Antarctic icebergs reorganize ocean circulation during Pleistocene glacials.

The dominant feature of large-scale mass transfer in the modern ocean is the Atlantic meridional overturning circulation (AMOC). The geometry and vigour of this circulation influences global climate on various timescales. Palaeoceanographic evidence suggests that during glacial periods of the past 1.5 million years the AMOC had markedly different features from today1; in the Atlantic basin, deep waters of Southern Ocean origin increased in volume while above them the core of the North Atlantic Deep Water (NADW) shoaled2. An absence of evidence on the origin of this phenomenon means that the sequence of events leading to global glacial conditions remains unclear. Here we present multi-proxy evidence showing that northward shifts in Antarctic iceberg melt in the Indian-Atlantic Southern Ocean (0-50° E) systematically preceded deep-water mass reorganizations by one to two thousand years during Pleistocene-era glaciations. With the aid of iceberg-trajectory model experiments, we demonstrate that such a shift in iceberg trajectories during glacial periods can result in a considerable redistribution of freshwater in the Southern Ocean. We suggest that this, in concert with increased sea-ice cover, enabled positive buoyancy anomalies to 'escape' into the upper limb of the AMOC, providing a teleconnection between surface Southern Ocean conditions and the formation of NADW. The magnitude and pacing of this mechanism evolved substantially across the mid-Pleistocene transition, and the coeval increase in magnitude of the 'southern escape' and deep circulation perturbations implicate this mechanism as a key feedback in the transition to the '100-kyr world', in which glacial-interglacial cycles occur at roughly 100,000-year periods.

Use of electronic health data to identify patients with moderate-to-severe osteoarthritis of the hip and/or knee and inadequate response to pain medications.

BACKGROUND: No algorithms exist to identify important osteoarthritis (OA) patient subgroups (i.e., moderate-to-severe disease, inadequate response to pain treatments) in electronic healthcare data, possibly due to the complexity in defining these characteristics as well as the lack of relevant measures in these data sources. We developed and validated algorithms intended for use with claims and/or electronic medical records (EMR) to identify these patient subgroups. METHODS: We obtained claims, EMR, and chart data from two integrated delivery networks. Chart data were used to identify the presence or absence of the three relevant OA-related characteristics (OA of the hip and/or knee, moderate-to-severe disease, inadequate/intolerable response to at least two pain-related medications); the resulting classification served as the benchmark for algorithm validation. We developed two sets of case-identification algorithms: one based on a literature review and clinical input (predefined algorithms), and another using machine learning (ML) methods (logistic regression, classification and regression tree, random forest). Patient classifications based on these algorithms were compared and validated against the chart data. RESULTS: We sampled and analyzed 571 adult patients, of whom 519 had OA of hip and/or knee, 489 had moderate-to-severe OA, and 431 had inadequate response to at least two pain medications. Individual predefined algorithms had high positive predictive values (all PPVs ≥ 0.83) for identifying each of these OA characteristics, but low negative predictive values (all NPVs between 0.16-0.54) and sometimes low sensitivity; their sensitivity and specificity for identifying patients with all three characteristics was 0.95 and 0.26, respectively (NPV 0.65, PPV 0.78, accuracy 0.77). ML-derived algorithms performed better in identifying this patient subgroup (range: sensitivity 0.77-0.86, specificity 0.66-0.75, PPV 0.88-0.92, NPV 0.47-0.62, accuracy 0.75-0.83). CONCLUSIONS: Predefined algorithms adequately identified OA characteristics of interest, but more sophisticated ML-based methods better differentiated between levels of disease severity and identified patients with inadequate response to analgesics. The ML methods performed well, yielding high PPV, NPV, sensitivity, specificity, and accuracy using either claims or EMR data. Use of these algorithms may expand the ability of real-world data to address questions of interest in this underserved patient population.

Moms in the NICU: developing a pilot to engage and empower women who have delivered a prematurely born infant.

BACKGROUND: Mothers spend long hours at their preterm infant's bedside in the Neonatal Intensive Care Unit (NICU), giving clinicians the opportunity to engage mothers in caring for their own health. OBJECTIVE: To develop a NICU based intervention to reduce the risk of a future premature birth by engaging and empowering mothers to improve their own health and identify barriers to implementing their improvement. DESIGN: Development based on a framework of narrative discourse refined by the Quality Improvement Plan Do Study Act Approach. SETTING: Level II Stepdown Neonatal Intensive Care Unit. PARTICIPANTS: 14 mothers of preterm infants, ages 24-39 years. METHODS: A team of Maternal Fetal Medicine Physicians, obstetricians, neonatologists, neonatal nurses, and parents developed guidelines to elicit the mother's birth story, review the story with a clinical expert to fill in knowledge gaps, identify strategies to improve health to reduce the risk of future preterm birth, and facilitate mother developing an action plan with specific six week goals. A phone interview was designed to assess success and identify barriers to implementing their health plan. The protocol was modified as needed after each intervention to improve the interventions. RESULTS: "Moms in the NICU" toolkit is effective to guide any clinical facilitator to engage, identify health improvement strategies, and co-develop an individualized health plan and its take home summary reached stability after the 5th mother. Mothers reported experiencing reassurance, understanding, and in some cases, relief. Participants were enthusiastic to inform future quality improvement activities by sharing the six week barriers faced implementing their health plan. CONCLUSION: Engaging in the NICU provides an opportunity to improve mothers' understanding of potential factors that may be linked to preterm birth, and promote personally selected actions to improve their health and reduce the risk of a future preterm birth.

The Effects of Transcranial Direct Current Stimulation and Exercise on Salivary S100B Protein Indicated Blood-Brain Barrier Permeability: A Pilot Study.

OBJECTIVE: This study aimed to assess the effect of transcranial direct current stimulation (tDCS) and exercise on blood-brain barrier (BBB) permeability in humans as assessed through the quantification of the salivary protein biomarker S100B. It was hypothesized that active tDCS would induce a significant increase in salivary S100B concentration when compared with sham stimulation and no stimulation. It also was hypothesized that the increase in salivary S100B concentration would be greater after active tDCS and exercise than after tDCS or exercise alone. MATERIALS AND METHODS: A total of 13 healthy adults (five male, eight female), ranging in age from 21 to 32 years, underwent three experimental conditions (active tDCS, sham tDCS, inactive control). To assess exercise- and tDCS-induced changes in BBB permeability, S100B in saliva was measured. Saliva samples were taken before tDCS, after tDCS, and immediately after a ramped cycling time-to-exhaustion (TTE) task. Active tDCS involved the application of anodal stimulation over the primary motor cortex for 20 minutes at 2 mA. RESULTS: S100B concentrations in the control condition did not differ significantly from the active condition (estimate = 0.10, SE = 0.36, t = 0.27, p = 0.79) or the sham condition (estimate = 0.33, SE = 0.36, t = 0.89, p = 0.38). Similarly, S100B concentrations at baseline did not differ significantly from post-intervention (estimate = -0.35, SE = 0.34, t = -1.03, p = 0.31) or post-TTE (estimate = 0.66, SE = 0.34, t = 1.93, p = 0.06). CONCLUSIONS: This research provides novel insight into the effect of tDCS and exercise on S100B-indicated BBB permeability in humans. Although the effects of tDCS were not significant, increases in salivary S100B after a fatiguing cycling task may indicate exercise-induced changes in BBB permeability.

Drivers and Cascading Ecological Consequences of Gambusia affinis Trait Variation.

AbstractPhenotypic trait differences among populations can shape ecological outcomes for communities and ecosystems. However, few studies have mechanistically linked heritable and plastic components of trait variation to generalizable processes of ecology, such as trophic cascades. Here, we assess morphological and behavioral trait variation in nine populations of common garden-reared western mosquitofish (Gambusia affinis) from three distinct ancestral predator environments (three populations per environment), each reared in the presence and absence of predator cues. We then use a pond mesocosm experiment to examine the ecological consequences of mosquitofish trait variation and density variation. Our results show significant among-population trait variation, but this variation was generally unrelated to ancestral predator environment. When traits did vary congruently with respect to ancestral predator environment, this trait variation was driven by gene-by-environment interactions. Variation in several mosquitofish traits altered the cascading effects of mosquitofish on zooplankton and primary producers, but the effect of any given trait was typically weaker than that of density. We note that the relatively stronger ecological effects of density may mask the effects of traits in some systems. Our example here shows that trait variation can be highly noncongruent with respect to a perceived selective agent, phenotypic change is a product of complex interactions between genes and the environment, and numerous interacting phenotypes generate significant but potentially cryptic cascading ecological change.

The legacy of predator threat shapes prey foraging behaviour.

Predators exert strong selection on prey foraging behaviour such that prey responses may reflect a combination of ancestral effects of predators (genetic and nongenetic transgenerational effects), past individual experience with predators (phenotypic plasticity), and current exposure to predators (behavioural response). However, the importance of these factors in shaping prey foraging behaviour is not well understood. To test the relative effects of ancestry, prior experience, and current exposure, we measured foraging rates and food size preference of different ancestry and exposure groups of Western mosquitofish in the presence and absence of immediate threat from predatory largemouth bass. Our results confirm that mosquitofish had lower foraging rate in the immediate presence of predator threat. Mosquitofish also foraged at a lower rate if they had ancestry with predators, regardless of immediate threat. In contrast, individual prior experience with predators only caused reduced foraging rates in the immediate presence of a predator. This suggests that phenotypic plasticity could carry a lower risk of maladaptive antipredator responses-i.e., reduced food intake-in the complete absence of a predator. Finally, in the presence of a predator, mosquitofish with both ancestry and experience with predators consumed larger, presumably more energetically valuable, food items. Overall, our results show that non-consumptive effects of predators on prey behaviour can persist within and across generations, such that the legacy of past predator exposure-or "the ghost of predation past"-may continue to shape prey behaviour even when predators are no longer around.

Concern about addiction is associated with lower quality of life in patients with osteoarthritis: an exploratory, real-world data analysis.

PURPOSE: To evaluate the relationship between self-reported concerns about becoming addicted to a medication and health-related quality of life (HRQoL) in patients with osteoarthritis (OA). METHODS: This real-world study used patient-level cross-sectional survey data collected from the US Adelphi Disease Specific Programme (DSP). The DSP for OA selected 153 physicians who collected de-identified data on their next nine adult patients with OA. Each patient completed a disease-relevant survey, which included the Likert-scale question, "I am concerned about becoming addicted to my medicine," (CAA) with responses ranging from "completely disagree" [1] to "completely agree" [5]. HRQoL was measured by the EQ-5D-5L index value and the EQ Visual Analogue Scale (VAS). A set of ordinary least squares regressions using HRQoL measures as outcomes and CAA as a continuous predictor were estimated. Standardized effect size (ES) was used to gauge the magnitude of effects. RESULTS: A total of 866 patients with OA completed the survey (female, 61.2%; White, 77.7%; mean age, 64.2 years). Of the 775 patients who completed the CAA question, almost one-third responded that they "agree" (18%) or "completely agree" (11%), while 27% responded "completely disagree" and 20% "disagree." Regression analyses found that patients who have concerns about medication addiction have significantly different EQ-5D-5L index values and EQ VAS scores compared with patients who do not have this concern (p < 0.0001). CONCLUSION: Our findings suggest that concern about medication addiction in patients with OA may have an impact on patient HRQoL, with more concerned patients reporting poorer HRQoL outcomes.

Factors associated with physician-reported treatment status of patients with osteoarthritis pain.

BACKGROUND: Osteoarthritis (OA) is typically associated with pain, but many patients are not treated. METHODS: This point in time study explored factors associated with treatment status, using logistic regression of data from the Adelphi OA Disease Specific Programme conducted in the United States. Patients' treatment status was based on physician-reported, current: 1) prescription medication for OA vs. none; and 2) physician treatment (prescription medication and/or recommendation for specified nonpharmacologic treatment for OA [physical or occupational therapy, acupuncture, transcutaneous electrical nerve stimulation, or cognitive behavior therapy/psychotherapy]) vs. self-management (no prescription medication or specified nonpharmacologic treatment). RESULTS: The 841 patients (including 57.0% knee OA, 31.9% hip OA) reported mild (45.4%) or moderate or severe (54.6%) average pain intensity over the last week. The majority were prescribed medication and/or recommended specified nonpharmacologic treatment; 218 were not prescription-medicated and 122 were self-managed. Bivariate analyses showed less severe patient-reported pain intensity and physician-rated OA severity, fewer joints affected by OA, lower proportion of joints affected by knee OA, better health status, lower body mass index, and lower ratings for cardiovascular and gastrointestinal risks, for those not prescribed medication (vs. prescription-medicated). Multivariate analyses confirmed factors significantly (p < 0.05) associated with prescription medication included (odds ratio): physician-rated current moderate OA severity (vs. mild, 2.03), patient-reported moderate OA severity 6 months ago (vs. mild, 1.71), knee OA (vs. not, 1.81), physician-recommended (0.28) and patient-reported (0.43) over-the-counter medication use (vs. not), prior surgery for OA (vs. not, 0.37); uncertain income was also significant. Factors significantly (p < 0.05) associated with physician treatment included (odds ratio): physician-recommended nonpharmacologic therapy requiring no/minimal medical supervision (vs. not, 2.21), physician-rated current moderate OA severity (vs. mild, 2.04), patient-reported over-the-counter medication use (vs. not, 0.26); uncertain time since diagnosis was also significant. Patient-reported pain intensity and most demographic factors were not significant in either model. CONCLUSIONS: Approximately 1 in 4 patients were not prescribed medication and 1 in 7 were self-managed, although many were using over-the-counter medications or nonpharmacologic therapies requiring no/minimal medical supervision. Multiple factors were significantly associated with treatment status, including OA severity and over-the-counter medication, but not pain intensity or most demographics.

Comparison of two topical treatments of gastro-oesophageal regurgitation in dogs during general anaesthesia.

OBJECTIVE: To determine whether suction, lavage and instillation of sodium bicarbonate, following a gastro-oesophageal regurgitation event under general anaesthesia, would alter oesophageal pH to a greater degree than when lavage was not used. STUDY DESIGN: Prospective, randomised, clinical study. ANIMALS: A group of 22 client-owned dogs. METHODS: Dogs presenting with gastro-oesophageal regurgitation (GOReg) under general anaesthesia were randomised into groups: no lavage (G1) or lavage (G2). All dogs underwent oesophageal suctioning until no further regurgitant material was retrieved. Dogs in G2 had oesophageal lavage with tap water until the suctioned water was clear. All dogs then had 4.2% sodium bicarbonate (0.6 mL kg-1) instilled into the oesophagus. An oesophageal pH probe was placed to record pH immediately after: GOReg (T1), suctioning (T2), lavage of the oesophagus (T3; G2 only) and sodium bicarbonate instillation (T4). Categorical data were analysed using Fisher's exact test, and continuous data were analysed using either the two-sample t-test or the Wilcoxon rank-sum test. Parametric data are reported as mean ± standard deviation and non-parametric data as median (interquartile range). A p value < 0.05 was considered significant. RESULTS: Oesophageal pH was low in both groups immediately after GOReg [G1: 2.95 (2.20-4.18), G2: 3.29 (1.41-4.03)] but oesophageal pH was not significantly different between groups at T1, T2 and T4. Oesophageal lavage significantly increased pH but the overall change in pH following bicarbonate administration (T2-T4) was not significantly different between groups [G1: 3.16 ± 1.52, G2: 3.52 ± 1.47]. No adverse events following GOReg were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: Both groups had similar and clinically important increases in oesophageal pH. Although oesophageal lavage increased pH, this did not affect the final oesophageal pH when sodium bicarbonate was instilled and therefore may be an unnecessary step.

Eco-evolutionary feedbacks link prey adaptation to predator performance.

Eco-evolutionary feedbacks may determine the outcome of predator-prey interactions in nature, but little work has been done to quantify the feedback effect of short-term prey adaptation on predator performance. We tested the effects of prey availability and recent (less than 100 years) prey adaptation on the feeding and growth rate of largemouth bass (Micropterus salmoides), foraging on western mosquitofish (Gambusia affinis). Field surveys showed higher densities and larger average body sizes of mosquitofish in recently introduced populations without bass. Over a six-week mesocosm experiment, bass were presented with either a high or low availability of mosquitofish prey from recently established populations either naive or experienced with bass. Naive mosquitofish were larger, less cryptic and more vulnerable to bass predation compared to their experienced counterparts. Bass consumed more naive prey, grew more quickly with naive prey, and grew more quickly per unit biomass of naive prey consumed. The effect of mosquitofish history with the bass on bass growth was similar in magnitude to the effect of mosquitofish availability. In showing that recently derived predation-related prey phenotypes strongly affect predator performance, this study supports the presence of reciprocal predator-prey trait feedbacks in nature.

Side Streets and U-Turns: Effects of Context Switching, Direction Switching, and Factor Switching on Interitem Correlations and Misresponse Rates.

This study tested implications of the context switching perspective proposed by Hamby, Ickes, and Babcock ( 2016 ). Using trained raters to assess the amount of reframing required to interpret the meaning of the subsequent (second) item within all adjacent item pairs, we first established that this process variable could be measured reliably. Then, in the data for 18 personality measures drawn from 3 individual-difference domains, we found that the amount of reframing (i.e., context switching) needed to interpret successive items predicted both lower interitem correlations and a greater percentage of misresponders. Similarly, item pairs that were mismatched in "directional" wording also predicted both lower interitem correlations and more misresponders. Finally, item pairs representing different factors predicted lower interitem correlations. Although the effects of direction switching and factor switching were partially mediated by the amount of reframing required, they remained significant even when the mediating effect of reframing was statistically controlled. These results indicate that interpreting the meaning of test items is a task for which the level of difficulty can vary with each successive item, as a function of how the current item compares to the previous item in aspects such as its context generality or specificity, directional wording, and content domain.

Clozapine is associated with secondary antibody deficiency.

BACKGROUND: Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood.AimsTo investigate the potential association between clozapine and antibody deficiency. METHODS: Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured. RESULTS: Immunoglobulins were all significantly reduced in the clozapine-treated group (n = 123) compared with the clozapine-naive group (n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31-27.44); IgA, OR = 16.75 (95% CI 2.18-128.60); and IgM, OR = 3.26 (95% CI 1.75-6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% (n = 5) versus 1% (n = 1). CONCLUSIONS: Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.Declaration of interestS.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.

A Cenozoic record of the equatorial Pacific carbonate compensation depth.

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

Effect of benzodiazepines on the dose of alfaxalone needed for endotracheal intubation in healthy dogs.

OBJECTIVE: To evaluate the dose-sparing effect of midazolam or diazepam on the dose of alfaxalone required to achieve endotracheal intubation in premedicated dogs. STUDY DESIGN: Prospective, randomized, 'blinded', controlled clinical trial. ANIMALS: Ninety healthy dogs anaesthetized for elective surgery or diagnostic procedures. METHODS: Saline (0.1 mL kg-1), or midazolam or diazepam (0.2, 0.3, 0.4 or 0.5 mg kg-1) intravenously (IV) was randomly assigned; investigators were unaware of group designation. After premedication with IV acepromazine 0.01 mg kg-1 and methadone 0.2 mg kg-1, the degree of sedation was assessed. Alfaxalone (0.5 mg kg-1) was administered IV, followed by the assigned treatment. Further alfaxalone was administered until endotracheal intubation could be performed. Ease of endotracheal intubation, pulse rate and arterial blood pressure were assessed. General linear models were used to examine the effect of treatment drug and dose on induction dose of alfaxalone with Tukey's post hoc tests. Incidence of adverse reactions was assessed with chi-square tests. RESULTS: There were no significant differences between groups with regard to demographic data or sedation. Median (range) induction dose of alfaxalone in the saline group was 0.74 (0.43-1.26) mg kg-1 compared with 0.5 (0.46-0.75) mg kg-1 and 0.5 (0.42-1.2) mg kg-1 for the midazolam and diazepam groups, respectively. Midazolam 0.3 and 0.5 mg kg-1 (p = 0.005 and 0.044, respectively) and diazepam 0.4 mg kg-1 (p = 0.032) reduced the alfaxalone dose compared with saline. Adverse effects were not significantly different between groups. Midazolam 0.2, 0.3, 0.4 and 0.5 mg kg-1 (p < 0.044, p = 0.001, p = 0.007, p = 0.044, respectively) and diazepam 0.2 and 0.5 mg kg-1 (p = 0.025 and p = 0.025) improved intubation score compared with saline. CONCLUSION AND CLINICAL RELEVANCE: Midazolam 0.3 and 0.5 mg kg-1 and diazepam 0.4 mg kg-1 coadministered at anaesthetic induction allow alfaxalone dose reduction in healthy dogs. Use of benzodiazepines improved the ease of endotracheal intubation.

Clinical Characteristics and Treatment Patterns Among Patients Diagnosed With Cluster Headache in U.S. Healthcare Claims Data.

OBJECTIVE: To characterize demographics, clinical characteristics, and treatment patterns of patients with cluster headache (CH). BACKGROUND: CH is an uncommon trigeminal autonomic cephalalgia with limited evidence-based treatment options. Patients suffer from extremely painful unilateral headache attacks and autonomic symptoms with episodic and chronic cycles. DESIGN/METHODS: This retrospective analysis used insurance claims from Truven Health Analytics MarketScan® research databases from 2009 to 2014. Two cohorts were compared: CH patients (with ≥2 CH claims) were propensity score matched with 4 non-headache controls, all with continuous enrollment for 12 months before and after the date of first CH claim or matched period among controls. RESULTS: CH patients (N = 7589) were mainly male (57.4%) and 35-64 years old (73.2%), with significantly more claims for comorbid conditions vs controls (N = 30,341), including depressive disorders (19.8% vs 10.0%), sleep disturbances (19.7% vs 9.1%), anxiety disorders (19.2% vs 8.7%), and tobacco use disorders (12.8% vs 5.3%), with 2.5 times greater odds of suicidal ideation (all P < .0001). Odds of drug dependence were 3-fold greater among CH patients (OR = 2.8 [95% CI 2.3-3.4, P < .0001]). CH patients reported significantly greater use of prescription medications compared with controls; 25% of CH patients had >12 unique prescription drug claims. Most commonly prescribed drug classes for CH patients included: opiate agonists (41%), corticosteroids (34%), 5HT-1 agonists (32%), antidepressants (31%), NSAIDs (29%), anticonvulsants (28%), calcium antagonists (27%), and benzodiazepines (22%). Only 30.4% of CH patients received recognized CH treatments without opioids during the 12-month post-index period. These patients were less likely to visit emergency departments or need hospitalizations (26.8%) as compared to CH patients with no pharmacy claims for recognized CH treatments or opioids (33.6%; P < .0001). CONCLUSIONS: The burden of CH is associated with significant co-morbidity, including substance use disorders and suicidal ideation, and treatment patterns indicating low use of recognized CH treatments.

The importance of unresolved fatigue in depression: costs and comorbidities.

OBJECTIVE: To assess the cost outcomes of patients with a history of depression and clinically significant fatigue. METHODS: Adults with ≥ 2 claims with depression diagnosis codes identified from the HealthCore Integrated Research Database were invited to participate in this study linking survey data with retrospective claims data (12-mo presurvey and postsurvey periods). Patient surveys included measures for depression (Quick Inventory of Depressive Symptomatology), fatigue (Fatigue Associated with Depression Questionnaire), anxiety (7-item Generalized Anxiety Disorder scale), sleep difficulty (Athens Insomnia Scale), and pain (Brief Pain Inventory). After adjusting for demographic and clinical characteristics using propensity scores, postsurvey costs were compared between patients with and without fatigue using nonparametric bootstrapping methods. RESULTS: Of the 1982 patients who had completed the survey and had complete claims data, 653 patients had significant levels of fatigue. Patients with fatigue reported significantly higher scores, indicating greater severity, on measures of depression, pain, sleep difficulty, and anxiety (all p < 0.05). These patients also had higher levels of overall medication use and were more likely to have lower measures of socioeconomic status than patients without significant levels of fatigue (all p < 0.05). Mean annual total costs were greater for patients with fatigue than those without fatigue ($14,462 vs $9971, respectively, p < 0.001). These cost differences remained statistically significant after adjusting for clinical and demographic differences. CONCLUSIONS: Clinically significant fatigue appears to add to the economic burden of depression. This reinforces the need for aggressive treatment of all symptoms and further examination of the variability of this relationship as patients approach remission.

Dominant eukaryotic export production during ocean anoxic events reflects the importance of recycled NH4+.

The Mesozoic is marked by several widespread occurrences of intense organic matter burial. Sediments from the largest of these events, the Cenomanian-Turonian Oceanic Anoxic Event (OAE 2) are characterized by lower nitrogen isotope ratios than are seen in modern marine settings. It has remained a challenge to describe a nitrogen cycle that could achieve such isotopic depletion. Here we use nitrogen-isotope ratios of porphyrins to show that eukaryotes contributed the quantitative majority of export production throughout OAE 2, whereas cyanobacteria contributed on average approximately 20%. Such data require that any explanation for the OAE nitrogen cycle and its isotopic values be consistent with a eukaryote-dominated ecosystem. Our results agree with models that suggest the OAEs were high-productivity events, supported by vigorous upwelling. Upwelling of anoxic deep waters would have supplied reduced N species (i.e., NH(4)(+)) to primary producers. We propose that new production during OAE 2 primarily was driven by direct NH(4)(+)-assimilation supplemented by diazotrophy, whereas chemocline denitrification and anammox quantitatively consumed NO(3)(−) and NO(2)(−). A marine nitrogen reservoir dominated by NH(4)(+), in combination with known kinetic isotope effects, could lead to eukaryotic biomass depleted in (15)N.

Physical activity and health in adolescence.

Adolescence represents a critical period of development during which personal lifestyle choices and behaviour patterns establish, including the choice to be physically active. Physical inactivity, sedentary behaviour and low cardiorespiratory fitness are strong risk factors for the development of chronic diseases with resulting morbidity and mortality, as well as economic burden to wider society from health and social care provision, and reduced occupational productivity. Worrying trends in adverse physical activity behaviours necessitate urgent and concerted action. Healthcare professionals caring for adolescents and young adults are ideally placed and suited to deliver powerful messages promoting physical activity and behaviour change. Every encounter represents an opportunity to ask about physical activity, provide advice, or signpost to appropriate pathways or opportunities. Key initial targets include getting everyone to reduce their sedentary behaviour and be more active, with even a little being more beneficial than none at all.

The effects of diazepam or midazolam on the dose of propofol required to induce anaesthesia in cats.

OBJECTIVES: Assess effects of benzodiazepine administration on the propofol dose required to induce anaesthesia in healthy cats, investigate differences between midazolam and diazepam, and determine an optimal benzodiazepine dose for co-induction. STUDY DESIGN: Prospective, randomised, blinded, placebo-controlled clinical trial. ANIMALS: Ninety client-owned cats (ASA I and II) with a median (interquartile range) body mass of 4.0 (3.4-4.9) kg. METHODS: All cats received 0.01 mg kg(-1) acepromazine and 0.2 mg kg(-1) methadone intravenously (IV). Fifteen minutes later, sedation was scored on a scale of 1-5, with 5 indicating greatest sedation. Propofol, 2 mg kg(-1) , administered IV, was followed by either midazolam or diazepam at 0.2, 0.3, 0.4 or 0.5 mg kg(-1) or saline 0.1 mL kg(-1) . Further propofol was administered until endotracheal intubation was possible. Patient signalment, sedation score, propofol dosage and adverse reactions were recorded. RESULTS: Midazolam and diazepam (all doses) significantly reduced the propofol dose required compared with saline (p < 0.001). There was no difference between midazolam and diazepam in propofol dose reduction (p = 0.488). All individual doses of midazolam reduced propofol requirement compared with saline (0.2 mg kg(-1) , p = 0.028; 0.3 mg kg(-1) , p = 0.006; 0.4 mg kg(-1) , p < 0.001; 0.5 mg kg(-1) , p = 0.009). Diazepam 0.2 mg kg(-1) did not reduce the propofol dose compared with saline (p = 0.087), but the remaining doses did (0.3 mg kg(-1) , p = 0.001; 0.4 mg kg(-1) , p = 0.032; 0.5 mg kg(-1) , p = 0.041). Cats with sedation scores of 3 required less propofol than cats with scores of 2 (p = 0.008). There was no difference between groups in adverse events. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam (0.2-0.5 mg kg(-1) ) and diazepam (0.3-0.5 mg kg(-1) ) administered IV after 2 mg kg(-1) propofol significantly reduced the propofol dose required for tracheal intubation.

Predictors of outcome in dogs undergoing thoracic surgery (2002-2011).

OBJECTIVE: To evaluate mortality in a canine population undergoing thoracic surgery and identify factors which may be associated with outcome. STUDY DESIGN: Retrospective cohort study. ANIMALS: 286 dogs anaesthetized for thoracic surgery at the Royal Veterinary College between June 2002 - June 2011. METHODS: Variables examined included: signalment; ASA status; nature of disease; presence of co-morbidities; pre-anaesthetic oxygen requirement; surgical approach; anaesthesia management [anaesthetic agents; requirement for thoracocentesis; central venous pressure measurement; duration of surgery and anaesthesia; use of colloids, blood products, inotropes or neuromuscular blocking agents (NMBA)]. Outcome was defined as either non-survival to 24 hours after surgery or (having survived to 24 hours) to discharge. Univariate and multivariable logistic regressions were performed to identify risk factors associated with non-survival. RESULTS: Overall non-survival (excluding those euthanased) to discharge was 5.9%. Non-survival was 2.2% at 24 hours and 3.6% at time of discharge. Non-survival to 24 hours was associated with pre-anaesthetic oxygen requirement (odds ratio (OR) 12.2 [95% CI 1.8-84.5]) and NMBA use (OR 9.6 [95% CI 1.6-57.9]). Non-survival to discharge was associated with surgical duration, with surgeries >180 minutes having OR 16.9 [95% CI 2.0-144.0] compared to surgeries ≤90 minutes and blood product use (OR 4.6 [95% CI 1.3-14.6]). No association was found between ASA category and non-survival at 24 hours (OR 1.4 [95% CI 0.2-11.7]) or discharge (OR 4.4 [95% CI 0.6-34.3]). Significant associations were found between NMBA use and ASA category (p = 0.046), surgical duration (p = 0.002), use of colloids (p = 0.011), blood products (p = 0.001) and inotropes and/or vasopressors (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Variables significantly associated with non-survival from canine thoracic surgery at 24 hours include NMBA use and pre-anaesthetic oxygen requirement. Blood product use and increasing surgical duration were associated with non-survival to hospital discharge. The associations may relate to the need for such products in the most complicated cases.