Evidence-based severity assessment of the forced swim test in the rat.

The forced swim test (FST) is a traditional assay, which has been used for more than 40 years to assess antidepressant effects of novel drug candidates. In recent years, a debate about the test has focused on the assumption that the FST is highly aversive and burdening for the animals because of the earlier anthropomorphic interpretation and designation as a "behavioral despair test". The Directive 2010/63/EU and the German Animal Welfare law require a prospective severity classification of the planned experimental procedures. Still, an objective examination of the animals' burden in this test has not been performed yet. To fill this gap, we conducted an evidence-based severity assessment of the forced swim test in rats according to a 'standard protocol' with a water temperature of 25°C. We examined parameters representing the physiological and the affective state, and natural as well as locomotion-associated behaviors in three separate experiments to reflect as many dimensions as possible of the animal's condition in the test. Hypothermia was the only effect observed in all animals exposed to the FST when using this standard protocol. Additional adverse effects on body weight, food consumption, and fecal corticosterone metabolite concentrations occurred in response to administration of the antidepressant imipramine, which is frequently used as positive control when testing for antidepressant effects of new substances. We conclude that this version of the FST itself is less severe for the animals than assumed, and we suggest a severity classification of 'moderate' because of the acute and short-lasting effects of hypothermia. To refine the FST according to the 3Rs, we encourage confirming the predictive validity in warmer water temperatures to allow the rats to maintain physiological body temperature.

A systematic mapping review of the evolution of the rat Forced Swim Test: Protocols and outcome parameters.

As depression is projected to become the leading mental disease burden globally by 2030, understanding the underlying pathology, as well as screening potential anti-depressants with a higher efficacy, faster onset of action, and/or fewer side-effects is essential. A commonly used test for screening novel antidepressants and studying depression-linked aspects in rodents is the Porsolt Forced Swim Test. The present systematic mappping review gives a comprehensive overview of the evolution and of the most prevalently used set-ups of this test in rats, including the choice of animals (strain, sex, and age), technical aspects of protocol and environment, as well as reported outcome measures. Additionally, we provide an accessible list of all existing publications, to support informed decision-making for procedural and technical aspects of the test, to thereby enhance reproducibility and comparability. This should further contribute to reducing the number of unnecessarily replicated experiments, and consequently, reduce the number of animals used in future.

Heat-Introduced Formation of Acrylamide in Table Olives: Analysis of Acrylamide, Free Asparagine, and 3-Aminopropionamide.

Acrylamide was detected in considerable amounts in black table olives. In this study, besides black, also green and naturally black table olives were investigated for their acrylamide, free asparagine, and 3-aminopropionamide contents before and after heat treatment. Acrylamide amount was 208-773 µg/kg in black table olives and did not change due to heat treatment. In green and naturally black table olives acrylamide was ≤24 µg/kg before heat treatment and rose to 1200 µg/kg afterward. Asparagine content was 0.35-35 mg/kg in all samples before heat treatment and after heat treatment with no considerable change in the range. 3-Aminopropionamide showed amounts of ≤56 µg/kg in the unheated samples and increased up to 131 µg/kg due to heat impact. However, quantified asparagine and 3-aminopropionamide amounts were insufficient in almost all samples to explain the acrylamide quantities formed due to heat treatment based on the formation via the Maillard reaction.

Procedure for Organizing a Post-FDA-approval Evaluation of Antidepressants.

PURPOSE: The study reports the construction of a cohort used to study the effectiveness of antidepressants. METHODS: The cohort includes experiences of 3,678,082 patients with depression in the United States on antidepressants between January 1, 2001, and December 31, 2018. A total of 10,221,145 antidepressant treatment episodes were analyzed. Patients who had no utilization of health services for at least two years, or who had died, were excluded from the analysis. Follow-up was passive, automatic, and collated from fragmented clinical services of diverse providers. RESULTS: The average follow-up was 2.93 years, resulting in 15,096,055 person-years of data. The mean age of the cohort was 46.54 years (standard deviation of 17.48) at first prescription of antidepressant, which was also the enrollment event (16.92% were over 65 years), and most were female (69.36%). In 10,221,145 episodes, within the first 100 days of start of the episode, 4,729,372 (46.3%) continued their treatment, 1,306,338 (12.8%) switched to another medication, 3,586,156 (35.1%) discontinued their medication, and 599,279 (5.9%) augmented their treatment. CONCLUSIONS: We present a procedure for constructing a cohort using claims data. A surrogate measure for self-reported symptom remission based on the patterns of use of antidepressants has been proposed to address the absence of outcomes in claims. Future studies can use the procedures described here to organize studies of the comparative effectiveness of antidepressants.

Dopamine Transporter Knockout Rats Show Impaired Wellbeing in a Multimodal Severity Assessment Approach.

In preclinical psychiatry research, animals are central to modeling and understanding biological mechanisms of behavior and psychiatric disorders. We here present the first multimodal severity assessment of a genetically modified rat strain used in psychiatric research, lacking the dopamine transporter (DAT) gene and showing endophenotypes of several dopamine-associated disorders. Absence of the DAT leads to high extracellular dopamine (DA) levels and has been associated with locomotor hyperactivity, compulsive behaviors and stereotypies in the past. The German Animal Welfare Law, which is based on the EU Directive (2010/63/EU), requires a prospective severity assessment for every animal experiment, depending on the extent of the expected degree of pain, suffering, distress or lasting harm that the animals will experience. This should consider all procedures but also the impact of the genotype on the phenotype. Therefore, we examined multiple parameters indicating animal welfare, like burrowing behavior, social interaction, saccharin preference, baseline stress hormone levels and nesting behavior. Additionally, a footprint analysis was performed and home cage activity was analyzed for a more detailed characterization of locomotion. DAT KO rats demonstrated reduced burrowing, social interaction and saccharin preference. We also found pronounced stereotypies and alterations in the gait analysis in DAT KO rats. Moreover, we confirmed the hyperactivity and the impaired sensorimotor gating mechanisms to assure that our rats are exhibiting the correct phenotype. In conclusion, we provide evidence that DAT KO rats show alterations in natural behavior patterns and deduce that the marked stereotypies are a sign for coping difficulties, both indicating a negative influence of the genotype on wellbeing. We suggest to assess further rat models in an objectified severity assessment as previously done in mice to create a relative severity assessment based on scientific evidence. Until then, we propose the classification of homozygous DAT KO rats as "moderate" in accordance with the criteria of the EU directive 2010/63.

Tolerance of biofilm of a carbapenem-resistant Klebsiella pneumoniae involved in a duodenoscopy-associated outbreak to the disinfectant used in reprocessing.

BACKGROUND: One possible transmission route for nosocomial pathogens is contaminated medical devices. Formation of biofilms can exacerbate the problem. We report on a carbapenemase-producing Klebsiella pneumoniae that had caused an outbreak linked to contaminated duodenoscopes. To determine whether increased tolerance to disinfectants may have contributed to the outbreak, we investigated the susceptibility of the outbreak strain to disinfectants commonly used for duodenoscope reprocessing. Disinfection efficacy was tested on planktonic bacteria and on biofilm. METHODS: Disinfectant efficacy testing was performed for planktonic bacteria according to EN standards 13727 and 14561 and for biofilm using the Bead Assay for Biofilms. Disinfection was defined as ≥ 5log10 reduction in recoverable colony forming units (CFU). RESULTS: The outbreak strain was an OXA-48 carbapenemase-producing K. pneumoniae of sequence type 101. We found a slightly increased tolerance of the outbreak strain in planktonic form to peracetic acid (PAA), but not to other disinfectants tested. Since PAA was the disinfectant used for duodenoscope reprocessing, we investigated the effect of PAA on biofilm of the outbreak strain. Remarkably, disinfection of biofilm of the outbreak strain could not be achieved by the standard PAA concentration used for duodenoscope reprocessing at the time of outbreak. An increased tolerance to PAA was not observed in a K. pneumoniae type strain tested in parallel. CONCLUSIONS: Biofilm of the K. pneumoniae outbreak strain was tolerant to standard disinfection during duodenoscope reprocessing. This study establishes for the first time a direct link between biofilm formation, increased tolerance to disinfectants, reprocessing failure of duodenoscopes and nosocomial transmission of carbapenem-resistant K. pneumoniae.

Expenditures in Young Adults with Hodgkin Lymphoma: NCI-Designated Comprehensive Cancer Centers versus Other Sites.

BACKGROUND: Outcomes among Hodgkin lymphoma (HL) patients diagnosed between 22 and 39 years are worse than among those diagnosed <21 years, and have not seen the same improvement over time. Treatment at an NCI-designated Comprehensive Cancer Center (CCC) mitigates outcome disparities, but may be associated with higher expenditures. METHODS: We examined cancer-related expenditures among 22- to 39-year-old HL patients diagnosed between 2001 and 2016 using deidentified administrative claims data (OptumLabs Data Warehouse; CCC: n = 1,154; non-CCC: n = 643). Adjusting for sociodemographics, clinical characteristics, and months enrolled, multivariable general linear models modeled average monthly health-plan paid (HPP) expenditures, and incidence rate ratios compared CCC/non-CCC monthly visit rates. RESULTS: In the year following diagnosis, CCC patients had higher HPP expenditures ($12,869 vs. $10,688, P = 0.001), driven by higher monthly rates of CCC nontreatment outpatient hospital visits (P = 0.001) and per-visit expenditures for outpatient hospital chemotherapy ($632 vs. $259); higher CCC inpatient expenditures ($1,813 vs. $1,091, P = 0.001) were driven by 3.1 times higher rates of chemotherapy admissions (P = 0.001). Out-of-pocket expenditures were comparable (P = 0.3). CONCLUSIONS: Young adults with HL at CCCs saw higher health-plan expenditures, but comparable out-of-pocket expenditures. Drivers of CCC expenditures included outpatient hospital utilization (monthly rates of non-therapy visits and per-visit expenditures for chemotherapy). IMPACT: Higher HPP expenditures at CCCs in the year following HL diagnosis likely reflect differences in facility structure and comprehensive care. For young adults, it is plausible to consider incentivizing CCC care to achieve superior outcomes while developing approaches to achieve long-term savings.

Effectiveness of common antidepressants: a post market release study.

BACKGROUND: This study summarizes the experiences of patients, who have multiple comorbidities, with 15 mono-treated antidepressants. METHODS: This is a retrospective, observational, matched case control study. The cohort was organized using claims data available through OptumLabs for depressed patients treated with antidepressants between January 1, 2001 and December 31, 2018. The cohort included patients from all states within United States of America. The analysis focused on 3,678,082 patients with major depression who had 10,221,145 antidepressant treatments. Using the robust, and large predictors of remission, and propensity to prescribe an antidepressant, the study created 16,770 subgroups of patients. The study reports the remission rate for the antidepressants within the subgroups. The overall impact of antidepressant on remission was calculated as the common odds ratio across the strata. FINDINGS: The study accurately modelled clinicians' prescription patterns (cross-validated Area under the Receiver Operating Curve, AROC, of 82.0%, varied from 77% to 90%) and patients' remission (cross-validated AROC of 72.0%, varied from 69.5% to 78%). In different strata, contrary to published randomized studies, remission rates differed significantly and antidepressants were not equally effective. For example, in age and gender subgroups, the best antidepressant had an average remission rate of 50.78%, 1.5 times higher than the average antidepressant (30.30% remission rate) and 20 times higher than the worst antidepressant. The Breslow-Day chi-square test for homogeneity showed that across strata a homogenous common odds-ratio did not exist (alpha<0.0001). Therefore, the choice of the optimal antidepressant depended on the strata defined by the patient's medical history. INTERPRETATION: Study findings may not be appropriate for specific patients. To help clinicians assess the transferability of study findings to specific patient, the web site http://hi.gmu.edu/ad assesses the patient's medical history, finds similar cases in our data, and recommends an antidepressant based on the experience of remission in our data. Patients can share this site's recommendations with their clinicians, who can then assess the appropriateness of the recommendations. FUNDING: This project was funded by the Robert Wood Johnson foundation grant #76786. The development of related web site was supported by grant 247-02-20 from Virginia's Commonwealth Health Research Board.

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures. METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled. RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable. CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings. LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

Health Care Cost Associated With Contemporary Chronic Myelogenous Leukemia Therapy Compared With That of Other Hematologic Malignancies.

PURPOSE: Given the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making. METHODS: A retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs. RESULTS: Mean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib's mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239). CONCLUSION: Contemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.

Impact of Dependent Coverage Provision of the Affordable Care Act on Insurance Continuity for Adolescents and Young Adults With Cancer.

PURPOSE: The 2010 Dependent Coverage Provision (DCP) of the Affordable Care Act (ACA) allowed enrollees to remain on their parents' health insurance until 26 years of age. We compared rates of insurance disenrollment among patients with cancer who were DCP-eligible at age 19 to those who were not eligible at age 19. METHODS: Using OptumLabs Data Warehouse, which contains longitudinal, real-world, de-identified administrative claims for commercial enrollees, we examined patients born between 1982 and 1993 and diagnosed with cancer between 2000 and 2015. In the recent cohort, patients who turned 19 in 2010-2012 (DCP-eligible to stay on parents' insurance) were matched to patients who turned 19 in 2007-2009 (not DCP-eligible when turning 19). In an earlier control cohort, patients who turned 19 between 2004 and 2006 (not DCP-eligible) were matched to patients who turned 19 between 2001 and 2003 (not DCP-eligible). Patients were matched on cancer type, diagnosis date, demographics, and treatment characteristics. The time to loss of coverage was estimated using Cox models. Difference-in-difference between the recent and earlier cohorts was also evaluated. RESULTS: A total of 2,829 patients who turned 19 years of age in 2010-2012 were matched to patients who turned 19 in 2007-2009. Median time to disenrollment was 26 months for younger patients versus 22 months for older patients (hazard ratio [HR], 0.85; 95% CI, 0.80 to 0.90; P = .001). In 8,978 patients who turned 19 between 2001 and 2006, median time to disenrollment was 20 months among both younger and older patients (HR, 0.99; 95% CI, 0.94 to 1.03; P = .59). The difference between the recent cohort and the earlier control cohort was a 15% greater reduction in coverage loss (P < .0001), favoring those turning 19 after the DCP went into effect. CONCLUSION: In the vulnerable population of adolescent and young adult cancer survivors, the ACA may have lowered the insurance dropout rate.

Patterns and compound specific stable carbon isotope analysis (δ13 C) of capsaicinoids in Cayenne chilli fruits of different ripening stages.

INTRODUCTION: Capsaicinoids are alkaloids of high pungency which are exclusively formed by fruits of the genus Capsicum. Capsaicinoid content and composition of Capsicum fruits are influenced by ripening. OBJECTIVE: Determination of changes in content and pattern of individual capsaicinoids in chilli pods with fruit ripening. Compound specific stable carbon isotope analysis (δ13 C values (‰), CSIA) was used for a better understanding of capsaicinoid development during fruit ripening. METHODOLOGY: Cayenne chillies (Capsicum annuum) were grown in a glasshouse and harvested from different plants at four ripening stages (unripe, semi-ripe, ripe, overripe). Nine capsaicinoids (one verified by synthesis) were quantified by gas chromatography with mass spectrometry (GC-MS). For CSIA, an acetylation method for derivatising capsaicinoids was developed. RESULTS: Variations in the patterns of the nine capsaicinoids were not relatable to a distinct ripening stage and also total contents varied extensively from plant to plant. However, changes in total capsaicinoid concentrations were systematic. In almost all plants, maximum values were reached in unripe fruits, then decreased to semi-ripe samples and increased again in the following ripening process. Likewise, δ13 C values of individual capsaicinoids were always by ~2‰ heavier in unripe than in semi-ripe or ripe fruits. However, direction of changes in sum-δ13 C values (‰) (taking contributions of all capsaicinoids together) could not be explained by corresponding variations in capsaicinoid concentrations. CONCLUSIONS: Both quantification and δ13 C values (‰) verified the presence of ripening-related changes in the capsaicinoid content which may be caused by simultaneously proceeding reactions like synthesis, storage and degradation of capsaicinoids.

Adverse events among chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors: a real-world analysis of health plan enrollees.

With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p < 0.05). Increased risk of infections, cardiopulmonary and skin issues associated with later generation TKIs persisted in subsequent years. In this real-world population, TKI therapy was associated with a high burden of adverse events. Later generation TKIs may have greater toxicity than imatinib.

Nutrition data use and needs: Findings from an online survey of global nutrition stakeholders.

BACKGROUND: There is growing global demand for country-specific information to track nutritional status and its determinants, including intervention coverage. Periodic population-based surveys form the backbone of most national nutrition information systems. However, data on the coverage of many nutrition specific and sensitive interventions remain sparse. METHODS: An online survey was administered to the international nutrition community in 2018 through relevant listservs and professional networks to characterize their use of nutrition-related indicators and data sources. Respondents were asked about their professional background, access and use of specific indicators and data sources in the previous year, and unmet data needs. Results were tabulated by respondent characteristics and χ2 tests used for statistical testing. RESULTS: Complete survey responses were received from 235 respondents, the majority from non-governmental organizations and research communities, and few from governments. Demographic Health Surveys (DHS) were the most frequently accessed country-specific data source and the Global Nutrition Report (GNR) was the most accessed consolidated data source, each accessed by approximately 75% of respondents. Respondents with a multi-country focus were more likely to have accessed DHS than those with a single-country focus (85% vs 60%, P < 0.001). Similarly, respondents with a multi-country focus were more likely to have accessed the GNR compared to those with a single-country focus (82% vs 66%, P < 0.05). The most commonly accessed indicators overall were the prevalence of exclusive breastfeeding (69%), child minimum dietary diversity (66%), under-5 stunting (65%), and under-5 wasting (65%). Reported data gaps included adult and household diet quality indicators (n = 32), nutrition-sensitive intervention coverage (n = 25), and infant and young child feeding promotion coverage (n = 11). Lack of data availability for the desired geographic level (82%) or demographic group of interest (82%) and out-of-date data (77%) were common data challenges experienced by respondents. CONCLUSIONS: The survey results highlight the continued need for high-quality, actionable nutrition data to help facilitate progress towards national and global nutrition targets.

How are countries planning for costs of nutrition data and information systems?

Background: The first Global Nutrition Report in 2014 called for a "data revolution" in nutrition, so that countries have the latest data to set priorities and monitor progress. Integral to this revolution is understanding how countries are investing in the data, systems and capacity required to support decision-making around nutrition, i.e. their nutrition data and information system (NDIS). Methods: For this reason, our team conducted a desk review of national nutrition plans for 58 Scaling Up Nutrition (SUN) countries to better understand how countries are planning for and estimating the costs of their NDIS. Results: We found that of the SUN national nutrition plans that are publicly accessible, not all are costed and less than half of these have explicit data and monitoring and evaluation (M&E) sections. Of the 19 national plans that had costed data and M&E sections, our initial estimates show costs for data systems ranged from 0.1%-12.8% of total plan costs with limited information on data system components. Conclusions: There is an imminent need for more comprehensive and strategic approaches - including the planning for and financing of - NDIS in countries.

Is Adult Second Language Acquisition Defective?

There is a large literature showing that adult L2 learners, in contrast to children, often fail to acquire native-like competence in the second language. Because of such age effects, adult L2 learning is often viewed as "fundamentally different" from child acquisition and defective in some way. However, adult L2 learners do not always do worse than child learners. Several studies (e.g., Sasaki, 1997; Dabrowska and Street, 2006; Street, 2017; Dabrowska, 2019) found considerable overlap between L1 and L2 speakers' performance on tasks tapping morphosyntactic knowledge. Crucially, these studies used grammatical comprehension tasks (e.g., picture selection) to test mastery of "functional" grammar (i.e., grammatical contrasts which correspond to a clear difference in meaning, such as the assignment of agent and patient roles in sentences with noncanonical word order and quantifier scope). In contrast, most ultimate attainment studies (e.g., Johnson and Newport, 1989; Flege et al., 1999; DeKeyser, 2000; DeKeyser et al., 2010) used a grammaticality judgment task (GST) which assessed mastery of "decorative" grammar, i.e., grammatical morphemes such as tense and agreement markers which make relatively little contribution to the meaning conveyed by a sentence. In this study, we directly compared native speakers, late immersion learners, and classroom foreign language learners on tasks assessing both aspects of grammar. As in earlier studies, we found significant differences between native speakers and both non-native groups in performance on "decorative" grammar, particularly when performance was assessed using spoken rather than written stimuli. However, the differences in performance on the "functional" grammar task were much smaller and statistically non-significant. Furthermore, even in the "decorative" grammar task, there was more overlap between native speakers and late L2 learners than reported in earlier research. We argue that this is because earlier studies underestimated the amount of variation found in native speakers.

Altered thyroid hormone levels affect the capacity for temperature-induced developmental plasticity in larvae of Rana temporaria and Xenopus laevis.

Anuran larvae show phenotypic plasticity in age and size at metamorphosis as a response to temperature variation. The capacity for temperature-induced developmental plasticity is determined by the thermal adaptation of a population. Multiple factors such as physiological responses to changing environmental conditions, however, might influence this capacity as well. In anuran larvae, thyroid hormone (TH) levels control growth and developmental rate and changes in TH status are a well-known stress response to sub-optimal environmental conditions. We investigated how chemically altered TH levels affect the capacity to exhibit temperature-induced developmental plasticity in larvae of the African clawed frog (Xenopus laevis) and the common frog (Rana temporaria). In both species, TH level influenced growth and developmental rate and modified the capacity for temperature-induced developmental plasticity. High TH levels reduced thermal sensitivity of metamorphic traits up to 57% (R. temporaria) and 36% (X. laevis). Rates of growth and development were more plastic in response to temperature in X. laevis (+30%) than in R. temporaria (+6%). Plasticity in rates of growth and development is beneficial to larvae in heterogeneous habitats as it allows a more rapid transition into the juvenile stage where rates of mortality are lower. Therefore, environmental stressors that increase endogenous TH levels and reduce temperature-dependent plasticity may increase risks and the vulnerability of anuran larvae. As TH status also influences metabolism, future studies should investigate whether reductions in physiological plasticity also increases the vulnerability of tadpoles to global change.

Long-Term Stability of Benefits of Cognitive Behavioral Therapy for Obsessive Compulsive Disorder Depends on Symptom Remission During Treatment.

Background: Cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) and may afford stable long-term improvements. It is not clear, however, how stability or symptom recurrence can be predicted at the time of termination of CBT. Method: In a 1-year follow-up intention-to-treat study with 120 OCD patients receiving individual CBT at a university outpatient unit, we investigated the predictive value of international consensus criteria for response only (Y-BOCS score reduction by at least 35%) and remission status (Y-BOCS score ≤ 12). Secondly, we applied receiver-operating characteristic (ROC) curves in order to find an optimal cut-off score to classify for deterioration and for sustained gains. Results: Response only at post-treatment increased the likelihood of deterioration at follow-up compared to remission at an odds ratio of 8.8. Moreover, ROC curves indicated that a post-treatment score of ≥ 13 differentiated optimally between patients with and without symptom deterioration at follow-up assessment. The optimal cut-off score to classify for any sustained gains (response, remission, or both) at follow-up relative to baseline was 12. Importantly, previous findings of generally high long-term symptom stability after treatment in OCD could be replicated. Conclusion: The findings highlight the clinical importance of reaching remission during CBT, and suggest that a recently published expert consensus for defining remission has high utility.

Development of the Mitochondrial Intermembrane Space Disulfide Relay Represents a Critical Step in Eukaryotic Evolution.

The mitochondrial intermembrane space evolved from the bacterial periplasm. Presumably as a consequence of their common origin, most proteins of these compartments are stabilized by structural disulfide bonds. The molecular machineries that mediate oxidative protein folding in bacteria and mitochondria, however, appear to share no common ancestry. Here we tested whether the enzymes Erv1 and Mia40 of the yeast mitochondrial disulfide relay could be functionally replaced by corresponding components of other compartments. We found that the sulfhydryl oxidase Erv1 could be replaced by the Ero1 oxidase or the protein disulfide isomerase from the endoplasmic reticulum, however at the cost of respiration deficiency. In contrast to Erv1, the mitochondrial oxidoreductase Mia40 proved to be indispensable and could not be replaced by thioredoxin-like enzymes, including the cytoplasmic reductase thioredoxin, the periplasmic dithiol oxidase DsbA, and Pdi1. From our studies we conclude that the profound inertness against glutathione, its slow oxidation kinetics and its high affinity to substrates renders Mia40 a unique and essential component of mitochondrial biogenesis. Evidently, the development of a specific mitochondrial disulfide relay system represented a crucial step in the evolution of the eukaryotic cell.

Thyroid hormone levels and temperature during development alter thermal tolerance and energetics of Xenopus laevis larvae.

Environmental variation induced by natural and anthropogenic processes including climate change may threaten species by causing environmental stress. Anuran larvae experiencing environmental stress may display altered thyroid hormone (TH) status with potential implications for physiological traits. Therefore, any capacity to adapt to environmental changes through plastic responses provides a key to determining species vulnerability to environmental variation. We investigated whether developmental temperature (T dev), altered TH levels and whether the interactive effect of both affect standard metabolic rate (SMR), body condition (BC), survival and thermal tolerance in larvae of the African clawed frog (Xenopus laevis) reared at five temperatures with experimentally altered TH levels. At metamorphosis, SMR, BC and survival were significantly affected by T dev, TH status and their interaction with the latter often intensified impacts. Larvae developing at warmer temperatures exhibited significantly higher SMRs and BC was reduced at warm T dev and high TH levels suggesting decreased ability to acclimate to variation in temperature. Accordingly, tadpoles that developed at warm temperatures had higher maximum thermal limits but more narrow thermal tolerance windows. High and low TH levels decreased and increased upper thermal limits, respectively. Thus, when experiencing both warmer temperatures and environmental stress, larvae may be less able to compensate for changes in T dev. Our results demonstrate that physiological traits in larvae of X. laevis are strongly affected by increased TH levels and warmer temperatures. Altered TH levels and increasing T dev due to global change may result in a reduced capacity for physiological plasticity. This has far reaching consequences since the energetic requirement at the onset of metamorphosis is known to determine metamorphic success and thus, is indirectly linked to individual fitness in later life stages.