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In the Southern Bolivian Altiplano recent research has suggested to introduce deficit irrigation as a strategy to boost quinoa yields and to stabilize it at 2.0 ton ha-1. In this study we carried out an economic assessment of the implementation of deficit irrigation at farm level using a hydro-economic model for simulating profit for quinoa production. As input of the model we worked with previously developed farms typology (livestock, quinoa and subsistence farms), simulated quinoa production with and without irrigation using AquaCrop model, and calculated yield response functions for four different climate scenarios (wet, normal, dry and very dry years). Results from the hydro-economic model demonstrate that maximum profit is achieved with less applied irrigated water than for maximum yield, and irrigated quinoa earned more profit than rainfed production for all farms types and climate scenarios. As expected, the benefits of irrigation under dry and very dry climate conditions were higher than those under normal and wet years, and benefits among farms types were higher for quinoa farms. In fact, profit of irrigated quinoa might be stabilized at around BOB 6500 ha-1 (about USD 920) compared with the huge differences found for rainfed conditions for all climate scenarios. Interestingly, the economic water productivity, expressed in terms of economic return for amount of applied irrigated water (BOB mm-1), reached the highest values with intermediate and low level of water availability schemes of deficit irrigation for all climate scenarios.

[This corrects the article DOI: 10.1371/journal.pone.0220480.].

ObjectivesTo determine whether implementation of comprehensive in-school eyecare results in measurable benefits for children and young people in terms of visual status, classroom behaviours and how well their visual needs are met.DesignSchool-based observational study.Participants & methods200 pupils [mean age 10 years 9 months, 70% male, majority moderate (40%) or severe (35%) learning difficulty] of a special education school in the UK. A sector-agreed in-school eyecare framework including full eye examination and cycloplegic refraction, dispensing of spectacles (as appropriate) and written reporting of outcomes to parents/teachers was applied. Classroom behaviours were observed and recorded prior to, and after, the in-school eyecare. Surveys were employed to obtain visual histories from parents/teachers. School records and statutory documents were reviewed for diagnostic and learning disability classifications. Visual function and ocular health were profiled at baseline and significant visual deficits identified. Where such deficits were previously unrecognised, untreated or not compensated for (e.g. correction of refractive error, enlargement of educational material) they were recorded as 'unmet visual need'. At follow-up, 2-5 months after initial (baseline) measures, eye examinations, parent/teacher surveys and behaviour observations were repeated. Follow-up measures were used to determine if measurable improvements were evident in visual function, ocular health, the level of unmet need and classroom behaviour following implementation of in-school eyecare.Results199 participants completed baseline and follow-up measures. 122 (61%) participants presented with at least one significant visual or ocular health deficit and 90 (45%) participants had at least one unmet visual need. Younger pupils and those with no previous history of eyecare were more likely to demonstrate unmet visual needs at baseline (OR 1.12 95% CI 1.03 to 1.21) p = 0.012; (OR 4.44 95% CI 1.38 to 14.29 p = 0.007 respectively). On follow-up, the number of pupils with unmet visual needs dropped significantly to 36 (18%) (McNemar's test p0.05). Where significant refractive deficits were corrected at follow-up, near visual acuity improved significantly (Wilcoxon signed rank p = 0.013), however, poor spectacle compliance was a persistent cause of unmet visual need. Off-task behaviour reduced significantly after actions to address unmet visual needs were communicated to parents and teachers (Wilcoxon signed rank p = 0.035).ConclusionsThe present study demonstrates for the first time measurable visual and behaviour benefits to children in special education settings when they receive comprehensive in-school eye examinations, on-site spectacle dispensing and jargon-free reporting of outcomes to teachers and parents.

Objective: In 2009, Palliative care was incorporated into the medical curriculum as Cross-Sectional Subject 13 (QB13) by means of the revision of the Medical Licensing Regulations for Physicians. The aim of this study was to determine the strengths and deficits of QB13 student education for palliative care in clinical practice in a multi-centre setting and to identify potential for improvement., Methods: Online questionnaires filled out by medical students during their Practical Year (PY) and resident physicians from the university hospitals in Aachen, Düsseldorf, and Cologne were descriptively analyzed using SPSS; free-text responses were categorized and quantified. Semi-structured interviews with the resident physicians (using a mixed-methods design) were analyzed through content analysis. Emerging categories were quantified., Results: Analysis of 130 fully completed questionnaires and 23 interviews revealed that participants particularly benefited from patient- and practice-oriented small-group sessions for their clinical work. Despite some university-specific differences, the PY students identified a need for training in end-of-life-care, while resident physicians saw a need for training primarily in dealing with patients and their relatives. They also reported deficits in transferability., Conclusion: QB13 should be organised in cross-university curricula and provide sufficient resources for practical-oriented small-group teaching. Based on the "unit of care", besides caring for palliative patients, dealing with patients' families should also be an education focus. To improve transferability into clinical practice, students should be actively involved in the care of palliative patients., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Dronia et al.)

Background: Persons with severe Multiple Sclerosis (PwsMS) face complex needs and daily limitations that make it challenging to receive optimal care. The implementation and coordination of health care, social services, and support in financial affairs can be particularly time consuming and burdensome for both PwsMS and caregivers. Care and case management (CCM) helps ensure optimal individual care as well as care at a higher-level. The goal of the current qualitative study was to determine the experiences of PwsMS, caregivers and health care specialists (HCSs) with the CCM., Methods: In the current qualitative sub study, as part of a larger trial, in-depth semi-structured interviews with PwsMS, caregivers and HCSs who had been in contact with the CCM were conducted between 02/2022 and 01/2023. Data was transcribed, pseudonymized, tested for saturation and analyzed using structuring content analysis according to Kuckartz. Sociodemographic and interview characteristics were analyzed descriptively., Results: Thirteen PwsMS, 12 caregivers and 10 HCSs completed interviews. Main categories of CCM functions were derived deductively: (1) gatekeeper function, (2) broker function, (3) advocacy function, (4) outlook on CCM in standard care. Subcategories were then derived inductively from the interview material. 852 segments were coded. Participants appreciated the CCM as a continuous and objective contact person, a person of trust (92 codes), a competent source of information and advice (on MS) (68 codes) and comprehensive cross-insurance support (128 codes), relieving and supporting PwsMS, their caregivers and HCSs (67 codes)., Conclusions: Through the cross-sectoral continuous support in health-related, social, financial and everyday bureaucratic matters, the CCM provides comprehensive and overriding support and relief for PwsMS, caregivers and HCSs. This intervention bears the potential to be fine-tuned and applied to similar complex patient groups., Trial Registration: The study was approved by the Ethics Committee of the University of Cologne (#20-1436), registered at the German Register for Clinical Studies (DRKS00022771) and in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Background: Recently, a new resting-state functional magnetic resonance imaging (rs-fMRI) measure to evaluate the concordance between different rs-fMRI metrics has been proposed and has not been investigated in Alzheimer's disease (AD). Methods: 3T rs-fMRI data were obtained from healthy young controls (YC, n  = 26), healthy senior controls (SC, n  = 29), and AD patients ( n  = 35). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were analyzed, followed by the calculation of their concordance using Kendall's W for each brain voxel across time. Group differences in the concordance were compared globally, within seven intrinsic brain networks, and on a voxel-by-voxel basis with covariates of age, sex, head motion, and gray matter volume. Results: The global concordance was lowest in AD among the three groups, with similar differences for the single metrics. When comparing AD to SC, reductions of concordance were detected in each of the investigated networks apart from the limbic network. For SC in comparison to YC, lower global concordance without any network-level difference was observed. Voxel-wise analyses revealed lower concordance in the right middle temporal gyrus in AD compared to SC and lower concordance in the left middle frontal gyrus in SC compared to YC. Lower fALFF were observed in the right angular gyrus in AD in comparison to SC, but ReHo and DC showed no group differences. Conclusions: The concordance of resting-state measures differentiates AD from healthy aging and may represent a novel imaging marker in AD.

Background: To combine the benefits of hospice and palliative care, the integration of both seems self-evident. Aim of this study was to explore clinical staff's and volunteers' expectations and concerns of the first university hospice in Germany planning for implementation., Methods: Staff and volunteers of the Department of Palliative Medicine of the University Hospital in Cologne received questionnaires and were interviewed following three themes of interest: opportunities, challenges, general criteria. Questionnaire results were analyzed descriptively using mean ± SD and percentages, open-ended questions and interviews were analysed using content analysis., Results: A total of 28/100 questionnaires was returned (n = 17 clinical staff, n = 11 volunteers) and 18 interviews conducted. The majority of both clinical staff and volunteers estimated the need for a university inpatient hospice as rather to very high (64.7% and 81.8%, respectively). Our findings revealed that most clinical staff and volunteers anticipated improvements with the intended university inpatient hospice, although their expectations were divided between both hope and concern while adhering to legal and general requirements, which they feared might oppose such a project. Participants expressed concern about leadership and staffing plans, albeit most pronounced among clinical staff. Nursing staff repeatedly articulated concerns about being interchanged between the palliative care ward and the intended inpatient hospice while they had explicitly chosen to work in palliative medicine., Conclusions: The overall high level of anticipated progress and excitement is very encouraging. Albeit serious concerns were mentioned, our results indicate that all participants believe in a positive impact and highlight the need of developing a solid concept. In order to implement such a hospice within a university setting, it is important to consider multilevel contextual factors such as system-level factors (funding, external and internal regulations), organization-level factors (leadership, staff motivation), and patient-level factors (adaptability to patients' needs). Our findings illustrate the importance of understanding the context of practice before implementation. Our pre-implementation study helps identify critical views from staff members and volunteers that may hinder or advance the implementation., Trial Registration: The study was registered at the German Clinical Trials Register (#DRKS00021258) on April 17 th 2020., (© 2023. The Author(s).)

Purpose/objectives: Care and case management (CCM) aims to provide optimal care for patients and their caregivers on an individual and superordinate level of health care providers and authorities. To facilitate a clear and systematic CCM process as part of a clinical study intervention, a semistructured manual is the prerequisite., Primary Practice Settings: The ongoing COCOS-MS (Communication, Coordination and Security for People with Multiple Sclerosis) study is a randomized controlled Phase II clinical intervention study. The CCM manual is being tested on the intervention group consisting of severely affected individuals with multiple sclerosis (MS; Expanded Disability Status Scale [EDSS] >5) and their caregivers receiving CCM for 12 months in addition to standard care. The intervention comprises monthly personal visits and weekly telephone calls during which the CCM manual is applied., Findings/conclusions: The CCM manual has been developed on the basis of previous literature and well-established questionnaires following theoretical aspects and prior scientific work covering individual domains of life of people with MS. Within the COCOS-MS study, its feasibility is being tested meticulously. It allows for a standardized assessment while being tailored to the individual. At the end of the intervention period, it will be analyzed statistically and qualitatively. Consequently, conclusions can be drawn as to whether the CCM manual is feasible or has to be adapted for use in standard care after analyzation., Implications for Case Management Practice: The CCM manual serves as a tool for the continuous, long-term, cross-sectoral care for patients suffering from severe MS and their caregivers. The manual provides guidance in adequately addressing patients' complex symptoms, problems, and needs, as well as assessing existing resources both at the individual patient level and at a superordinate level., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Objective: Elevated cortisol levels have been frequently reported in Alzheimer's disease (AD) and linked to brain atrophy, especially of the hippocampus. Besides, high cortisol levels have been shown to impair memory performance and increase the risk of developing AD in healthy individuals. We investigated the associations between serum cortisol levels, hippocampal volume, gray matter volume and memory performance in healthy aging and AD., Methods: In our cross-sectional study, we analyzed the relationships between morning serum cortisol levels, verbal memory performance, hippocampal volume, and whole-brain voxel-wise gray matter volume in an independent sample of 29 healthy seniors (HS) and 29 patients along the spectrum of biomarker-based AD., Results: Cortisol levels were significantly elevated in patients with AD as compared to HS, and higher cortisol levels were correlated with worse memory performance in AD. Furthermore, higher cortisol levels were significantly associated with smaller left hippocampal volumes in HS and indirectly negatively correlated to memory function through hippocampal volume. Higher cortisol levels were further related to lower gray matter volume in the hippocampus and temporal and parietal areas in the left hemisphere in both groups. The strength of this association was similar in HS and AD., Conclusion: In AD, cortisol levels are elevated and associated with worse memory performance. Furthermore, in healthy seniors, higher cortisol levels show a detrimental relationship with brain regions typically affected by AD. Thus, increased cortisol levels seem to be indirectly linked to worse memory function even in otherwise healthy individuals. Cortisol may therefore not only serve as a biomarker of increased risk for AD, but maybe even more importantly, as an early target for preventive and therapeutic interventions., Competing Interests: GF serves as an editorial board member of Cortex, Neurological Research and Practice, NeuroImage: Clinical, Zeitschrift für Neuropsychologie, and DGNeurologie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dronse, Ohndorf, Richter, Bischof, Fassbender, Behfar, Gramespacher, Dillen, Jacobs, Kukolja, Fink and Onur.)

Introduction: Patients with multiple sclerosis (MS) have complex needs that range from organising one's everyday life to measures of disease-specific therapy monitoring to palliative care. Patients with MS are likely to depend on multiple healthcare providers and various authorities, which are often difficult to coordinate. Thus, they will probably benefit from comprehensive cross-sectoral coordination of services provided by care and case management (CCM). Though studies have shown that case management improves quality of life (QoL), functional status and reduces service use, such benefits have not yet been investigated in severely affected patients with MS. In this explorative phase ll clinical trial, we evaluated a CCM with long-term, cross-sectoral and outreaching services and, in addition, considered the unit of care (patients and caregivers)., Methods and Analysis: Eighty patients with MS and their caregivers will be randomly assigned to either the control (standard care) or the intervention group (standard care plus CCM (for 12 months)). Regular data assessments will be done at baseline and then at 3-month intervals. As primary outcome, we will evaluate patients' QoL. Secondary outcomes are patients' treatment-related risk perception, palliative care needs, anxiety/depression, use of healthcare services, caregivers' burden and QoL, meeting patients' and caregivers' needs, and evaluating the CCM intervention. We will also evaluate CCM through individual interviews and focus groups. The sample size calculation is based on a standardised effect of 0.5, and one baseline and four follow-up assessments (with correlation 0.5). Linear mixed models for repeated measures will be applied to analyse changes in quantitative outcomes over time. Multiple imputation approaches are taken to assess the robustness of the results. The explorative approach (phase ll clinical trial) with embedded qualitative research will allow for the development of a final design for a confirmative phase lll trial., Ethics and Dissemination: The trial will be conducted under the Declaration of Helsinki and has been approved by the Ethics Commission of Cologne University's Faculty of Medicine. Trial results will be published in an open-access scientific journal and presented at conferences., Trial Registration Number: German Register for Clinical Studies (DRKS) (DRKS00022771)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: A sense of security is important in palliative home care. Yet, knowledge about which components contribute most to feeling secure from the patients' and family caregivers' perspectives, especially since the introduction of specialist palliative home care, is sparse. The goal of the current study was to determine the key components contributing to a sense of security and how they relate to each other as experienced by patients and family caregivers in specialist and generalist palliative home care., Methods: The current sub-study, as part of a larger study, was performed in different regions in Germany. Palliative care patients and family caregivers of at least 18 years of age, being cared for at home were interviewed using semi-structured interview guides following a three-factor model and analyzed by using a combined quantitative-qualitative-content approach., Results: One hundred and ninty-seven patients and 10 carers completed interviews between December 2017 and April 2019. The majority of patients were diagnosed with an oncological disease. Sense of security was mentioned particularly often suggesting its high relevance. We identified nine subcategories that were all mentioned more frequently by specialist than generalist palliative home care recipients in the following order of priority and relation: (i) patient-centeredness: availability, provision of information/education, professional competence, patient empowerment, and trust (ii) organizational work: comprehensive responsibility, external collaboration, and internal cooperation, and (iii) direct communication., Significance of Results: The work of specialist palliative home care services in particular was perceived as very effective and beneficial. Our findings confirm a previously developed three-factor model allowing for generalizability and revealed that availability was most important for improving the sense of security for effective palliative home care.

γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer's disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in post-Golgi compartments., (© 2021 Wouters et al.)

Background: There is growing interest to integrate palliative care and its structures into the care of neurological patients. However, in Germany there is no comprehensive assessment tool capturing the symptoms of patients with advanced neurological diseases., Aim: To validate a newly developed palliative care measurement tool based on an extension of the validated core documentation system Hospice and Palliative Care Evaluation considering additional neurological issues (HOPE+)., Design: Prospective, observational study using HOPE+ and as external criteria, the Eastern Cooperative Oncology Group (ECOG) performance status and the 12 months "surprise" question (12-SQ) in a neurological population, and assessment for its construct validity and diagnostic accuracy., Setting/participants: All newly admitted patients to the Department of Neurorehabilitation, Dr. Becker Rhein-Sieg-Clinic aged 18-100 years (#DRKS00010947)., Results: Data from 263 patients (63 ± 14 years of age) were analyzed. HOPE+ revealed a moderately correlated six-factor structure ( r  = -0.543-0.525). Correlation analysis to evaluate discriminant validity using ECOG as external criterion was high ( r s(261) = 0.724, p  < 0.001) and confirmed for severely affected patients by adding the 12-SQ ("No"-group: 48.00 ± 14.92 vs "Yes"-group: 18.67 ± 7.57, p  < 0.009). Operating characteristics show satisfactory diagnostic accuracy (area under the curve: 0.746 ± 0.049, 95% confidence interval = 0.650-0.842)., Conclusion: HOPE+ demonstrates promising psychometric properties. It helps to assess palliative care issues of patients in neurological settings and, in combination with the 12-SQ, conceivably conditions when to initiate the palliative care approach in a population underrepresented in palliative care structures so far.

Elucidating the relationship between neuronal metabolism and the integrity of the cholinergic system is prerequisite for a profound understanding of cholinergic dysfunction in Alzheimer's disease. The cholinergic system can be investigated specifically using positron emission tomography (PET) with [ 11 C]N-methyl-4-piperidyl-acetate (MP4A), while neuronal metabolism is often assessed with 2-deoxy-2-[ 18 F]fluoro-d-glucose-(FDG) PET. We hypothesised a close correlation between MP4A-perfusion and FDG-uptake, permitting inferences about metabolism from MP4A-perfusion, and investigated the patterns of neuronal hypometabolism and cholinergic impairment in non-demented AD patients. MP4A-PET was performed in 18 cognitively normal adults and 19 patients with mild cognitive impairment (MCI) and positive AD biomarkers. In nine patients with additional FDG-PET, the sum images of every combination of consecutive early MP4A-frames were correlated with FDG-scans to determine the optimal time window for assessing MP4A-perfusion. Acetylcholinesterase (AChE) activity was estimated using a 3-compartmental model. Group comparisons of MP4A-perfusion and AChE-activity were performed using the entire sample. The highest correlation between MP4A-perfusion and FDG-uptake across the cerebral cortex was observed 60-450 s after injection (r = 0.867). The patterns of hypometabolism (FDG-PET) and hypoperfusion (MP4A-PET) in MCI covered areas known to be hypometabolic early in AD, while AChE activity was mainly reduced in the lateral temporal cortex and the occipital lobe, sparing posterior midline structures. Data indicate that patterns of cholinergic impairment and neuronal hypometabolism differ significantly at the stage of MCI in AD, implying distinct underlying pathologies, and suggesting potential predictors of the response to cholinergic pharmacotherapy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The diagnosis of Alzheimer's disease (AD), especially in the early stage, is still not very reliable and the development of new diagnosis tools is desirable. A diagnosis based on functional magnetic resonance imaging (fMRI) is a suitable candidate, since fMRI is non-invasive, readily available, and indirectly measures synaptic dysfunction, which can be observed even at the earliest stages of AD. However, the results of previous attempts to analyze graph properties of resting state fMRI data are contradictory, presumably caused by methodological differences in graph construction. This comprises two steps: clustering the voxels of the functional image to define the nodes of the graph, and calculating the graph's edge weights based on a functional connectivity measure of the average cluster activities. A variety of methods are available for each step, but the robustness of results to method choice, and the suitability of the methods to support a diagnostic tool, are largely unknown. To address this issue, we employ a range of commonly and rarely used clustering and edge definition methods and analyze their graph theoretic measures (graph weight, shortest path length, clustering coefficient, and weighted degree distribution and modularity) on a small data set of 26 healthy controls, 16 subjects with mild cognitive impairment (MCI) and 14 with Alzheimer's disease. We examine the results with respect to statistical significance of the mean difference in graph properties, the sensitivity of the results to model and parameter choices, and relative diagnostic power based on both a statistical model and support vector machines. We find that different combinations of graph construction techniques yield contradicting, but statistically significant, relations of graph properties between health conditions, explaining the discrepancy across previous studies, but casting doubt on such analyses as a method to gain insight into disease effects. The production of significant differences in mean graph properties turns out not to be a good predictor of future diagnostic capacity. Highest predictive power, expressed by largest negative surprise values, are achieved for both atlas-driven and data-driven clustering (Ward clustering), as long as graphs are small and clusters large, in combination with edge definitions based on correlations and mutual information transfer.

Background: The 12-months "surprise" question (12-SQ) for estimating prognosis and the need for integrating palliative care (PC) services has not yet been investigated for neurological patients. Objective: Test the value of the 12-SQ on a sample of neurorehabilitation patients. Methods: All patients newly registered in the Department of Neurorehabilitation, Dr. Becker Rhein-Sieg-Clinic (8/2016-03/2017) were asked to participate. The treating neurorehabilitation physicians (NP) and an external consulting PC physician (PCP) independently estimated patients' prognosis using the 12-SQ; while symptom burden was independently assessed using the standardized palliative outcome measurement HOPE-SP-CL, a set of additional neurological issues, and ECOG. Follow-up with consenting patients 12 months later was via telephone. Descriptive and inferential statistics were utilized in data analysis. Results: Of 634 patients, 279 (44%) patients (male: 57.7%, female: 42.3%; mean age: 63 ± 14) (or, alternatively, their legal representative) consented and were assessed at baseline. Per patient NP and PCP both answered the 12-SQ with "Yes" (164), with "No" (42), or had different opinions (73). The "No" group displayed the highest symptom burden on all three measures for both disciplines. Overall, PCP scored higher (i.e., worse) than NP on all measures used. Follow-up was possible for 236 (drop-out: 15.4%) patients (deceased: 34 (14.4%), alive: 202 (85.6%)). Baseline scores on all measures were higher for deceased patients compared to those still living. Prognostic characteristics were: sensitivity: NP 50%, PCP 67.6%; specificity: NP 86.1%, PCP 70.3%, p < 0.001; positive predictive value: NP 37.8%, PCP 27.7%; negative predictive value: NP 91.1%, PCP 92.8%; area under the curve: NP 0.68, PCP 0.69; success rate: NP 80.9%, PCP 69.9%, p = 0.002. Regression analysis indicated that age, dysphagia and overburdening of family (NP answering the 12-SQ), dysphagia and rehabilitation phase (PCP answering the 12-SQ) were associated with increased likelihood of dying within 12 months. Without the 12-SQ as relevant predictor, age, dysphagia and ECOG were significant predictors (NP and PCP). Conclusion: Combining the 12-SQ with a measurement assessing PC and neurological issues could potentially improve the 12-SQ's predictive performance of 12-month survival and help to identify when to initiate the PC approach. Clinical experiences influence assessment and prognosis estimation.

γ-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing γ-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Aβ further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of γ-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone Aβ42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

What Is Known and Objective: Drug-related problems (DRPs) occur frequently in hospitalized patients. Patient discharge from the intensive care unit (ICU) to a non-ICU ward is one of the most challenging and high-risk transitions of care due to the number of medications, and the complexity and acuity of the medical conditions that characterize this patient group. Pharmacists could play an important role in preventing DRPs. This study was undertaken to evaluate the impact on the number and severity of drug-related problems by assigning a clinical pharmacist to the transfer process from ICU to wards., Methods: The study was a randomized controlled multicentre trial conducted at the Hospital Network of Antwerp between December 2010 and January 2012. The clinical pharmacist performed a medical review in both the intervention and control group. Recommendations for drug therapy changes were immediately communicated in the intervention group but were kept blinded in the control group. The primary outcome was expressed as the number of implemented recommendations for drug therapy changes. Differences between groups were calculated using mixed effects binary logistic regression., Results: Drug-related problems were found in the medical records of 360 of the 600 participants (60%). A total of 743 recommendations could be made, 375 in the intervention group and 368 in the control group. 54·1% of these problems were adjusted on time in the intervention group vs. 12·8% in the control group. Of 743 recommendations, 24·8% were judged by the expert group as major, 13·1% as moderate, 53.4% as minor and 8·9% as having no clinical impact. The odds of implementing recommendations of drug therapy changes in the intervention group were 10 times the odds of implementing recommendations of drug therapy changes in the control group (odds ratio = 10·1; 95%CI [6·3-16·1]; P < 0·001), even after accounting for differences in types of DRP between the groups (odds ratio = 15·6; 95%CI [9·4-25·9]; P < 0·001)., What Is New and Conclusion: The integration of a clinical pharmacist at the transfer point from ICU to ward led to a significant reduction in DRPs., (© 2015 John Wiley & Sons Ltd.)

Member states in the European Union (EU) implemented both ex ante coexistence regulations and ex post liability schemes to ensure that genetically modified (GM) and non-GM crops can be cultivated side by side without excluding any agricultural option. Although proportionate coexistence is best achieved if regulated in a flexible manner, most implemented coexistence regulations merely rely on rigid measures. Flexible coexistence regulations, however, would reduce the regulatory burden on certain agricultural options and avoid jeopardizing economic incentives for coexistence. Flexibility can be integrated at: (i) the regulatory level by relaxing the rigidity of coexistence measures in ex ante regulations, yet without offsetting incentives to implement coexistence measures; (ii) the farm level by recommending the use of pollen barriers instead of large and fixed isolation distances; and (iii) the national/regional level by allowing diversified coexistence measures, which are adapted to the heterogeneity of farming in the EU. Owing to difficulties of implementation, the adoption of flexible and proportionate coexistence regulations will inevitably entail challenges., (© 2013 Society of Chemical Industry.)

In 2007, a genetically modified herbicide tolerant (GMHT) sugar beet (Beta vulgaris L.) tolerant against glyphosate, a commonly used broad spectrum herbicide, was commercialised in the USA and Canada. The speed of uptake of GMHT sugar beet by farmers has no precedent. While it took the hitherto most successful GM crop in the USA 15 years to reach an adoption rate of 95%, GMHT sugar beet achieved this figure after only 2 years. This paper traces the history of GMHT sugar beet which started at the European continent and describes the economic and environmental impact of its introduction in the USA. The results suggest that the rapid adoption is economically sound with adopter rents averaging $257/ha. Moreover the adoption has a high potential to reduce the environmental impact of sugar beet production. Will these experiences bring GMHT sugar beet back to its roots in Europe?, (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: During the early 1990s, the western corn rootworm, Diabrotica virgifera virgifera Le Conte (WCR), a maize pest, invaded the European continent. The continuous spread of the pest has introduced a new constraint into European maize production. As the damage caused by the invasive species is highly variable and different crop protection (CP) strategies are available, farmers' optimal strategies are not obvious. This study uses a simulation model to assess the competitiveness of different CP strategies in seven Central European countries., Results: Results indicate a high degree of heterogeneity in the profitability of different CP strategies, depending on the production parameters in each country. In general, crop rotation and Bt maize offer the best solutions to farmers, but, in continuous (non-rotated) maize cultivation, chemical CP options may capture part of the market. For Austrian continuous maize production it is found that not deregulating Bt maize implies that farmers forego revenues of up to euro 59 ha(-1)., Conclusions: In the presence of WCR, producing maize by an economically sound method requires incorporating country- and farm-specific characteristics into the decision framework. Also, not deregulating Bt maize has direct monetary consequences for many farmers that could influence total maize output and resistance management., ((c) 2010 Society of Chemical Industry.)

The aim of present study was to examine whether cationic Eudragit containing poly(lactide-co-glycolide) (PLGA) nanoparticles can adhere to Pseudomonas aeruginosa and Staphylococcus aureus. In order to prepare fluorescent nanoparticles, fluorescein was covalently coupled to PLGA. Fluorescent PLGA and Eudragit/PLGA nanoparticles were prepared by w/o/w emulsification solvent evaporation. Particle size and zeta potential of the nanoparticles were measured. Nanoparticles were incubated for a short time with P. aeruginosa and S. aureus followed by measurement of the size of nanoparticles and of P. aeruginosa and S. aureus with and without adherent nanoparticles. Flow cytometric measurements were performed to detect the attachment of particles to microorganisms. Eudragit containing nanoparticles possessed a positive zeta potential, while PLGA nanoparticles were negatively charged. Following adsorption of Eudragit containing nanoparticles, a size increase for P. aeruginosa was observed. Flow cytometric analyses confirmed that Eudragit containing particles showed stronger interactions with the test organisms than PLGA nanoparticles. Adhesion of particles was more pronounced for P. aeruginosa than for S. aureus. Cationic Eudragit containing nanoparticles showed better adhesion to microorganisms than anionic PLGA nanoparticles, which is probably due to enhanced electrostatic interactions.

The gamma-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this "proteasome of the membrane" are unknown. We characterize a new interaction partner of nicastrin, the retrieval receptor Rer1p. Rer1p binds preferentially immature nicastrin via polar residues within its transmembrane domain that are also critical for interaction with APH-1. Absence of APH-1 substantially increased binding of nicastrin to Rer1p, demonstrating the competitive nature of these interactions. Moreover, Rer1p expression levels control the formation of gamma-secretase subcomplexes and, concomitantly, total cellular gamma-secretase activity. We identify Rer1p as a novel limiting factor that negatively regulates gamma-secretase complex assembly by competing with APH-1 during active recycling between the endoplasmic reticulum (ER) and Golgi. We conclude that total cellular gamma-secretase activity is restrained by a secondary ER control system that provides a potential therapeutic value.

Presenilin-1 is a polytopic membrane protein that assembles with nicastrin, PEN-2, and APH-1 into an active gamma-secretase complex required for intramembrane proteolysis of type I transmembrane proteins. Although essential for a correct understanding of structure-function relationships, its exact topology remains an issue of strong controversy. We revisited presenilin-1 topology by inserting glycosylation consensus sequences in human PS1 and expressing the obtained mutants in a presenilin-1 and 2 knock-out background. Based on the glycosylation status of these variants we provide evidence that presenilin-1 traffics through the Golgi after a conformational change induced by complex assembly. Based on our glycosylation variants of presenilin-1 we hypothesize that complex assembly occurs during transport between the endoplasmic reticulum and the Golgi apparatus. Furthermore, our data indicate that presenilin-1 has a nine-transmembrane domain topology with the COOH terminus exposed to the lumen/extracellular surface. This topology is independently underscored by lysine mutagenesis, cell surface biotinylation, and cysteine derivation strategies and is compatible with the different physiological functions assigned to presenilin-1.

The objective of present study was to prepare positively charged ciprofloxacin-loaded nanoparticles providing a controlled release formulation. The particles were prepared by water-in-oil-in-water (w/o/w) emulsification and solvent evaporation, followed by high-pressure homogenisation. Two non-biodegradable positively charged polymers, Eudragit RS100 and RL100, and the biodegradable polymer poly(lactic-co-glycolic acid) or PLGA were used alone or in combination, with varying ratios. The formulations were evaluated in terms of particle size and zeta potential. Differential scanning calorimetry measurements were carried out on the nanoparticles and on the pure polymers Eudragit and PLGA. Drug loading and release properties of the nanoparticles were examined. The antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus was determined. During solvent evaporation, the size and zeta potential of the nanoparticles did not change significantly. The mean diameter was dependent on the presence of Eudragit and on the viscosity of the organic phase. The zeta potential of all Eudragit containing nanoparticles was positive in ultrapure water (around +21/+25 mV). No burst effect but a prolonged drug release was observed from all formulations. The particles' activity against P. aeruginosa and S. aureus was comparable with an equally concentrated ciprofloxacin solution.

Alzheimer's disease (AD), described for the first time 100 years ago, is a neurodegenerative disease characterized by two neuropathological hallmarks: neurofibrillary tangles containing hyperphosphorylated tau and senile plaques. These lesions are likely initiated by an imbalance between production and clearance of amyloid beta, leading to increased oligomerization of these peptides, formation of amyloid plaques in the brain of the patient, and final dementia. Amyloid beta is generated from amyloid precursor protein (APP) by subsequent beta- and gamma-secretase cleavage, the latter being a multiprotein complex consisting of presenilin-1 or -2, nicastrin, APH-1, and PEN-2. Alternatively, APP can be cleaved by alpha- and gamma-secretase, precluding the production of Abeta. In this review, we discuss the major breakthroughs during the past two decades of molecular cell biology and the current genetic and cell biological state of the art on APP proteolysis, including structure-function relationships and subcellular localization. Finally, potential directions for cell biological research toward the development of AD therapies are briefly discussed.

In the present study, the influence of freeze-drying with several cryoprotective agents and gamma (gamma)-irradiation sterilization on the physicochemical characteristics of ciprofloxacin HCl-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles was evaluated. Nanoparticles were prepared by W/O/W emulsification solvent evaporation followed by high-pressure homogenization. They were freeze-dried in the presence of 5.0% (w/v) mannitol, trehalose or glucose, with 5.0% (w/v) or 15.0% (w/v) dextran as cryoprotectants. The nanoparticles were irradiated at a dose of 25 kGy using a 60Co source. The following physicochemical properties of the formulations were investigated: the ratio of particle size before (initial) and after freeze-drying, the ease of reconstitution of the nanoparticle suspensions and the drug-release profiles of irradiated and non-irradiated nanoparticles. The antibacterial activity against Pseudomonas aeruginosa was measured. The freeze-drying process induced a significant increase in particle size when no cryoprotectant was employed. Similar results were observed when cryoprotectants were added to the formulation. Only when mannitol was used was no significant size increase measured. Moreover, for formulations with dextran, reconstitution after freeze-drying was difficult by manual agitation and particle size could not be determined because of aggregation. After gamma-sterilization no significant difference in mean particle size was observed, but reconstitution was more difficult and drug release was influenced negatively. Ciprofloxacin HCl incorporated in the nanoparticles was still effective against the micro-organism selected after freeze-drying and gamma-sterilization.

Poly(lactide-co-glycolide) nanoparticles incorporating ciprofloxacin HCl were prepared by means of a W/O/W emulsification solvent evaporation method. The physicochemical properties of these particles were evaluated by measuring particle size, zeta potential and drug loading efficiency. Gamma-sterilised nanoparticles were dispersed in different isoviscous polymer solutions, commonly used as vehicles in eye drops. The influence of gamma-irradiation of the viscosifying agents on the drug release properties of the dispersed nanoparticles was evaluated with respect to release in mannitol solution. The viscosity of the polymer solutions prepared was measured by flow rheometry and thereby the influence of temperature and sterilisation by autoclaving on viscosity was examined. Before and after freeze-drying and subsequent sterilisation by gamma-irradiation, the polymer solutions were also characterised by dynamic stress sweep and dynamic frequency sweep oscillation measurements to deduce possible structural changes. A possible relationship between the differences in ciprofloxacin release from the nanoparticles suspended in the various media and the network structure or rheological behaviour of the polymers was investigated.

Poly(lactide-co-glycolide) nanoparticles incorporating ciprofloxacin HCl were prepared by means of a W/O/W emulsification solvent evaporation method. The stabiliser selected was poly(vinylalcohol). A 2(4) full factorial design based on four independent variables was used to plan the experiments and the variable parameters were the number of homogenisation cycles, addition of boric acid to the inner water phase containing the drug, ciprofloxacin concentration in the inner water phase and oil:outer water phase ratio. The effects of these parameters on the particle size, zeta potential, drug loading efficiency and drug release were investigated. Also the effect of gamma irradiation on the particle size and drug release was evaluated and DSC and XRD analyses of the compounds and the nanoparticles were performed. The activity on two series of microorganisms, Pseudomonas aeruginosa and Staphylococcus aureus, was examined.