methods: Tissue samples from women (n=46) were used for RNA extraction (n=26) or fixed (n=20) for immunohistochemistry. Results: Messenger RNAs encoded by TPSAB1 (tryptase) and CMA1 (chymase) were detected in endometrial tissue homogenates. Immunohistochemistry revealed the relative abundance of tryptase MCs was myometrium>basal endometrium>functional endometrium. We show for the first time that uterine MCs are predominantly of the classical MC subtypes: (positive, +; negative, -) tryptase+/chymase- and tryptase+/chymase+, but a third subtype was also identified (tryptase-/chymase+). Tryptase+ MCs were of an ERβ+/ERα-/PR-/GR+ phenotype mirroring other uterine immune cell populations, including natural killer cells. Conclusions: Endometrial tissue resident immune MCs have three protease-specific phenotypes. Expression of both ERβ and GR in MCs mirrors that of other immune cells in the endometrium and suggests that MC function may be altered by the local steroid microenvironment.

Background: Human mast cells (MCs) are long-lived tissue-resident immune cells characterised by granules containing the proteases chymase and/or tryptase. Their phenotype is modulated by their tissue microenvironment. The human uterus has an outer muscular layer (the myometrium) surrounding the endometrium, both of which play an important role in supporting a pregnancy. The endometrium is a sex steroid target tissue consisting of epithelial cells (luminal, glandular) surrounded by a multicellular stroma, with the latter containing an extensive vascular compartment as well as fluctuating populations of immune cells that play an important role in regulating tissue function. The role of MCs in the human uterus is poorly understood with little known about their regulation or the impact of steroids on their differentiation status. The current study had two aims: 1) To investigate the spatial and temporal location of uterine MCs and determine their phenotype; 2) To determine whether MCs express receptors for steroids implicated in uterine function, including oestrogen (ERα, ERβ), progesterone (PR) and glucocorticoids (GR). Methods: Tissue samples from women (n=46) were used for RNA extraction or fixed for immunohistochemistry. Results: Messenger RNAs encoded by TPSAB1 (tryptase) and CMA1 (chymase) were detected in endometrial tissue homogenates. Immunohistochemistry revealed the relative abundance of tryptase MCs was myometrium>basal endometrium>functional endometrium. We show for the first time that uterine MCs are predominantly of the classical MC subtypes: (positive, +; negative, -) tryptase+/chymase- and tryptase+/chymase+, but a third subtype was also identified (tryptase-/chymase+). Tryptase+ MCs were of an ERβ+/ERα-/PR-/GR+ phenotype mirroring other uterine immune cell populations, including natural killer cells. Conclusions: Endometrial tissue resident immune MCs have three protease-specific phenotypes. Expression of both ERβ and GR in MCs mirrors that of other immune cells in the endometrium and suggests that MC function may be altered by the local steroid microenvironment.

There has been substantial interest of late on the issue of coherence as a resource in quantum thermodynamics. To date, however, analyses have focused on somewhat artificial theoretical models. We seek to bring these ideas closer to experimental investigation by examining the ‘catalytic’ nature of quantum optical coherence. Here the interaction of a coherent state cavity field with a sequence of two-level atoms is considered, a state ubiquitous in quantum optics as a model of a stable, classical source of light. The Jaynes–Cummings interaction Hamiltonian is used, so that an exact solution for the dynamics can be formed, and the evolution of the atomic and cavity states with each atom-field interaction analysed. In this way, the degradation of the coherent state is examined as coherence is transferred to the sequence of atoms. The associated degradation of the coherence in the cavity mode is significant in the context of the use of coherence as a thermodynamic resource.

Longitudinal magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies reveal significant changes in brain structure and structural networks that occur together with cognitive and behavioral maturation in childhood. However, the underlying cellular changes accompanying brain maturation are less understood. Examining regional age-related changes in metabolite levels provides insight into the physiology of neurodevelopment. Magnetic resonance spectroscopy (MRS) measures localize brain metabolism. The majority of neuroimaging studies of healthy development are from the developed world. In a longitudinal MRS study of 64 South African children aged 5 to 10 years old (29 female; 29 HIV exposed, uninfected), we examined the age-related trajectories of creatine (Cr+PCr), N-acetyl-aspartate (NAA), the combined NAA+N-acetyl-aspartyl-glutamate (NAAG), choline (GPC+PCh), glutamate (Glu) and the combined Glu+glutamine (Glu+Gln) in voxels within gray and white matter, as well as subcortically in the basal ganglia (BG). In frontal gray matter, we found age-related increases in Cr+PCr, NAA, NAA+NAAG and Glu+Gln levels pointing to synaptic activity likely related to learning. In the BG we observed increased levels of Glu, Glu+Gln and NAA+NAAG with age that point to subcortical synaptic reorganization. In white matter, we found increased levels of Cr+PCr, NAA, NAA+NAAG, Glu and Glu+Gln with age, implicating these metabolites in ongoing myelination. We observed no sex-age or HIV exposure-age interactions, indicating that physiological changes are independent of sex during this time period. The metabolite trajectories presented, therefore, provide a critical benchmark of normal cellular growth for a low socioeconomic pediatric population in the developing world against which pathology and abnormal development may be compared.

Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells. If Link-N appears to be effective in canines, this would facilitate translation of Link-N into the clinic using the dog as an in vivo large animal model for human IVD degeneration.This study's objective was to determine the effect of the human and canine variant of Link-N and short (s) Link-N on canine chondrocyte-like cells (CLCs) and compare this to those on already studied species, i.e. human and bovine CLCs. Extracellular matrix (ECM) production was determined by measuring glycosaminoglycan (GAG) content and histological evaluation. Additionally, the micro-aggregates' DNA content was measured. Phosphorylated (p) Smad1 and -2 levels were determined using ELISA.Human (s)Link-N induced GAG deposition in human and bovine CLCs, as expected. In contrast, canine (s)Link-N did not affect ECM production in human CLCs, while it mainly induced collagen type I and II deposition in bovine CLCs. In canine CLCs, both canine and human (s)Link-N induced negligible GAG deposition. Surprisingly, human and canine (s)Link-N did not induce Smad signaling in human and bovine CLCs. Human and canine (s)Link-N only mildly increased pSmad1 and Smad2 levels in canine CLCs.Human and canine (s)Link-N exerted species-specific effects on CLCs from early degenerated IVDs. Both variants, however, lacked the potency as canine IVD regeneration agent. While these studies demonstrate the challenges of translational studies in large animal models, (s)Link-N still holds a regenerative potential for humans.

Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that, despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA, and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.

This study examines the performance of the policy of community management for rural groundwater supply in Africa. Across the continent, policies that promote community management have dominated the rural water supply sector for decades. As a result, hundreds of thousands of village-level committees have been formed to manage community boreholes equipped with handpumps. With a significant proportion of these handpumps non-functional at any one time, increasing effort is targeted toward understanding the interacting social and physical determinants of this ‘hidden crisis’. We conducted a survey of community management arrangements across six hundred sites in rural Ethiopia, Malawi, and Uganda, examining the extent to which management capacity is related to borehole functionality whilst accounting for a range of contextual variables. The capacity of water management arrangements (WMAs) was assessed according to four dimensions: finance system; affordable maintenance and repair; decision making, rules, and leadership; and external support. The survey reveals that 73.3% of WMAs have medium or high capacity. However, we found no strong relationship between the capacity of the WMA and the functionality of the borehole. Of the four management dimensions, affordable maintenance and repair was the best predictor of borehole functionality. However, the capacity of this dimension was seen to be the lowest overall, with 61.9% of sites weak or non-existent. Our results provide very limited support for the policy of community management, and we suggest that evidence alone has not accounted for its persistence over decades. After a short historical analysis, we conclude that explanation for the endurance of this model can be found in the nexus between evidence, ideology, and policy. We argue that it is this same nexus that will likely ensure the popularity of community management for some time to come, despite new ideas and evidence to the contrary.

A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE.

B cell hybridomas are an important source of monoclonal antibodies. In this paper, we developed a high-throughput method to characterize mouse IgG antibodies using surface plasmon resonance technology. This assay rapidly determines their sub-isotypes, whether they bind native antigen and their approximate affinities for the antigen using only 50 μl of hybridoma cell culture supernatant. Moreover, we found that mouse hybridomas secreting IgG antibodies also have membrane form IgG expression without Igα. Based on this surface IgG, we used flow cytometry to isolate rare γ2a isotype switched variants from a γ2b antibody secreting hybridoma cell line. Also, we used fluorescent antigen to single cell sort antigen binding hybridoma cells from bulk mixture of fused hybridoma cells instead of the traditional multi-microwell plate screening and limiting dilution sub-cloning thus saving time and labor. The IgG monoclonal antibodies specific for the native antigen identified with these methods are suitable for in vivo therapeutic uses, but also for sandwich ELISA assays, histology, flow cytometry, immune precipitation and x-ray crystallography.

BackgroundDiagnosing obstructive sleep apnea (OSA) is clinically relevant because untreated OSA has been associated with increased morbidity and mortality. The STOP-Bang questionnaire is a validated screening tool for OSA. We conducted a systematic review and meta-analysis to determine the effectiveness of STOP-Bang for screening patients suspected of having OSA and to predict its accuracy in determining the severity of OSA in the different populations.MethodsA search of the literature databases was performed. Inclusion criteria were: 1) Studies that used STOP-Bang questionnaire as a screening tool for OSA in adult subjects (>18 years); 2) The accuracy of the STOP-Bang questionnaire was validated by polysomnography--the gold standard for diagnosing OSA; 3) OSA was clearly defined as apnea/hypopnea index (AHI) or respiratory disturbance index (RDI) ≥ 5; 4) Publications in the English language. The quality of the studies were explicitly described and coded according to the Cochrane Methods group on the screening and diagnostic tests.ResultsSeventeen studies including 9,206 patients met criteria for the systematic review. In the sleep clinic population, the sensitivity was 90%, 94% and 96% to detect any OSA (AHI ≥ 5), moderate-to-severe OSA (AHI ≥15), and severe OSA (AHI ≥30) respectively. The corresponding NPV was 46%, 75% and 90%. A similar trend was found in the surgical population. In the sleep clinic population, the probability of severe OSA with a STOP-Bang score of 3 was 25%. With a stepwise increase of the STOP-Bang score to 4, 5, 6 and 7/8, the probability rose proportionally to 35%, 45%, 55% and 75%, respectively. In the surgical population, the probability of severe OSA with a STOP-Bang score of 3 was 15%. With a stepwise increase of the STOP-Bang score to 4, 5, 6 and 7/8, the probability increased to 25%, 35%, 45% and 65%, respectively.ConclusionThis meta-analysis confirms the high performance of the STOP-Bang questionnaire in the sleep clinic and surgical population for screening of OSA. The higher the STOP-Bang score, the greater is the probability of moderate-to-severe OSA.

Appearance-based trustworthiness inferences may reflect the misinterpretation of emotional expression cues. Children and adults typically perceive faces that look happy to be relatively trustworthy and those that look angry to be relatively untrustworthy. Given reports of atypical expression perception in children with Autism Spectrum Disorder (ASD), the current study aimed to determine whether the modulation of trustworthiness judgments by emotional expression cues in children with ASD is also atypical. Cognitively-able children with and without ASD, aged 6-12 years, rated the trustworthiness of faces showing happy, angry and neutral expressions. Trust judgments in children with ASD were significantly modulated by overt happy and angry expressions, like those of typically-developing children. Furthermore, subtle emotion cues in neutral faces also influenced trust ratings of the children in both groups. These findings support a powerful influence of emotion cues on perceived trustworthiness, which even extends to children with social cognitive impairments.

A large number of studies have been published examining the implications of climate change for agricultural productivity that, broadly speaking, can be divided into process-based modeling and statistical approaches. Despite a general perception that results from these methods differ substantially, there have been few direct comparisons. Here we use a data-base of yield impact studies compiled for the IPCC Fifth Assessment Report (Porter et al 2014 ) to systematically compare results from process-based and empirical studies. Controlling for differences in representation of CO _2 fertilization between the two methods, we find little evidence for differences in the yield response to warming. The magnitude of CO _2 fertilization is instead a much larger source of uncertainty. Based on this set of impact results, we find a very limited potential for on-farm adaptation to reduce yield impacts. We use the Global Trade Analysis Project (GTAP) global economic model to estimate welfare consequences of yield changes and find negligible welfare changes for warming of 1 °C–2 °C if CO _2 fertilization is included and large negative effects on welfare without CO _2 . Uncertainty bounds on welfare changes are highly asymmetric, showing substantial probability of large declines in welfare for warming of 2 °C–3 °C even including the CO _2 fertilization effect.

Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder affecting 2% to 5% of the general population. Both genetic and environmental factors may be involved. To ascertain in an unbiased manner which genes play a role in the disorder, we performed complete exome sequencing on a subset of FMS patients. Out of 150 nuclear families (trios) DNA from 19 probands was subjected to complete exome sequencing. Since >80,000 SNPs were found per proband, the data were further filtered, including analysis of those with stop codons, a rare frequency (

Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surface of APCs cultured both with and without bacteria, we undertook extensive mutational analysis of both the MAIT TCR and MR1 molecule. We found differential contribution of particular amino acids to the MAIT TCR-MR1 interaction based upon the presence of bacteria, supporting the hypothesis that the structure of the MR1 molecules with the microbial-derived ligand(s) differs from the one with the endogenous ligand(s). Furthermore, we demonstrate that microbial-derived ligand(s) is resistant to proteinase K digestion and does not extract with common lipids, suggesting an unexpected class of antigen(s) might be recognized by this unique lymphocyte population.

On 9 June 2008, the UK's largest mass stranding event (MSE) of short-beaked common dolphins (Delphinus delphis) occurred in Falmouth Bay, Cornwall. At least 26 dolphins died, and a similar number was refloated/herded back to sea. On necropsy, all dolphins were in good nutritive status with empty stomachs and no evidence of known infectious disease or acute physical injury. Auditory tissues were grossly normal (26/26) but had microscopic haemorrhages (5/5) and mild otitis media (1/5) in the freshest cases. Five lactating adult dolphins, one immature male, and one immature female tested were free of harmful algal toxins and had low chemical pollutant levels. Pathological evidence of mud/seawater inhalation (11/26), local tide cycle, and the relative lack of renal myoglobinuria (26/26) suggested MSE onset on a rising tide between 06:30 and 08∶21 hrs (9 June). Potential causes excluded or considered highly unlikely included infectious disease, gas/fat embolism, boat strike, by-catch, predator attack, foraging unusually close to shore, chemical or algal toxin exposure, abnormal weather/climatic conditions, and high-intensity acoustic inputs from seismic airgun arrays or natural sources (e.g., earthquakes). International naval exercises did occur in close proximity to the MSE with the most intense part of the exercises (including mid-frequency sonars) occurring four days before the MSE and resuming with helicopter exercises on the morning of the MSE. The MSE may therefore have been a "two-stage process" where a group of normally pelagic dolphins entered Falmouth Bay and, after 3-4 days in/around the Bay, a second acoustic/disturbance event occurred causing them to strand en masse. This spatial and temporal association with the MSE, previous associations between naval activities and cetacean MSEs, and an absence of other identifiable factors known to cause cetacean MSEs, indicates naval activity to be the most probable cause of the Falmouth Bay MSE.

cAMP-dependent protein kinase (PKA) has been implicated in the asexual stage of the Toxoplasma gondii life cycle through assaying the effect of a PKA-specific inhibitor on its growth rate. Since inhibition of the host cell PKA cannot be ruled out, a more precise evaluation of the role of PKA, as well as characterization of the kinase itself, is necessary.The inhibitory effects of two PKA inhibitors, H89, an ATP-competitive chemical inhibitor, and PKI, a substrate-competitive mammalian natural peptide inhibitor, were estimated. In the in vitro kinase assay, the inhibitory effect of PKI on a recombinant T. gondii PKA catalytic subunit (TgPKA-C) was weaker compared to that on mammalian PKA-C. In a tachyzoite growth assay, PKI had little effect on the growth of tachyzoites, whereas H89 strongly inhibited it. Moreover, T. gondii PKA regulatory subunit (TgPKA-R)-overexpressing tachyzoites showed a significant growth defect.Our data suggest that PKA plays an important role in the growth of tachyzoites, and the inhibitory effect of substrate-competitive inhibitor PKI on T. gondii PKA was low compared to that of the ATP competitive inhibitor H89.

In humans, emotions from music serve important communicative roles. Despite a growing interest in the neural basis of music perception, action and emotion, the majority of previous studies in this area have focused on the auditory aspects of music performances. Here we investigate how the brain processes the emotions elicited by audiovisual music performances. We used event-related functional magnetic resonance imaging, and in Experiment 1 we defined the areas responding to audiovisual (musician's movements with music), visual (musician's movements only), and auditory emotional (music only) displays. Subsequently a region of interest analysis was performed to examine if any of the areas detected in Experiment 1 showed greater activation for emotionally mismatching performances (combining the musician's movements with mismatching emotional sound) than for emotionally matching music performances (combining the musician's movements with matching emotional sound) as presented in Experiment 2 to the same participants. The insula and the left thalamus were found to respond consistently to visual, auditory and audiovisual emotional information and to have increased activation for emotionally mismatching displays in comparison with emotionally matching displays. In contrast, the right thalamus was found to respond to audiovisual emotional displays and to have similar activation for emotionally matching and mismatching displays. These results suggest that the insula and left thalamus have an active role in detecting emotional correspondence between auditory and visual information during music performances, whereas the right thalamus has a different role.

BACKGROUND:Fibromyalgia syndrome (FMS), a common, chronic, widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, has both genetic and environmental contributions. Patients and their parents have high plasma levels of the chemokines MCP-1 and eotaxin, providing evidence for both a genetic and an immunological/inflammatory origin for the syndrome (Zhang et al., 2008, Exp. Biol. Med. 233: 1171-1180). METHODS AND FINDINGS:In a search for a candidate gene affecting inflammatory pathways, among five screened in our patient samples (100 probands with FMS and their parents), we found 10 rare and one common alleles for MEFV, a gene in which various compound heterozygous mutations lead to Familial Mediterranean Fever (FMF). A total of 2.63 megabases of genomic sequence of the MEFV gene were scanned by direct sequencing. The collection of rare missense mutations (all heterozygotes and tested in the aggregate) had a significant elevated frequency of transmission to affecteds (p = 0.0085, one-sided, exact binomial test). Our data provide evidence that rare missense variants of the MEFV gene are, collectively, associated with risk of FMS and are present in a subset of 15% of FMS patients. This subset had, on average, high levels of plasma IL-1beta (p = 0.019) compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype. IL-1beta is a cytokine associated with the function of the MEFV gene and thought to be responsible for its symptoms of fever and muscle aches. CONCLUSIONS:Since misregulation of IL-1beta expression has been predicted for patients with mutations in the MEFV gene, we conclude that patients heterozygous for rare missense variants of this gene may be predisposed to FMS, possibly triggered by environmental factors.

The mean input and variance of the total synaptic input to a neuron can vary independently, suggesting two distinct information channels. Here we examine the impact of rapidly varying signals, delivered via these two information conduits, on the temporal dynamics of neuronal firing rate responses. We examine the responses of model neurons to step functions in either the mean or the variance of the input current. Our results show that the temporal dynamics governing response onset depends on the choice of model. Specifically, the existence of a hard threshold introduces an instantaneous component into the response onset of a leaky-integrate-and-fire model that is not present in other models studied here. Other response features, for example a decaying oscillatory approach to a new steady-state firing rate, appear to be more universal among neuronal models. The decay time constant of this approach is a power-law function of noise magnitude over a wide range of input parameters. Understanding how specific model properties underlie these response features is important for understanding how neurons will respond to rapidly varying signals, as the temporal dynamics of the response onset and response decay to new steady-state determine what range of signal frequencies a population of neurons can respond to and faithfully encode.

BackgroundThoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA.Methods and findingsWhole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set.ConclusionsThis study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA.