First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses.

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 µg m-3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

Terminological Confusion About Sedation in Palliative Care: Results of an International Online Vignette Survey.

Background: Terminological problems concerning sedation in palliative care and consequences for research and clinical decision making have been reported frequently. Objectives: To gather data on the application of definitions of sedation practices in palliative care to clinical cases and to analyze implications for high-quality definitions. Design: We conducted an online survey with a convenience sample of international experts involved in the development of guidelines on sedation in palliative care and members of the European Association for Palliative Care (EAPC). Participants were asked to apply four published definitions to four case vignettes. Data were analyzed using descriptive statistics. Results: A total of 32 experts and 271 EAPC members completed the survey. The definitions were applied correctly in n = 2200/4848 cases (45.4%). The mean number of correct applications of the definitions (4 points max.) was 2.2 ± 1.14 for the definition of the SedPall study group, 1.8 ± 1.03 for the EAPC definition, 1.7 ± 0.98 for the definition of the Norwegian Medical Association, and 1.6 ± 1.01 for the definition of the Japanese Society of Palliative Medicine. The rate of correct applications for the 16 vignette-definition pairs varied between 70/303 (23.1%) and 227/303 (74.9%). The content of definitions and vignettes together with free-text comments explains participants' decisions and misunderstandings. Conclusions: Definitions of sedation in palliative care are frequently incorrectly applied to clinical case scenarios under simplified conditions. This suggests that clinical communication and research might be negatively influenced by misunderstandings and inconsistent labeling or reporting of data. Clinical Trial Registration Number: DRKS00015047.

Implementation and the effects of a Parkinson Network Therapy (PaNTher) on activities of daily living and health-related quality of life in Parkinson's disease patients: study protocol of an mixed-method observational cohort study in outpatient care.

INTRODUCTION: Parkinson's disease (PD) represents the fastest growing neurodegenerative disease with an increasing prevalence worldwide. It is characterised by complex motor and non-motor symptoms that lead to considerable disability. Specialised physiotherapy has been shown to benefit patients with PD. The Parkinson Netzwerk Therapie (PaNTher) was created to improve access to specialised physiotherapy tailored to care priorities of PD patients. This study aims to evaluate the effectiveness, acceptability and needs of the PaNTher network by neurologists and physiotherapists involved in the network in outpatient care. METHODS AND ANALYSIS: This is a mixed-method, prospective, pragmatic non-randomised cohort study of parallel groups, with data collection taking place in Bavaria, Germany, between 2020 and 2024. Patients with PD insured by the Allgemeine Ortskrankenkasse Bayern (AOK Bayern) living in Bavaria will be recruited for study participation by network partners. Patients in the intervention group must reside in Munich or the surrounding area to ensure provision of specialised physiotherapy in close proximity to their place of residence. Controls receive care as usual. Six and 12 months after baseline, all patients receive a follow-up questionnaire. Mixed-effect regression models will be used to examine changes in impairment of activities of daily living and quality of life of patients with PD enrolled in the programme over time compared with usual care. Qualitative interviews will investigate the implementation processes and acceptability of the PaNTher network among neurologists and physiotherapists. The study is expected to show that the PaNTher network with an integrative care approach will improve the quality and effectiveness of the management and treatment of patients with PD. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee at the medical faculty of the Ludwig-Maximilians-University Munich (20-318). Results will be published in scientific, peer-reviewed journals and presented at national and international conferences.

Expert-approved best practice recommendations on the use of sedative drugs and intentional sedation in specialist palliative care (SedPall).

BACKGROUND: The use of sedative drugs and intentional sedation in end-of-life care is associated with clinical, ethical and legal challenges. In view of these and of the issue's great importance to patients undergoing intolerable suffering, we conducted a project titled SedPall ("From anxiolysis to deep continuous sedation - Development of recommendations for sedation in palliative care") with the purpose of developing best practice recommendations on the use of sedative drugs and intentional sedation in specialist palliative care and obtaining feedback and approval from experts in this area. DESIGN: Our stepwise approach entailed drafting the recommendations, obtaining expert feedback, conducting a single-round Delphi study, and convening a consensus conference. As an interdisciplinary group, we created a set of best practice recommendations based on previously published guidance and empirical and normative analysis, and drawing on feedback from experts, including patient representatives and of public involvement participants. We set the required agreement rate for approval at the single-round Delphi and the consensus conference at ≥80%. RESULTS: Ten experts commented on the recommendations' first draft. The Delphi panel comprised 50 experts and patient and public involvement participants, while 46 participants attended the consensus conference. In total, the participants in these stages of the process approved 66 recommendations, covering the topics "indications", "intent/purpose [of sedation]", "decision-making", "information and consent", "medication and type of sedation", "monitoring", "management of fluids and nutrition", "continuing other measures", "support for relatives", and "team support". The recommendations include suggestions on terminology and comments on legal issues. CONCLUSION: Further research will be required for evaluating the feasibility of the recommendations' implementation and their effectiveness. The recommendations and the suggested terminology may serve as a resource for healthcare professionals in Germany on the use of sedative drugs and intentional sedation in specialist palliative care and may contribute to discussion on the topic at an international level. TRIAL REGISTRATION: DRKS00015047 (German Clinical Trials Register).

Documentation of Sedation in Palliative Care: A Scoping Review of Requirements, Recommendations, and Templates.

Objective: To identify and describe requirements, recommendations, and templates for the documentation of sedation in adult palliative care. Introduction: International literature shows inconsistency in clinical practice regarding sedation in palliative care accompanied by legal, ethical, and medical uncertainties. Documentation in general serves as proof for previous treatments. In the context of intentional sedation to relieve suffering at the end of life, documentation provides a clear demarcation against practices of euthanasia. Inclusion Criteria: Articles with full-text version published in English or German since 2000, covering documentation requirements, recommendations, monitoring parameters or templates for sedation in adult palliative care were included. Methods: Scoping review following the JBI methodology. Search in online databases, websites of professional associations in palliative care, reference lists of relevant publications, the archive of the German "Journal of Palliative Medicine" and databases for unpublished literature were used. Search terms included "palliative care,' "sedation," and "documentation." The search was conducted from January 2022 to April 2022 with an initial hand search in November 2021. Data were screened and charted by one reviewer after conducting a pilot test of the criteria. Results: From the initial 390 articles (database search), 22 articles were included. In addition, 15 articles were integrated from the hand search. The results can be clustered in two sets of items, regarding either the documentation before or during sedation. The documentation requirements referred both to inpatient and homecare settings but in many cases, a clear assignment was missing. Conclusions: The guidelines analyzed in this study rarely cover setting-specific differences in documentation and often treat documentation as minor topic. Further research is needed addressing legal and ethical concerns of health care teams and, therefore, help to improve treatment of patients suffering from otherwise intractable burden at the end of life.

Activities of Daily Living Are Improved by Inpatient Multimodal Complex Treatment for PD-a Real-World Cohort Study.

Background: The multimodal complex treatment for Parkinson's disease (MCT) provides inpatient care by a multi-disciplinary team for people with Parkinson's disease (PwP) in Germany. Objectives: We conducted a 5-year real-world mono-center cohort study to describe the effectiveness of MCT in the full cohort and various subgroups and outcome predictors. Methods: We collected an anonymized dataset between Jan 2015 and Dec 2019, involving N = 1773. The self-reported MDS-UPDRS part II was used as primary outcome, and clinical routine data for explanatory variables. PwP were categorized as responders or non-responders according to a response of at least 3 points 4 weeks after discharge. Results: N = 591 complete data records were available for statistical analyses. The full group improved by -2.4 points on the MDS-UPDRS II (P = <0.0001). 47.7% (n = 282) and 52.3% (n = 309) were coded as responders and non-responders, respectively. A clinically meaningful response was positively associated to age (χ2 = 11.07, P = 0.018), as well as baseline-severity of the MDS-UPDRS II (χ2 = 6.05, P = 0.048) and negatively associated to the presence of psychiatric disorder (χ2 = 3.9, P = 0.048) and cognitive dysfunction (χ2 = 7.29, P = 0.007). Logistic regression showed that baseline severity of the MDS-UPDRS II predicted therapy success. PwP with moderate baseline-severity had an about 2fold chance (OR 2.08; 95% CI 1.20-3.61; P = 0.009) and with severe an about 6fold chance (OR 5.92; 95% CI 2.76-12.68; P < 0.0001) to benefit clinically meaningful. Discussion: In a naturalistic setting of a specialized Parkinson's center, MCT improved ADL disability of PwP at least 4 weeks after discharge. Moderately and severely impaired patients were more likely to achieve clinically meaningful responses.

Intentional Sedation as a Means to Ease Suffering: A Systematically Constructed Terminology for Sedation in Palliative Care.

Background: Terminology concerning sedation in palliative care is heterogeneous, vague, and difficult to apply with negative impact on the reliability of quantitative data, practice, and ethical discourse. Design: To clarify the concept, we systematically developed definitions of core terms in an interdisciplinary research group comprising palliative care, ethics, law, and philosophy, integrating feedback from external experts. Results: We define terms stepwise, separating matters of terminology (What is the practice?) from matters of good practice (How to use it?). We start with an operational definition of "reduced level of consciousness" (score < 0 on the Richmond Agitation-Sedation Scale modified for palliative care inpatients (RASS-PAL), followed by defining "sedating," "sedation," and "intentional sedation" as the result or process of sedating a patient as a means of achieving a previously defined treatment goal and the terms "light," "deep," "temporary," and "sedation until death." Conclusion: The terminology facilitates the precise phrasing of aims, indications, and rules for good practice. Empirical research on acceptance and feasibility is needed.

Dysregulation of prostaglandins, leukotrienes and lipoxin A4 in bronchiectasis.

INTRODUCTION: Bronchiectasis is characterised by excessive neutrophilic inflammation. Lipid mediators such as prostaglandins and leukotrienes have crucial roles in the inflammatory response. Further characterisation of these lipids and understanding the interplay of anti-inflammatory and proinflammatory lipid mediators could lead to the development of novel anti-inflammatory therapies for bronchiectasis. AIM: The aim of our study was to characterise the lipids obtained from serum and airways in patients with bronchiectasis in the stable state. METHODS: Six healthy volunteers, 10 patients with mild bronchiectasis, 15 with moderate bronchiectasis and 9 with severe bronchiectasis were recruited. All participants had 60 mL of blood taken and underwent a bronchoscopy while in the stable state. Lipidomics was done on serum and bronchoalveolar lavage fluid (BALF). RESULTS: In the stable state, in serum there were significantly higher levels of prostaglandin E2 (PGE2), 15-hydroxyeicosatetranoic acid (15-HETE) and leukotriene B4 (LTB4) in patients with moderate-severe disease compared with healthy volunteers. There was a significantly lower level of lipoxin A4 (LXA4) in severe bronchiectasis.In BALF, there were significantly higher levels of PGE2, 5-HETE, 15-HETE, 9-hydroxyoctadecadienoic acid and LTB4 in moderate-severe patients compared with healthy volunteers.In the stable state, there was a negative correlation of PGE2 and LTB4 with % predicted forced expiratory volume in 1 s and a positive correlation with antibiotic courses.LXA4 improved blood and airway neutrophil phagocytosis and bacterial killing in patients with bronchiectasis. Additionally LXA4 reduced neutrophil activation and degranulation. CONCLUSION: There is a dysregulation of lipid mediators in bronchiectasis with excess proinflammatory lipids. LXA4 improves the function of reprogrammed neutrophils. The therapeutic efficacy of LXA4 in bronchiectasis warrants further studies.

The Minimal Clinically Relevant Change of the FOG Score.

BACKGROUND: Freezing of gait is a highly disabling symptom in persons with Parkinson's disease (PwP). Despite its episodic character, freezing can be reliably evaluated using the FOG score. The description of the minimal clinically relevant change is a requirement for a meaningful interpretation of its results. OBJECTIVE: To determine the minimal clinically relevant change of the FOG score. METHODS: We evaluated video recordings of a standardized freezing-evoking gait parkour, i.e., the FOG score just before and 30 minutes after the intake of a regular levodopa dose in a randomized blinded fashion. The minimal clinically relevant response was considered a value of one or more on a 7-step Likert-type response scale [-3; +3] that served as the anchor. The minimal clinically relevant change was determined by ROC analysis. RESULTS: 37 PwP (Hoehn & Yahr stages 2.5-4, 27 male, 10 female) were aged 68.2 years on average (range 45-80). Mean disease duration was 12.9 years (2-29 years). Minimum FOG score was 0 and Maximum FOG score was 29. Mean FOG scores before medication were 10.6, and 11.1 after medication intake, with changes ranging from -14.7 to +16.7. The minimal clinically relevant change (MCRC) for improvement based on expert clinician rating was three scale points with a sensitivity of 0.67 and a specificity of 0.96. CONCLUSIONS: The FOG score is recognized as a useful clinical instrument for the evaluation of freezing in the clinical setting. Knowledge of the MCRC should help to define responses to interventions that are discernible and meaningful to the expert physician and to the patient.

Body height loss characterizes camptocormia in Parkinson's disease.

Axial deformities such as camptocormia or Pisa syndrome in people with Parkinson's disease (PwP) are poorly understood. The scarcity of information may result from the shortage of reliable and responsive evaluation instruments. We evaluated the body height loss (BHL) as a new measure for PwP with axial deformities. 50 PwP with axial deformity defined by an UPDRS item 28 value of at least 2 were included in this mono-center study. We measured body height while lying supine and after 1 min of standing, providing a percentage value of BHL, and compared this measure to other clinical variables. BHL depended on the Hoehn and Yahr clinical stage and correlated with clinical scales for function and mobility, but not with timely measures of the axial disorder such as age at diagnosis or duration of disease. ANOVA showed that only lumbar flexion explained the variability of BHL (F = 21.0, p < 0.0001), but not kyphosis (F = 0.4, p = 0.74) or lateroflexion (F = 0.6, p = 0.6). Re-test reliability of BHL was good with к = 0.76 (p < 0.0001). BHL resulted from the lumbar spine and the hip joint and not from the thoracic spine or lateroflexion. This observation conforms to the concept of upper-type and lower-type camptocormia with only the latter leading to a BHL. The assessment of the BHL is shown to be a well defined, easy to perform, and reliable measure for the clinical evaluation of lower-type camptocormia.

Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4).

Ferulic acid is released by microbial hydrolysis in the colon, where butyric acid, a major by-product of fermentation, constitutes the main energy source for colonic enterocytes. We investigated how varying concentrations of this short chain fatty acid may influence the absorption of the phenolic acid. Chronic treatment of Caco-2 cells with butyric acid resulted in increased mRNA and protein abundance of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4), previously proposed to facilitate ferulic acid absorption in addition to passive diffusion. Short term incubation with butyric acid only led to upregulation of MCT4 while both conditions increased transepithelial transport of ferulic acid in the apical to basolateral, but not basolateral to apical, direction. Chronic treatment also elevated intracellular concentrations of ferulic acid, which in turn gave rise to increased concentrations of ferulic acid metabolites. Immunofluorescence staining of cells revealed uniform distribution of MCT1 protein in the cell membrane, whereas MCT4 was only detected in the lateral plasma membrane sections of Caco-2 cells. We therefore propose that MCT1 may be acting as an uptake transporter and MCT4 as an efflux system across the basolateral membrane for ferulic acid, and that this process is stimulated by butyric acid.

Cellular asymmetric catalysis by UDP-glucuronosyltransferase 1A8 shows functional localization to the basolateral plasma membrane.

UDP-glucuronosyltransferases (UGTs) are highly expressed in liver, intestine and kidney, and catalyze the glucuronic acid conjugation of both endogenous compounds and xenobiotics. Using recombinant human UGT isoforms, we show that glucuronic acid conjugation of the model substrate, (-)-epicatechin, is catalyzed mainly by UGT1A8 and UGT1A9. In HepG2 cells, pretreatment with polyunsaturated fatty acids increased substrate glucuronidation. In the intestinal Caco-2/HT29-MTX co-culture model, overall relative glucuronidation rates were much higher than in HepG2 cells, and (-)-epicatechin was much more readily conjugated when applied to the basolateral side of the cell monolayer. Under these conditions, 95% of the conjugated product was effluxed back to the site of application, and none of the other phase 2-derived metabolites followed this distribution pattern. HT29-MTX cells contained >1000-fold higher levels of UGT1A8 mRNA than Caco-2 or HepG2 cells. Gene expression of UGT1A8 increased after treatment of cells with docosahexaenoic acid, as did UGT1A protein levels. Immunofluorescence staining and Western blotting showed the presence of UGT1A in the basal and lateral parts of the plasma membrane of HT29-MTX cells. These results suggest that some of the UGT1A8 enzyme is not residing in the endoplasmic reticulum but spans the plasma membrane, resulting in increased accessibility to compounds outside the cell. This facilitates more efficient conjugation of substrate and is additionally coupled with rapid efflux by functionally associated basolateral transporters. This novel molecular strategy allows the cell to carry out conjugation without the xenobiotic entering into the interior of the cell.

Randomized cross-over trial to investigate the efficacy of a two-week physiotherapy programme with repetitive exercises of cueing to reduce the severity of freezing of gait in patients with Parkinson's disease.

OBJECTIVE: To investigate the efficacy of a two-week programme of repetitive exercise with cueing and movement strategies upon freezing of gait in people with Parkinson's disease. DESIGN: Randomized cross-over trial. SETTING: Specialist clinic for Parkinson's disease. SUBJECTS: A total of 22 patients with Parkinson's disease and freezing while other symptoms had favorably responded to dopaminergic treatment. INTERVENTION: Patients were randomized into a four-week cross-over trial, and received either treatment (Group 1) or no treatment (Group 2) during Period 1, and switched during Period 2. Treatment consisted of a two-week programme during which the patients exercised cueing, and movement strategies together with a physiotherapist. MAIN MEASURE: The primary outcome measure was a freezing score assessed from blinded and random ratings of video recordings. The secondary outcome measure was a patient-reported freezing questionnaire. Mean differences between the treatment periods (treatment arms) were evaluated for treatment (period) effects. Sums of treatment periods were evaluated for carry-over effects. RESULTS: The programme led to a significant treatment effect in the freezing score of 3.0 improvement (95% confidence interval 0.9-5.0; p < 0.01). No carry-over or period effects were detected. The questionnaire revealed a period effect, so groups were compared after Period 1, where a significant difference was found (15.0 vs. 11.7; p < 0.05). CONCLUSIONS: The two-week physiotherapy programme reduced the severity of freezing in patients with Parkinson's disease.

Levodopa changes the severity of freezing in Parkinson's disease.

Oral levodopa has been proposed to be one of the more effective medications to alleviate freezing of gait, but there is limited data on its efficacy. We evaluated the gait phenomenology of 20 Parkinson's disease patients with freezing of gait before and 60 min after a standardized levodopa dose using a rating scale based on the assumption that festination and akinetic freezing share a common pathophysiology. Levodopa abolished festination and freezing in 20% of patients (p < 0.0001), and reduced the freezing sum score from a median of 15 (IQR 6.75-27.5) to 3.5 (1-11.25), p < 0.001) in all but one of the remainder. Pre-dose ratings correlated with post-dose ratings, in that those patients with lower pre-dose item-scores also showed lower post-dose outcome scores. Levodopa's effect on both festination and akinetic freezing was linear, thereby supporting the concept that festination and freezing are variants on a continuity of episodic gait disorders in PD.

Recruitment of glutathione into the nucleus during cell proliferation adjusts whole-cell redox homeostasis in Arabidopsis thaliana and lowers the oxidative defence shield.

Cellular redox homeostasis and signalling are important in progression of the eukaryotic cell cycle. In animals, the low-molecular-weight thiol tripeptide glutathione (GSH) is recruited into the nucleus early in the cell proliferation cycle. To determine whether a similar process occurs in plants, we studied cell proliferation in Arabidopsis thaliana. We show that GSH co-localizes with nuclear DNA during the proliferation of A. thaliana cells in culture. Moreover, GSH localization in the nucleus was observed in dividing pericycle cells of the lateral root meristem. There was pronounced accumulation of GSH in the nucleus at points in the growth cycle at which a high percentage of the cells were in G(1) phase, as identified by flow cytometry and marker transcripts. Recruitment of GSH into the nucleus led to a high abundance of GSH in the nucleus (GSHn) and severe depletion of the cytoplasmic GSH pool (GSHc). Sequestration of GSH in the nucleus was accompanied by significant decreases in transcripts associated with oxidative signalling and stress tolerance, and an increase in the abundance of hydrogen peroxide, an effect that was enhanced when the dividing cells were treated with salicylic acid. Total cellular GSH and the abundance of GSH1 and GSH2 transcripts increased after the initial recruitment of GSH into the nucleus. We conclude that GSH recruitment into the nucleus during cell proliferation has a profound effect on the whole-cell redox state. High GSHn levels trigger redox adjustments in the cytoplasm, favouring decreased oxidative signalling and enhanced GSH synthesis.

A new rating instrument to assess festination and freezing gait in Parkinsonian patients.

Festination and freezing of gait (FOG) are sudden episodic inabilities to initiate or sustain locomotion mostly experienced during the later stages of Parkinson's disease (PD) or other higher-level gait disorders. The aim of this study was to develop a clinical rating instrument for short-interval rating of festination and FOG. Foot movements of 33 patients were video taped and rated during 12 episodes in a standardized course on a four-level interval scale according to severity. Motor blocks were provoked in four situations and by three levels of dual-tasking (tasks). Addition of the item scores produced a FOG score. The assessment requires less than 15 min. The inter-rater and re-test reliability of the FOG score is high (Kendall kappa = 0.85-0.92, P < 0.0001). Variability of the item scale due to situations and tasks can be attributed to unidimensional group factors (Cronbach's alpha 0.84 and 0.94). Group comparisons and a logistic regression model show significant effects for both situations and tasks on the item scale (Friedman test: "situation": P < 0.0001, "task": P < 0.0001). Six patients with PD have significantly different scores during mobile (practical ON; 6.2 +/- 3.9) and immobile (practical OFF; 15.8 +/- 4.6) medication states (P < 0.05). The FOG score correlates with the 10 m number of steps (rho = 0.58; P = 0.001) and with the self-evaluation of FOG (rho = 0.51; P < 0.01). Our results encourage the further use of the FOG score to evaluate festination and FOG.