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Given their antioxidative stress, anti-allergic, anti-inflammatory, and immune-modulating effects, flavonoids are hypothesized to play a role in preventing chronic obstructive pulmonary disease (COPD) and asthma.

Colorectal surgery still experiences high rates of infectious complications, such as anastomotic leakage (AL) and surgical site infections (SSIs). Therefore, oral antibiotic bowel decontamination (OABD) has experienced a renaissance. However, data on perioperative selective digestive tract decontamination (SDD)–based regimens or combined bowel preparation are inconsistent. Nonetheless, with widespread use of Enhanced Recovery After Surgery concepts, the ideal length for perioperative SDD treatment has to be reconsidered.

From previous studies, it is evident that metal–organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1and 2are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.

Background: Postoperative delirium (POD) is a serious complication following deep brain stimulation (DBS) but only received little attention. Its main risk factors are higher age and preoperative cognitive deficits. These are also main risk factors for long-term cognitive decline after DBS in Parkinson’s disease (PD).Objective: To identify risk factors for POD severity after DBS surgery in PD.Methods: 57 patients underwent DBS (21 female; age 60.2±8.2; disease duration 10.5±5.9 years). Preoperatively, general, PD– and surgery-specific predictors were recorded. Montreal Cognitive Assessment and the neuropsychological test battery CANTAB ConnectTMwere used to test domain-specific cognition. Volumes of the cholinergic basal forebrain were calculated with voxel-based morphometry. POD severity was recorded with the delirium scales Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Nursing Delirium Scale (NU-DESC). Spearman correlations were calculated for univariate analysis of predictors and POD severity and linear regression with elastic net regularization and leave-one-out cross-validation was performed to fit a multivariable model.Results: 21 patients (36.8%) showed mainly mild courses of POD following DBS. Correlation between predicted and true POD severity was significant (spearman rho?=?0.365, p?=?0.001). Influential predictors were age (p?

Postoperative delirium (POD) is a serious complication following deep brain stimulation (DBS) but only received little attention. Its main risk factors are higher age and preoperative cognitive deficits. These are also main risk factors for long-term cognitive decline after DBS in Parkinson’s disease (PD). To identify risk factors for POD severity after DBS surgery in PD. 57 patients underwent DBS (21 female; age 60.2±8.2; disease duration 10.5±5.9 years). Preoperatively, general, PD– and surgery-specific predictors were recorded. Montreal Cognitive Assessment and the neuropsychological test battery CANTAB ConnectTMwere used to test domain-specific cognition. Volumes of the cholinergic basal forebrain were calculated with voxel-based morphometry. POD severity was recorded with the delirium scales Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Nursing Delirium Scale (NU-DESC). Spearman correlations were calculated for univariate analysis of predictors and POD severity and linear regression with elastic net regularization and leave-one-out cross-validation was performed to fit a multivariable model. 21 patients (36.8%) showed mainly mild courses of POD following DBS. Correlation between predicted and true POD severity was significant (spearman rho = 0.365, p = 0.001). Influential predictors were age (p < 0.001), deficits in attention and motor speed (p = 0.002), visual learning (p = 0.036) as well as working memory (p < 0.001), Nucleus basalis of Meynert volumes (p = 0.003) and burst suppression (p = 0.005). General but also PD– and surgery-specific factors were predictive of POD severity. These findings underline the multifaceted etiology of POD after DBS in PD. Valid predictive models must therefore consider general, PD– and surgery-specific factors.

The significance of soil organic matter (SOM) in environmental contexts, particularly its role in pollutant adsorption, has prompted an increased utilization of molecular simulations to understand microscopic interactions. This study introduces a coarse-grained SOM model, parametrized within the framework of the versatile Martini 3 force field. Utilizing models generated by the Vienna Soil Organic Matter Modeler 2, which constructs humic substance systems from a fragment database, we employed Swarm-CG to parametrize the fragments and subsequently assembled them into macromolecules. Direct Boltzmann inversion (DBI) facilitated the determination of bonded parameters between fragments. The parametrization yielded favorable agreement in the radius of gyration and solvent-accessible surface area. Transfer free energies exhibited a strong correlation with hexadecane–water and chloroform–water values, albeit deviations were noted for octanol–water values. Comparing densities of modeled Leonardite humic acid systems at coarse-grained and atomistic levels revealed promising agreement, particularly at higher water concentrations. The DBI approach effectively reproduced average values of bonded interactions between fragments. Radial distribution functions between carboxylate groups and calcium ions showed partial agreement, however, reproducing certain peaks was challenging due to fixed bead sizes. Detailed analysis of atomistic systems revealed different configurations between the groups, explaining discrepancies. The present contribution provides a comprehensive insight into the properties, strengths, and weaknesses of the coarse-grained SOM model, serving as a foundation for future investigations encompassing pollutant interactions and varied SOM compositions.

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

IMPORTANCE: Data on oncological outcomes after omission of axillary lymph node dissection (ALND) in patients with breast cancer that downstages from node positive to negative with neoadjuvant chemotherapy are sparse. Additionally, the best axillary surgical staging technique in this scenario is unknown. OBJECTIVE: To investigate oncological outcomes after sentinel lymph node biopsy (SLNB) with dual-tracer mapping or targeted axillary dissection (TAD), which combines SLNB with localization and retrieval of the clipped lymph node. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter retrospective cohort study that was conducted at 25 centers in 11 countries, 1144 patients with consecutive stage II to III biopsy-proven node-positive breast cancer were included between April 2013 and December 2020. The cumulative incidence rates of axillary, locoregional, and any invasive (locoregional or distant) recurrence were determined by competing risk analysis. EXPOSURE: Omission of ALND after SLNB or TAD. MAIN OUTCOMES AND MEASURES: The primary end points were the 3-year and 5-year rates of any axillary recurrence. Secondary end points included locoregional recurrence, any invasive (locoregional and distant) recurrence, and the number of lymph nodes removed. RESULTS: A total of 1144 patients (median [IQR] age, 50 [41-59] years; 78 [6.8%] Asian, 105 [9.2%] Black, 102 [8.9%] Hispanic, and 816 [71.0%] White individuals; 666 SLNB [58.2%] and 478 TAD [41.8%]) were included. A total of 1060 patients (93%) had N1 disease, 619 (54%) had ERBB2 (formerly HER2)–positive illness, and 758 (66%) had a breast pathologic complete response. TAD patients were more likely to receive nodal radiation therapy (85% vs 78%; P = .01). The clipped node was successfully retrieved in 97% of TAD cases and 86% of SLNB cases (without localization). The mean (SD) number of sentinel lymph nodes retrieved was 3 (2) vs 4 (2) (P &lt; .001), and the mean (SD) number of total lymph nodes removed was 3.95 (1.97) vs 4.44 (2.04) (P &lt; .001) in the TAD and SLNB groups, respectively. The 5-year rates of any axillary, locoregional, and any invasive recurrence in the entire cohort were 1.0% (95% CI, 0.49%-2.0%), 2.7% (95% CI, 1.6%-4.1%), and 10% (95% CI, 8.3%-13%), respectively. The 3-year cumulative incidence of axillary recurrence did not differ between TAD and SLNB (0.5% vs 0.8%; P = .55). CONCLUSIONS AND RELEVANCE: The results of this cohort study showed that axillary recurrence was rare in this setting and was not significantly lower after TAD vs SLNB. These results support omission of ALND in this population.

Additional stimulation of the substantia nigra (SNr) has been proposed to target axial symptoms and gait impairment in patients with Parkinson’s disease (PD). This study aimed to characterize effects of combined deep brain stimulation (DBS) of the subthalamic nucleus (STN) and SNr on gait performance in PD and to map stimulation sites within the SNr. In a double-blinded crossover design, 10 patients with PD and gait impairment underwent clinical examination and kinematic assessment with STN DBS, combined STN+SNr DBS and OFF DBS 30 minutes after reprogramming. To confirm stimulation within the SNr, electrodes, active contacts, and stimulation volumes were modeled in a common space and overlap with atlases of SNr was computed. Overlap of stimulation volumes with dorsolateral SNr was confirmed for all patients. UPDRS III, scoring of freezing during turning and transitioning, stride length, stride velocity, and range of motion of shank, knee, arm, and trunk as well as peak velocities during turning and transitions and turn duration were improved with STN DBS compared to OFF. On cohort level, no further improvement was observed with combined STN+SNr DBS but additive improvement of spatiotemporal gait parameters was observed in individual subjects. Combined high frequency DBS of the STN and dorsolateral SNr did not consistently result in additional short-term kinematic or clinical benefit compared to STN DBS. Stimulation intervals, frequency, and patient selection for target symptoms as well as target region within the SNr need further refinement in future trials.

ABSTRACTOnshore wind power has experienced decades of controversies and conflicts between national policies and ambitions for development and local government and community opposition. This discrepancy has spurred extensive studies on economic, socio-cultural and environmental variables of (lack of) social acceptance. To understand controversies surrounding wind power development there is a need to investigate how decision-making is shaped by various factors in local governments affected by wind power. This paper develops a public administration perspective related to key assumptions of social acceptance theory and examines how different factors interact and mutually affect each other in local decision-making logic. We suggest an integrated analytical model that delineates three types of decision-making logic among local government officials: a logic of consequences, a logic of trajectory and a logic of appropriateness. As such we highlight the importance of public administration decision-making as a pivotal component of wind power development. This study is informed by interviews with municipal political and administrative leaders in Norway. The analysis shows that local decision-making logic is shaped by a reciprocation between considerations of socio-economic benefits (consequences), by past procedural experiences with energy development (trajectory) and by linkages to community, place and nature (appropriateness).

Introduction: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce.Patients and Methods: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0–2 at 3 months.Results: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10–2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93–0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59–3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25–0.72) and 0.55 (95% CI, 0.39–0.77), respectively.Conclusion: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette’s syndrome, the supplementary motor area in Parkinson’s disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

With the recent advances in the development of devices capable of performing quantum computations, a growing interest in finding near-term applications has emerged in many areas of science. In the era of nonfault tolerant quantum devices, algorithms that only require comparably short circuits accompanied by high repetition rates are considered to be a promising approach for assisting classical machines with finding a solution on computationally hard problems. The ADAPT approach previously introduced in Nat. Commun. 10, 3007 (2019) extends the class of variational quantum eigensolver algorithms with dynamically growing ansätze in order to find approximations to the ground and excited state energies of molecules. In this work, the ADAPT algorithm has been combined with a first-quantized formulation for the hydrogen molecule in the Born–Oppenheimer approximation, employing the explicitly correlated basis functions introduced in J. Chem. Phys. 43, 2429 (1965). By the virtue of their explicit electronic correlation properties, it is shown in classically performed simulations that chemical accuracy (<1.6 mHa) can be reached for ground and excited state potential curves using reasonably short circuits.

The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33–ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33–ST2 axis in infections and inflammatory diseases.

Ein Übergabeprozess von Patient*innen ist eine prozedural relevante Schnittstelle im medizinischen Informationstransfer und unabhängig von der Art der Übergabe (mündlich, schriftlich oder kombiniert) regelmäßig mit dem Risiko eines Informationsverlusts verbunden. Eine drohende Patient*innengefährdung oder ein Einfluss auf die Patient*innenbehandlung sind mögliche Folgen. Der Informationstransfer an notfallmedizinischen Schnittstellen zwischen Rettungsdienst und Notaufnahmepersonal ist grundsätzlich besonders fehleranfällig durch situative Besonderheiten (hohe Umgebungslautstärke, viele beteiligte Disziplinen) und im Fall einer akuten vitalen Bedrohung zeitkritische Entscheidungsfindungen. Da das Training von Übergaben bisher nicht flächendeckend in Aus- und Weiterbildungsprogrammen etabliert ist, besteht eine hohe Heterogenität in der tatsächlichen Umsetzung im Alltag. Strategien zur Optimierung der Übergabe haben ein hohes Potenzial in Bezug auf die Mitarbeiterzufriedenheit und die Prozessqualität sowie potenziell einen positiven prognostischen Einfluss.

Although dopamine replacement therapy remains a core component of Parkinson's disease treatment, the onset of motor fluctuations and dyskinetic movements might require a range of medical and surgical approaches from a multidisciplinary team, and important new approaches in the delivery of dopamine replacement are becoming available. The more challenging, wide range of non-motor symptoms can also have a major impact on the quality of life of a patient with Parkinson's disease, and requires careful multidisciplinary management using evidence-based knowledge, as well as appropriately tailored strategies according to the individual patient's needs. Disease-modifying therapies are urgently needed to prevent the development of the most disabling refractory symptoms, including gait and balance difficulties, cognitive impairment and dementia, and speech and swallowing impairments. In the third paper in this Series, we present the latest evidence supporting the optimal treatment of Parkinson's disease, and describe an expert approach to many aspects of treatment choice where an evidence base is insufficient.

The first macrocyclic abnormal N-heterocyclic carbene (aNHC) FeIIIcomplex, featuring a calix[4]3-methyl-1,2,3-triazole-5-ylidene ligand system is synthesised and characterised inter alia viaEA, SC-XRD, NMR and UV/vis spectroscopy. Including Mössbauer spectroscopy, SQUID and DFT calculations, the impact of the aNHC on the FeIIIcomplex and its corresponding FeIIderivative is investigated. A comprehensive study of the aNHC Fe complexes in their performance in homogenous epoxidation reactions is reported and compared to the established benchmark catalysts. The complexes demonstrate efficient and selective catalytic activity in the epoxidation of cis-cyclooctene with H2O2, with TOFs up to almost 60 000 h−1. Additionally, the epoxidation of more challenging olefinic substrates is possible. The reactivity under oxidative conditions of both complexes is investigated. NMR measurements reveal the formation of a mono-oxidised triazole ligand as degradation product. HR-ESI-MS measurements, supported by DFT calculations indicate the formation of an oxoiron species.

Process mining (PM) allows organizations to analyse their business processes based on data. This data is readily available in IT-systems, such es Enterprise Resource Planning (ERP) or Product Lifecycle Management (PLM). However, a wide variety of analysis techniques in PM lower the clarity for organizations how to exactly utilize PM within their product development or manufacturing processes. In this paper, we identify 18 application scenarios for PM in product development and manufacturing in collaboration with two real world companies. Each application scenario is classified based on standard criteria from literature, such as business benefits, analysis techniques or improvement possibility. We opt to use the term application scenario instead of use case, because we find that the term PM use case is not uniformly defined in literature. Hence, we propose a framework that relates the proposed application scenarios to the existing body of knowledge. From a managerial perspective, we provide organizations with the possibility to gain new ideas for utilizing PM within their product development or manufacturing. From a scientific perspective, we demonstrate the need for more sophisticated use case structures and characterization elements, especially for more complex domains like product development and manufacturing.

The Digital Factory Twin (DFT) is becoming more important in today’s manufacturing world, but many companies are struggling to plan for its successful implementation. This paper suggests using an Enterprise Architecture (EA) Management approach to make this process easier and more effective. We start by mapping out current hurdles, challenges and problems in the implementation of the DFT with a Meta-Review on existing studies based on the research method of a Structured Literature Review. Based on that we derive problem fields. Based on this problem fields we propose an integrated planning approach, that helps with these and is focused on helping practitioners in a real-world environment getting the DFT into productive use. Our approach consists of the following phases: (1) Determine initial situation & target picture for the DFT incl. deriving a short list of suitable DFT use cases; (2) Company specific DFT design; (3) Plan EA changes.

Hintergrund und Zielstellung: Eine hohe Händehygiene-Compliance (HHC) ist eine effektive Maßnahme zur Prävention von nosokomialen Infektionen. Die WHO empfiehlt direkte Beobachtungen als Goldstandard, um die HHC zu stratifizieren. Hohe Compliance-Raten bei der chirurgischen Händedesinfektion legen eine hohe Gesamt-Compliance im OP-Bereich nahe. Zahlen zur hygienischen Händedesinfektion im OP sind allerdings rar. Ziel war es, die HHC systematisch zu beobachten und durch maßgeschneiderte Interventionen zu steigern. Methode: Um die HHC in den Jahren 2017 und 2018 zu erfassen, wurde ein Beobachtungsbogen genutzt. Chirurgen und Op.-Pflege sowie Anästhesisten und Anästhesiepflege wurden erfasst. Für die Erprobung einer maßgeschneiderten Intervention wurden 2 OP-Bereiche ausgewählt. Zur Überprüfung der Effektivität erfolgten nur in einem OP-Bereich eine maßgeschneiderte Fortbildung und sog. Compliance-Begleitungen mit direktem Feedback durch die Hygienefachkräfte. In dem anderen OP-Bereich erfolgte keine Intervention. Ergebnis: Über 1500 Indikationen zur Händehygiene wurden in den Jahren 2017 und 2018 im operativen Bereich erfasst. Die Gesamt-Compliance der Interventionsgruppe konnte im Beobachtungszeitraum von 40 auf 75 % gesteigert werden (p&lt; 0,001). Die Gesamt-Compliance der Kontrollgruppe veränderte sich nicht signifikant (48 auf 55 %; p= 0,069). Diskussion: Durch die hohe Compliance-Rate bei der chirurgischen Händedesinfektion entstand die Annahme, die Compliance bei der hygienischen Händedesinfektion sei ebenfalls auf einem hohen Niveau. Im Rahmen der Feedbackgespräche zeigte sich, dass die Mitarbeiter nicht wussten, dass die Indikationen der „5 Momente der Händehygiene“ auch im OP anzuwenden seien, und zeigten somit ihr Unwissen über die assoziierten Indikationen.