Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial.

Importance: Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment. Objective: To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia. Design, Setting, and Participants: This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. Interventions: In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio. Main Outcomes and Measures: The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events. Results: A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo. Conclusions and Relevance: In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03548584.

A case of bilateral pneumothorax following computer-tomography guided transthoracic biopsy in a woman with suspected pulmonary cancer.

Computer-tomography-guided needle biopsies are useful for diagnosing, staging, and classification of peripheral pulmonary nodules. However, the procedure carries a risk of iatrogenic pneumothorax. This report describes a patient-case where a woman had undergone a computer-tomography guided biopsy. Approximately 4 hours following discharge the patient was admitted to the emergency ward with severe chest pain and dyspnea. Chest x-ray revealed bilateral pneumothorax and subcutaneous emphysema at the biopsy site. Pleural drainage was administered on the patient's right side. Another chest x-ray following drainage showed regression of pneumothorax on both sides thus indicating communicating pleural cavities. Medical history revealed that the patient had been thymectomized 2 years earlier and a computer tomography visualized that the patient lacked mediastinal separation of the two pleural cavities. It is possible that patients with a history of mediastinal or thoracic surgery should be observed longer following procedures carrying risk of iatrogenic pneumothorax.

Higher sensitivity of gross primary productivity than ecosystem respiration to experimental drought and warming across six European shrubland ecosystems.

Shrubland ecosystems across Europe face a range of threats including the potential impacts of climate change. Within the INCREASE project, six shrubland ecosystems along a European climatic gradient were exposed to ecosystem-level year-round experimental nighttime warming and long-term, repeated growing season droughts. We quantified the ecosystem level CO2 fluxes, i.e. gross primary productivity (GPP), ecosystem respiration (Reco) and net ecosystem exchange (NEE), in control and treatment plots and compared the treatment effects along the Gaussen aridity index. In general, GPP exhibited higher sensitivity to drought and warming than Reco and was found to be the dominant contributor to changes in overall NEE. Across the climate gradient, northern sites were more likely to have neutral to positive responses of NEE, i.e. increased CO2 uptake, to drought and warming partly due to seasonal rewetting. While an earlier investigation across the same sites showed a good cross-site relationship between soil respiration responses to climate over the Gaussen aridity index, the responses of GPP, Reco and NEE showed a more complex response pattern suggesting that site-specific ecosystem traits, such as different growing season periods and plant species composition, affected the overall response pattern of the ecosystem-level CO2 fluxes. We found that the observed response patterns of GPP and Reco rates at the six sites could be explained well by the hypothesized position of each site on site-specific soil moisture response curves of GPP/Reco fluxes. Such relatively simple, site-specific analyses could help improve our ability to explain observed CO2 flux patterns in larger meta-analyses as well as in larger-scale model upscaling exercises and thereby help improve our ability to project changes in ecosystem CO2 fluxes in response to future climate change.

Effects of adjunctive brexpiprazole on patient life engagement in major depressive disorder: Post hoc analysis of Inventory of Depressive Symptomatology Self-Report data.

BACKGROUND: Patient-reported outcomes can capture domains that are meaningful to patients, such as life engagement in major depressive disorder (MDD), which reflects life fulfillment, well-being, and participation in valued and meaningful activities. This analysis investigated the effects of brexpiprazole adjunct to antidepressant treatment (ADT) on patient life engagement over the short and long term, using the 10-item Inventory of Depressive Symptomatology Self-Report (IDS-SR10) Life Engagement subscale. METHODS: Short-term data were pooled from three 6-week, randomized, double-blind studies of ADT + brexpiprazole 2-3 mg/day versus ADT + placebo in adult outpatients with MDD (DSM-IV-TR criteria) and inadequate response to ADTs. Long-term data were from a 26-52-week, open-label extension study of ADT + brexpiprazole 0.5-3 mg/day. RESULTS: Over 6 weeks, ADT + brexpiprazole (n = 579) showed greater improvement in IDS-SR10 Life Engagement subscale score than ADT + placebo (n = 583), with a least squares mean difference of -1.19 (95% confidence limits: -1.78, -0.59; p = 0.0001; Cohen's d effect size: 0.23). Greater improvement for ADT + brexpiprazole versus ADT + placebo (p < 0.05) was also observed on eight life engagement items, with effect sizes ranging from 0.12 to 0.24. In the long-term study, mean (standard deviation) IDS-SR10 Life Engagement subscale score changed by -2.4 (4.9) points to Week 26 (n = 2047), and -3.7 (5.3) points to Week 52 (n = 768), with mean improvements on all ten items. CONCLUSIONS: Beyond its efficacy on depressive symptoms, adjunctive brexpiprazole may improve patient life engagement, thereby helping patients with MDD to achieve personally meaningful functional outcomes.

Long-term temporal patterns in ecosystem carbon flux components and overall balance in a heathland ecosystem.

Terrestrial ecosystems have strong feedback to atmospheric CO2 concentration and climate change. However, the long-term whole life cycle dynamics of ecosystem carbon (C) fluxes and overall balance in some ecosystem types, such as heathland ecosystems, have not been thoroughly explored. We studied the changes in ecosystem CO2 flux components and overall C balance over a full ecosystem lifecycle in stands of Calluna vulgaris (L.) Hull by using a chronosequence of 0, 12, 19 and 28 years after vegetation cutting. Overall, the ecosystem C balance was highly nonlinear over time and exhibited a sinusoidal-like curvature of C sink/source change over the three-decade timescale. After cutting, plant-related C flux components of gross photosynthesis (PG), aboveground autotrophic respiration (Raa) and belowground autotrophic respiration (Rba) were higher at the young age (12 years) than at middle (19 years) and old (28 years) ages. The young ecosystem was a C sink (12 years: -0.374 kg C m-2 year-1) while it became a C source with aging (19 years: 0.218 kg C m-2 year-1) and when dying (28 years: 0.089 kg C m-2 year-1). The post-cutting C compensation point was observed after four years, while the cumulative C loss in the period after cutting had been compensated by an equal amount of C uptake after seven years. Annual ecosystem C payback from the ecosystem to the atmosphere started after 16 years. This information may be used directly for optimizing vegetation management practices for maximal ecosystem C uptake capacity. Our study highlights that whole life cycle observational data of changes in C fluxes and balance in ecosystems are important and the ecosystem model needs to take the successional stage and vegetation age into account when projecting component C fluxes, ecosystem C balance, and overall feedback to climate change.

Assessment of patient life engagement in major depressive disorder using items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR).

BACKGROUND: Patient-reported outcomes can measure domains that are personally meaningful, such as life engagement, which reflects motivation, pleasure, and well-being. This study explored whether certain items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR) can capture patient life engagement in major depressive disorder (MDD). METHODS: IDS-SR life engagement items were identified by a) a panel of expert psychiatrists (n = 4), b) patient interviews (n = 20), and c) a principal component analysis (PCA) to explore clustering of items. Psychometric analyses were performed on potential subscales, and a minimal clinically important difference (MCID) was estimated by anchor- and distribution-based methods. IDS-SR data were obtained from three randomized controlled trials of adjunctive brexpiprazole in MDD. RESULTS: Expert psychiatrists selected 10 items by consensus from the IDS-SR that might capture patient life engagement (Cronbach's alpha, 0.82; item-total correlations, 0.36-0.58). Patient interviews identified 13 items as moderately to very relevant to life engagement (Cronbach's alpha, 0.85; item-total correlations, 0.35-0.61). The PCA revealed a cluster that included all 10 items selected by psychiatrists and 11 items identified by patients. Expert psychiatrists intentionally distinguished life engagement and core depressive symptoms, although patient insights and the PCA indicated that these aspects of MDD are strongly linked. The 10-item IDS-SR life engagement subscale had an MCID of 3-5 points. CONCLUSIONS: Different approaches consistently identified a subset of 10 IDS-SR items that can measure life engagement in MDD, which may be suitable to group into an IDS-SR life engagement subscale.

Correction: Christensen et al. Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer. Diagnostics 2021, 11, 279.

In the original publication [...].

Effect of nitrification inhibitor (DMPP) on nitrous oxide emissions from agricultural fields: Automated and manual measurements.

Nitrogen fertilisation contributes significantly to the atmospheric increase of nitrous oxide (N2O). Application of nitrification inhibitors (NIs) is a promising strategy to mitigate N2O emissions and improve N-use efficiency in agricultural systems. This study investigated the effect of NI, 3,4-dimethylpyrazol phosphate (DMPP) on N2O mitigation from spring barley and spring oilseed rape. Manual and automatic chamber methodologies were used to capture spatial and temporal variability in N2O emissions. In a second experiment, we study the effect of N fertiliser levels without NI (0 %, 50 %, 100 %, 150 % and 200 % of recommended amount of N fertiliser), as well as 100 % of N with NI on N2O emissions in spring barley. The automated chamber measurements showed dynamics of N2O changes throughout the season, including positive and negative peaks that were unobservable with manual chambers due to low temporal resolution. Although not significant, application of NI tended to reduce N2O emissions. The reduction was on average 16 % in spring barley and 58 % in spring oilseed rape in manual chamber measurements. However, N2O reduction was 108 % in continuous automatic chamber measurements in spring barley. The N2O EFs for the growing season were very low (0.025 % to 0.148 %), with a greater reduction in EF in spring oilseed rape (76 %) than in spring barley (32 %) with NI application. A positive correlation (R = 80 %) was observed between N fertiliser levels and N2O emissions. Crop yield and crop N uptake were not significantly affected by the use of NI. This study highlighted that NI can reduce N2O emissions, but the reduction effects are plot, crop and microclimate specific. Long-term experiments with continuous plot-scale measurements are needed to capture and optimise N2O mitigation effect of NIs across wide variability in soils and microclimates in agroecosystems.

Field experiments underestimate aboveground biomass response to drought.

Researchers use both experiments and observations to study the impacts of climate change on ecosystems, but results from these contrasting approaches have not been systematically compared for droughts. Using a meta-analysis and accounting for potential confounding factors, we demonstrate that aboveground biomass responded only about half as much to experimentally imposed drought events as to natural droughts. Our findings indicate that experimental results may underestimate climate change impacts and highlight the need to integrate results across approaches.

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Are self-reported and self-monitored adherence good proxies for reaching relevant plasma concentrations?: Experiences from a study of anti-depressants in healthy volunteers.

BACKGROUND: The use of electronic-based devices to measure and to improve adherence of subjects in clinical trials is increasing. AiCure has developed a mobile technology that is claimed to provide visual confirmation of drug ingestion. While there is evidence suggesting that including such self-monitoring device in a study increases adherence, the quality of the data produced by the device may be questionable. Can the mobile technology reliably distinguish whether a subject takes the study drug or not? METHODS: Adherence was calculated based on exposure, self-reporting and self-monitoring for subjects randomized to an anti-depressant. Levels of adherence and agreement between the three approaches were investigated based on calculation of proportions, two-way tables and receiver operating curves. RESULTS: A total of 214 subjects had measured concentrations of study drug at all three time points (end of weeks 3, 4 and 5), along with adherence data to define proportion of days adherent based on self-reporting and the self-monitoring instrument developed by AiCure. Self-reported adherence proportions were higher than self-monitored adherence proportions, although both were high (>90%). Neither self-reported and self-monitored adherence agreed with exposure-based adherence. CONCLUSION: Both self-reported and self-monitored adherence overestimated adherence. Neither the self-reported nor the self-monitored adherence measure reflected subjects' actual adherence. This prompts for cautiousness when interpreting either of them, and it underlines the need for thorough validation of electronic devices and software that claims to measure adherence. The AiCure instrument may not be able to reliably determine whether the subjects swallow the study medication.

Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer.

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01-1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

18F-FLT PET/CT Adds Value to 18F-FDG PET/CT for Diagnosing Relapse After Definitive Radiotherapy in Patients with Lung Cancer: Results of a Prospective Clinical Trial.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has previously demonstrated higher specificity for malignancy than 18F-FDG PET. We investigated the value of 18F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18F-FLT PET/CT was higher than that of 18F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [P = 0.0020]). The difference in specificity between 18F-FLT PET/CT and 18F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18F-FLT PET/CT was lower than that of 18F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [P = 0.0078]). Adding 18F-FLT PET/CT when 18F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion:18F-FLT PET/CT adds diagnostic value to 18F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18F-FLT PET/CT was highest after cRT. We suggest adding 18F-FLT PET/CT when 18F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained.

Patient Response Trajectories in Major Depressive Disorder.

Objective: To investigate whether the efficacy of antidepressants can be understood in terms of patient response-trajectory classes. Experimental Design: Patient-level data were analysed from 1357 adults with MDD randomised to either escitalopram 20 mg/day (n = 676) or placebo (n = 681) in five 8-week randomised placebo-controlled trials. Growth mixture models (GMMs) were used to identify the response trajectories; longitudinal latent class analysis (LLCA) was used to corroborate the findings. Principal Observations: Three classes of response were identified for escitalopram and placebo based on the trajectory of the patients' Montgomery-Åsberg Depression Rating Scale (MADRS) total scores during treatment. All three classes had similar mean baseline MADRS scores, but the change from baseline after 8 weeks differed: -4.2 MADRS points for non-responders, -18.4 MADRS points for slow responders, and -26.7 points for fast responders. The proportions of non-responders, slow responders and fast responders were 53%, 38% and 9%, respectively, with placebo and 27%, 58% and 14%, respectively, with escitalopram. Receiver operating curve analysis showed that a cut-off of ≥43% improvement from baseline to week 2 predicted fast responders, and a cut-off of ≥28% improvement from baseline to week 4 predicted responders (fast or slow). There were no clinically useful differences at baseline that predicted the trajectory class to which a patient would belong. Conclusions: The presence of fast-, slow- and non-responder classes has a clear clinical relevance for guiding treatment decisions; individual patients can be classified by the change in their MADRS score from baseline at 2 or 4 weeks.

Multimodal soft tissue markers for bridging high-resolution diagnostic imaging with therapeutic intervention.

Diagnostic imaging often outperforms the surgeon's ability to identify small structures during therapeutic procedures. Smart soft tissue markers that translate the sensitivity of diagnostic imaging into optimal therapeutic intervention are therefore highly warranted. This paper presents a unique adaptable liquid soft tissue marker system based on functionalized carbohydrates (Carbo-gel). The liquid state of these markers allows for high-precision placement under image guidance using thin needles. Based on step-by-step modifications, the image features and mechanical properties of markers can be optimized to bridge diagnostic imaging and specific therapeutic interventions. The performance of Carbo-gel is demonstrated for markers that (i) have radiographic, magnetic resonance, and ultrasound visibility; (ii) are palpable and visible; and (iii) are localizable by near-infrared fluorescence and radio guidance. The study demonstrates encouraging proof of concept for the liquid marker system as a well-tolerated multimodal imaging marker that can improve image-guided radiotherapy and surgical interventions, including robotic surgery.

Early initiated postoperative rehabilitation enhances quality of life in patients with operable lung cancer: Secondary outcomes from a randomized trial.

INTRODUCTION: Patients with lung cancer report a lower degree of Health Related Quality of Life (HRQoL) compared with other cancer patients. HRQoL reflects how patients experience the impact of their disease and its treatment on their quality of daily living. A widely used questionnaire in lung cancer patients is the Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire. Here we report the secondary outcomes on FACT-L data from the Postoperative Rehabilitation in Operation for Lung CAncer (PROLUCA) study, which describes the effect of early (14 days) versus late initiated (14 weeks) postoperative rehabilitation. MATERIALS AND METHODS: The PROLUCA study was designed as a two-armed randomized controlled trial with an early rehabilitation group (14 days after surgery (ERG)) or a control arm with a late rehabilitation group (14 weeks after surgery (LRG)). The results for seven domain scores obtained using the FACT-L at the following time-points: baseline, 14 weeks, 26 weeks and 52 weeks after surgery are presented here. RESULTS: 119 patients were randomized to the ERG and 116 to the LRG. In the ERG, HRQoL measured by both FACT-L and FACT-G (general core instrument) showed a continuous improvement up to 26 weeks after which HRQoL decreased after further 26 weeks without structured intervention. In the LRG a non-significant deterioration was detected over the first 14 weeks after surgery. After participation in the 12 weeks rehabilitation program, an increase in HRQoL was seen, without reaching the same level as the early group. CONCLUSION: Analyses of the seven domain scores obtained using FACT-L and FACT-G reflect the importance of starting exercise early after surgery since the ERG avoid a temporary decrease in HRQoL. It is therefore recommended to start up a structured rehabilitation program 14 days after surgery, containing high intensity interval training and strength exercise twice a week for 12 weeks.

Rainfall manipulation experiments as simulated by terrestrial biosphere models: Where do we stand?

Changes in rainfall amounts and patterns have been observed and are expected to continue in the near future with potentially significant ecological and societal consequences. Modelling vegetation responses to changes in rainfall is thus crucial to project water and carbon cycles in the future. In this study, we present the results of a new model-data intercomparison project, where we tested the ability of 10 terrestrial biosphere models to reproduce the observed sensitivity of ecosystem productivity to rainfall changes at 10 sites across the globe, in nine of which, rainfall exclusion and/or irrigation experiments had been performed. The key results are as follows: (a) Inter-model variation is generally large and model agreement varies with timescales. In severely water-limited sites, models only agree on the interannual variability of evapotranspiration and to a smaller extent on gross primary productivity. In more mesic sites, model agreement for both water and carbon fluxes is typically higher on fine (daily-monthly) timescales and reduces on longer (seasonal-annual) scales. (b) Models on average overestimate the relationship between ecosystem productivity and mean rainfall amounts across sites (in space) and have a low capacity in reproducing the temporal (interannual) sensitivity of vegetation productivity to annual rainfall at a given site, even though observation uncertainty is comparable to inter-model variability. (c) Most models reproduced the sign of the observed patterns in productivity changes in rainfall manipulation experiments but had a low capacity in reproducing the observed magnitude of productivity changes. Models better reproduced the observed productivity responses due to rainfall exclusion than addition. (d) All models attribute ecosystem productivity changes to the intensity of vegetation stress and peak leaf area, whereas the impact of the change in growing season length is negligible. The relative contribution of the peak leaf area and vegetation stress intensity was highly variable among models.

Patient-reported depression severity and cognitive symptoms as determinants of functioning in patients with major depressive disorder: a secondary analysis of the 2-year prospective PERFORM study.

PURPOSE: To investigate the temporal interrelationship between depression severity, cognitive symptoms, and functioning in patients with major depressive disorder (MDD) in the PERFORM study (NCT01427439). PATIENTS AND METHODS: PERFORM was a 2-year, multicenter, prospective, noninterventional cohort study in outpatients with MDD who were either initiating antidepressant monotherapy or undergoing their first switch of antidepressant. Patients were enrolled by a general practitioner or psychiatrist. Structural equation model (SEM) analysis was used to explore temporal associations between patient-reported depression severity (9-item Patient Health Questionnaire score), cognitive symptoms (5-item Perceived Deficits Questionnaire score), and functional impairment (Sheehan Disability Scale total score). Standardized regression coefficients (SRCs) were used to evaluate the relationship between each outcome and scores from the most recent prior visit over the 2 years of follow-up. RESULTS: Between February 25, 2011, and February 19, 2015, 1,159 eligible patients with MDD completed the baseline and ≥1 follow-up visit at 194 sites in five European countries (France, Germany, Spain, Sweden, and the UK). Overall, 1,090 patients had assessments for ≥1 outcome measure at two consecutive visits. Severity of cognitive symptoms at baseline and Months 2 and 18 predicted functional impairment at Months 2, 6, and 24, respectively (SRC: 0.18, 0.15, and 0.22; P<0.001). Depression severity at Months 2, 6, and 12 predicted functional impairment at Months 6, 12, and 18, respectively (SRC: 0.17, 0.25, and 0.22; P<0.001). Severity of cognitive symptoms at baseline and Month 18 predicted depression severity at Months 2 and 24, respectively (SRC: 0.19 and 0.22; P<0.001). Functional impairment did not significantly predict the severity of depression or cognitive symptoms, and depression severity did not significantly predict the severity of cognitive symptoms at any time point. CONCLUSION: Patient-reported severity of cognitive symptoms appears to be an independent and significant determinant of subsequent functional impairment and depression severity in patients with MDD.