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Objective: This systematic review and meta-analysis address the evidence on the association of psychological stressors with onset of multiple sclerosis, inflammatory disease activity (relapses or new disease activity on magnetic resonance imaging, MRI) and disability progression., Methods: PubMed was searched from 1946 to 15 July 2022. Studies and certain stressors were selected when they assessed stressors independent from stress elicited by the disease process itself. Risk of bias was assessed by the CASP Case Control Study Checklist and the CASP Cohort Study Checklist. Normal-Normal Hierarchical Model (NNHM) for random-effects meta-analysis was used in the Bayesian framework., Results: 30 studies reporting data from 26 cohorts reporting on 24.781 cases could be identified. Ten studies addressed stressors and MS disease onset showing a weak to modest effect of psychological stressors. A meta-analysis of three studies investigating diagnosed stress disorders and MS risk showed a 1.87-fold (CI 1.061 to 3.429) increased MS risk. Stress and MS relapse risk were addressed in 19 heterogeneous studies. Meta-analyses from two independent cohorts investigating the same military threat of a population showed a threefold increased risk for relapses in association with war (relapse rate: 3.0, CI 1.56 to 5.81). In addition, two studies confirmed an association of stressful life events and MRI activity. Three studies of stressors and disease progression were included indicating some effect on disease progression., Conclusions: Taken together studies indicate a minor to modest impact of psychological stressors on disease onset, inflammatory activity and progression of MS. Possible case-selection bias and lack of confounder analysis were present in many studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit., Competing Interests: DISCLOSURES The authors have no conflicts of interest to disclose.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: The diagnosis of delirium is challenging and requires precise definitions in both clinical routine and in studies., Aim: To point out various pitfalls in the clinical diagnosis of delirium and discuss solutions., Methods: Review., Results: Common problems include (a) clinical judgment of staff vs. the use of valid assessment tools, (b) different lists of criteria for delirium that may consider the symptoms of delirium differently and thus lead to inclusion or exclusion of patients, (c) different assessment tools that test the symptoms of delirium to different extents and thus have different accuracy, (d) patients with limited communication abilities, such as aphasia, where common tests often fail and alternative procedures may be more effective; (e) the decision whether to test delirium once, twice, three times, or more frequently in 24 h has consequences on the incidence and duration of delirium, (f) the end of delirium, often defined retrospectively as a delirium-free interval or prospectively as the time of transfer or occurrence of an exclusion criterion, can lead to considerable measurement inaccuracies., Conclusions: Although not all problems can be definitively answered, transparent definition, performance, and documentation of diagnostic procedures are recommended., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Optic nerve sheath (ONS) dilation indicates intracranial pressure elevation under clinical conditions but limited data exist with regard to the dynamics of sheath expansion., Objective: To assess the time course of ONS widening and its stability under controlled pressure conditions in vitro., Methods: Pre-defined pressure steps up to 65 mmHg were applied to the perineural space of ex-vivo human optic nerves (n = 16). Using ultrasound, the optic nerve sheath diameter (ONSD) was monitored over 500 s. Re-tests at low-pressure levels concluded each experimental series., Results: In most cases, 50% of the total diameter-change were achieved within 50 s after pressure onset and 95% of the maximal diameter after 200 s. The diametric gains in each experiment were strongly correlated with the applied pressure levels (coefficient of variance 0,96) within preparations with variability of the transfer function across preparations. The time course of the dilation was found to follow an approximate natural logarithmic function (R 2  = 0.93-0.99). The re-test condition revealed unchanged time course properties (5% significance level) despite starting regularly from a higher baseline-diameter after preceding exposures., Conclusions: ONS dilation commences rapidly after pressure exposure with a predictable time course over 3-4 min. Elasticity changes presumably affecting trabecular structures cause upward shifts of the optic nerve sheath pressure response. Clinically, ONSD shifts should be considered in serial measurements for increasing intracranial pressure monitoring, but relevant response delays are absent for lower or higher changes of intracranial pressure., (Copyright © 2022. Published by Elsevier B.V.)

Disorientation may present as a warning sign of developing delirium. The most commonly used delirium assessment tool in Germany, the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), does not rate "disorientation", since intubated patients cannot communicate verbally. However, the majority of German ICU patients are not orally intubated, so they could be examined for their orientation. This study was carried out to investigate whether the delirium feature "disorientation" in extubated patients yields diverging findings in comparison to the CAM-ICU and whether the sensitivity of the CAM-ICU may be improved when combined with the feature "disorientation" (CAM-IMC). A total of 86 paired assessments were completed in 50 extubated patients. Delirium was found in 19.8% (N = 17). The CAM-ICU had a sensitivity of 71% (95% confidence interval [CI] 44-90%) and a specificity of 100% (95-100%). Disorientation, if taken as the only delirium feature, had a sensitivity of 77% (50-93%) and a specificity of 93% (89-100%). The CAM-IMC reached a sensitivity of 88% (64-99%) and a specificity of 100% (95-100%). The receiver operating characteristics (ROC) analyses found an area under the curve (AUC) of 0.941 (95%CI 0.851-1.000) for the CAM-IMC, which was the highest compared to the other delirium tests (CAM-ICU, AUC 0.853 [0.720-0.986]; disorientation, AUC 0.868 [0.745-0.991]). This research emphasizes the importance of the feature "disorientation" for delirium assessments in patients able to verbally communicate and explains some controversial delirium ratings in daily practice. The CAM-IMC appears to be an attractive tool for delirium assessment in nonintubated patients and deserves further research., (© 2021. The Author(s).)

The potential toxicity and ecological risks of rare-earth nanoparticles in the environment have become a concern due to their widespread application and inevitable releases. The integration of hydroponics experiments, partial least squares structural equation modeling (PLS-SEM), and Transmission Electron Microscopy (TEM) were utilized to investigate the physiological toxicity, uptake and translocation of yttrium oxide nanoparticles (Y 2 O 3 NPs) under different hydroponic treatments (1, 5, 10, 20, 50 and 100 mg·L -1 of Y 2 O 3 NPs, 19.2 mg·L -1 Y(NO 3 ) 3 and control) in tomato (Lycopersicon esculentum) seedlings. The results indicated that Y 2 O 3 NPs had a phytotoxic effect on tomato seedlings' germination, morphology, physiology, and oxidative stress. The Y 2 O 3 NPs and soluble Y III reduced the root elongation, bud elongation, root activity, chlorophyll, soluble protein content and superoxide dismutase and accelerated the proline and malondialdehyde in the plant with increasing concentrations. The phytotoxic effects of Y 2 O 3 NPs on tomato seedlings had a higher phytotoxic effect than soluble Y III under the all treatments. The inhibition rates of different levels of Y 2 O 3 NPs in shoot and root biomass ranged from 0.2% to 6.3% and 1.0-11.3%, respectively. The bioaccumulation and translocation factors were less than 1, which suggested that Y 2 O 3 NPs significantly suppressed shoot and root biomass of tomato seedlings and easily bioaccumulated in the root. The observations were consistent with the process of concentration-dependent uptake and translocation factor and confirmed by TEM. Y 2 O 3 NPs penetrate the epidermis, enter the cell wall, and exist in the intercellular space and cytoplasm of mesophyll cells of tomato seedlings by endocytic pathway. Moreover, PLS-SEM revealed that the concentration of NPs significantly negatively affects the morphology and physiology, leading to the change in biomass of plants. This study demonstrated the possible pathway of Y 2 O 3 NPs in uptake, phytotoxicity and translocation of Y 2 O 3 NPs in tomato seedlings., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Meta-analyses show a variable relationship between optic nerve sheath diameter (ONSD) and the presence of raised intracranial pressure (ICP). Because optic nerve sheath (ONS) tissue can be deformed, it is possible that ONSD reflects not only the current ICP but also prior deforming biomechanical exposures. In this post hoc analysis of two published data sets, we characterize ONS Young's modulus (E, mechanical stress per unit of strain) and calculate threshold pressure for plastic deformation., Methods: The authors of two previously published articles contributed primary data for these unique post hoc analyses. Human cadaveric ex vivo measurements of ONSD (n = 10) and luminal distending pressure (range 5 to 65 mm Hg) were used to calculate E and the threshold pressure for plastic deformation. Clinical in vivo measurements of ONSD and ICP during endotracheal tube suction from patients with traumatic brain injury (n = 15) were used to validate the ex vivo cadaveric findings., Results: Ex vivo ONS estimate of E was 140 ± 1.3 mm Hg (mean ± standard error), with evidence of plastic deformation occurring with distending pressure at 45 mm Hg. Similar E (71 ± 10 mm Hg) was estimated in vivo with an average ICP of 34 ± 2 mm Hg., Conclusions: Ex vivo, ONS plastic deformation occurs at levels of pressure commonly seen in patients with raised ICP, leading to distortion of the ICP-ONSD relationship. This evidence of plastic deformation may illustrate why meta-analyses fail to identify a single threshold in ONSD associated with the presence of raised ICP. Future studies characterizing time-dependent viscous characteristics of the ONS will help determine the time course of ONS tissue biomechanical behavior., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Post-stroke delirium (POD) in patients on stroke units (SU) is associated with an increased risk for complications and poorer clinical outcome. The objective was to reduce the severity of POD by implementing an interprofessional delirium-management., Methods: Multicentric quality-improvement project on five SU implementing a delirium-management with pre/post-comparison. Primary outcome was severity of POD, assessed with the Nursing Delirium Screening Scale (Nu-DESC). Secondary outcome parameters were POD incidence, duration, modified Rankin Scale (mRS), length of stay in SU and hospital, mortality, and others., Results: Out of a total of 799 patients, 59.4% (n = 475) could be included with 9.5% (n = 45) being delirious. Implementation of a delirium-management led to reduced POD severity; Nu-DESC median: pre: 3.5 (interquartile range 2.6-4.7) vs. post 3.0 (2.2-4.0), albeit not significant (p = 0.154). Other outcome parameters were not meaningful different. In the post-period, delirium-management could be delivered to 75% (n = 18) of delirious patients, and only 24 (53.3%) of delirious patients required pharmacological treatments. Patients with a more severe stroke and POD remained on their disability levels, compared to similar affected, non-delirious patients who improved., Conclusions: Implementation of delirium-management on SU is feasible and can be delivered to most patients, but with limited effects. Nursing interventions as first choice could be delivered to the majority of patients, and only the half required pharmacological treatments. Delirium-management may lead to reduced severity of POD but had only partial effects on duration of POD or length of stay. POD hampers rehabilitation, especially in patients with more severe stroke., Registry: DRKS, DRKS00021436. Registered 04/17/2020, www.drks.de/DRKS00021436 ., (© 2022. The Author(s).)

The impact of land use type on the content of potentially toxic elements (PTEs) in the soils of the Qinghai-Tibet Plateau (QTP) and the associated ecological and human health risks has drawn great attention. Consequently, in this study, top- and subsurface soil samples were collected from areas with four different land uses (i.e., cropland, forest, grassland, and developed area) and the total contents of Cr, Cd, Cu, Pb and Zn were determined. Geostatistical analysis, self-organizing map (SOM), and positive matrix factorization (PMF), ecological risk assessment (ERA) and human health risk assessment (HRA) were applied and used to classify and identify the contamination sources and assess the potential risk. Partial least squares path modeling (PLS-PM) was applied to clarify the relationship of land use with PTE contents and risk. The PTE contents in all topsoil samples surpassed the respective background concentrations of China and corresponding subsurface concentrations. However, the ecological risk of all soil samples remained at a moderate or considerable level across the four land use types. Developed area and cropland showed a higher ecological risk than the other two land use types. Industrial discharges (32.8%), agricultural inputs (22.6%), natural sources (23.7%), and traffic emissions (20.9%) were the primary PTE sources in the tested soils, which indicate that anthropogenic activities have significantly affected soil PTE contents to a greater extent than other sources. Industrial discharge was the most prominent source of non-carcinogenic health risk, contributing 37.7% for adults and 35.2% for children of the total risk. The results of PLS-PM revealed that land use change associated with intensive human activities such as industrial activities and agricultural practices distinctly affected the PTE contents in soils of the Qinghai-Tibet Plateau., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

BPTF (bromodomain and PHD finger containing transcription factor) is a multidomain protein that plays essential roles in transcriptional regulation, T-cell homeostasis and stem cell pluripotency. As part of the chromatin remodeling complex hNURF (nucleosome remodeling factor), BPTF epigenetic reader subunits are particularly important for BPTF cellular function. Here we report the synthesis of NVS-BPTF-1, a previously reported highly potent and selective BPTF-bromodomain inhibitor. Evaluation of the impact of the inhibition of BPTF-bromodomain using NVS-BPTF-1 on selected proteins involved in the antigen processing pathway revealed that exclusively targeting BPTF-bromodomain is insufficient to observe an increase of PSMB8, PSMB9, TAP1 and TAP2 proteins., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

PB1 is a bromodomain-containing protein hypothesized to act as the nucleosome-recognition subunit of the PBAF complex. Although PB1 is a key component of the PBAF chromatin remodeling complex, its exact role has not been elucidated due to the lack of potent and selective inhibitors. Chemical probes that target specific bromodomains within the complex would constitute highly valuable tools to characterize the function and therapeutic pertinence of PB1 and of each of its bromodomains. Here, we report the design and synthesis of lead compound LM146 , which displays strong stabilization of the second and fifth bromodomains of PB1 as shown by DSF. LM146 does not interact with bromodomains outside of sub-family VIII and binds to PB1(2), PB1(5), and SMARCA2B with K D values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5) over SMARCA2., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Brain death (irreversible loss of brain function), according to German regulations, is investigated exclusively by qualified specialists in a strictly hierarchical three-step pattern and a four-eyes principle. In step 1 all necessary prerequisites are to be checked and the pathophysiology of brain damage has to be classified. Step 2 comprises the clinical investigation of reactivity to external stimuli and the upper, middle and lower brain stem reflexes including apnea testing. Step 3 exclusively checks for irreversibility of this condition. The latter is achieved by appropriate technical investigations or by repeated clinical examinations within context-specified intervals (range 12-72 h). However, exclusion of contributing primarily infratentorial pathologies is necessary to avoid limitations of the clinical findings. In this paper, both the initiation of brain death diagnostics and the approved clinical tests regarding to their execution, their alternatives and limits are presented and special situations like conditions with extracorporeal membrane oxygenation (ECMO) are also examined.

Layered double hydroxides (LDH) and their magnetic composites have been intensively investigated as recyclable high-capacity phosphate sorbents but with little attention to their stability as function of pH and phosphate concentration. The stability of a Fe 3 O 4 @SiO 2 -Mg 3 Fe LDH P sorbent as function of pH (5-11) and orthophosphate (P i ) concentration (1-300 mg P/L) was investigated. The composite has high adsorption capacity (approx. 80 mg P/g) at pH 5 but with fast dissolution of the LDH component resulting in formation of ferrihydrite as evidenced by Mössbauer spectroscopy. At pH 7 more than 60% of the LDH dissolves within 60 min, while at alkaline pH, the LDH is more stable but with less than 40% adsorption capacity as compared to pH 5. The high P i sorption at acid to neutral pH is attributed to P i bonding to the residual ferrihydrite. Under alkaline conditions P i is sorbed to LDH at low P i concentration while magnesium phosphates form at higher P i concentration evidenced by solid-state 31 P MAS NMR, powder X-ray diffraction and chemical analyses. Sorption as function of pH and P i concentration has been fitted by a Rational 2D function allowing for estimation of P i sorption and precipitation. In conclusion, the instability of the LDH component limits its application in wastewater treatment from acid to alkaline pH. Future use of magnetic LDH composites requires substantial stabilisation of the LDH component., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Biochars function as electron transfer mediators and thus catalyze redox transformations of environmental pollutants. A previous study has shown that bone char (BC) has high catalytic activity for reduction of chlorinated ethylenes using layered Fe(II)-Fe(III) hydroxide (green rust) as reductant. In the present study, we studied the rate of trichloroethylene (TCE) reduction by green rust in the presence of BCs obtained at pyrolysis temperatures (PTs) from 450 to 1050 °C. The reactivity increased with PT, yielding a maximum pseudo-first-order rate constant ( k ) of 2.0 h -1 in the presence of BC pyrolyzed at 950 °C, while no reaction was seen for BC pyrolyzed at 450 °C. TCE sorption, specific surface area, extent of graphitization, carbon content, and aromaticity of the BCs also increased with PT. The electron-accepting capacity (EAC) of BC peaked at PT of 850 °C, and EAC was linearly correlated with the sum of concentrations of quinoid, quaternary N, and pyridine-N-oxide groups measured by XPS. Moreover, no TCE reduction was seen with graphene nanoparticles and graphitized carbon black, which have high degrees of graphitization but low EAC values. Further analyses showed that TCE reduction rates are well correlated with the EAC and the C/H ratio (proxy of electrical conductivity) of the BCs, strongly indicating that both electron-accepting functional groups and electron-conducting domains are crucial for the BC catalytic reactivity. The present study delineates conditions for designing redox-reactive biochars to be used for remediation of sites contaminated with chlorinated solvents.

Bacillus licheniformis is frequently associated with food spoilage due to its ability to form highly resistant endospores. The present study reveals that B. licheniformis spore peptidoglycan shares a similar structure to spores of other species of Bacillus. Two enzymatic activities associated with depolymerisation of the cortical peptidoglycan, which represents a crucial step in spore germination, were detected by muropeptide analysis. These include lytic transglycosylase and N-acetylglucosaminidase activity, with non-lytic epimerase activity also being detected. The role of various putative cortex-lytic enzymes that account for the aforementioned activity was investigated by mutational analysis. These analyses indicate that SleB is the major lysin involved in cortex depolymerisation in B. licheniformis spores, with CwlJ and SleL having lesser roles. Collectively, the results of this work indicate that B. licheniformis spores employ a similar approach for cortical depolymerisation during germination as spores of other Bacillus species., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinicians are commonly confronted with the differential diagnosis of altered mental status, impaired cognition and altered level of consciousness in hospitalized patients including those admitted to medical, geriatric, emergency, intensive and post-operative care units. Although delirium is the most common acute neuropsychiatric condition in the acute hospital setting this diagnosis is commonly delayed, made too late or missed altogether., Difficulties and Importance of Timely Diagnosis: The causes of delirious states are manifold. Both, direct damage to the brain tissue as well as encephalopathy as a result of other medical diseases, can be the cause of delirium. Depending on the predisposition delirious syndromes can be provoked by minor medical interventions. Clinical presentation is very variable, but remains largely independent of the triggering mechanisms. Purely catatonic, hypoactive, hyperactive and excitatory types as well as mixed forms can be distinguished.Immediate diagnosis of a delirious syndrome and rapid elucidation of its causes are keys for the implementation of curative therapy. There is a need to act fast because delirious phases are associated with significantly longer hospital stay and increased morbidity as a result of long-term cognitive deficits as well as increased mortality. As negative outcome is closely linked to the duration of a delirious episode, early diagnosis and rapid termination of the delirium constitute a significant positive predictor of outcome. In this respect, delirium represents an emergency, with or without concomitant cerebral or extracerebral symptoms., Competing Interests: Die Autoren erhielten Vortragshonorare und Reisekosten von der Fa. ORION Pharma., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background/aim: For treatment of brain metastases, a patient's survival prognosis should be considered. Existing survival scores appear complex and require complete tumor staging. For many patients, a faster and simpler tool would be helpful., Patients and Methods: This retrospective study investigated the prognostic value of the number of pre-treatment symptoms plus eight other factors on survival of patients irradiated for brain metastases. Other factors included whole-brain radiotherapy (WBRT) regimen, age, gender, performance score, primary tumor type, number of brain metastases, extracranial metastases, and interval between cancer diagnosis and WBRT., Results: The number of symptoms (p=0.002) and all other factors were significantly associated with survival on univariate analyses. On multivariate analysis, all factors but the number of symptoms (p=0.47) and primary tumor type (p=0.48) were significant., Conclusion: Since the number of symptoms was not an independent predictor of survival, it cannot replace existing scoring tools and may only serve for orientation., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Personalized treatment helps one achieve optimal outcomes in patients with non-small cell lung cancer (NSCLC). Understanding patients' survival prognoses in a palliative situation like intracerebral metastases is critical. A new survival score, the WBRT-30-NSCLC, was developed for patients with intracerebral metastases from NSCLC., Methods: Eight factors were investigated in 157 patients receiving 10 × 3 Gy of whole-brain radiotherapy (WBRT) including age, gender, Karnofsky performance score (KPS), interval from diagnosis of NSCLC to WBRT, pre-WBRT systemic treatment, primary tumor control, number of intracerebral metastases, and metastasis outside the brain. Factors significant (p < 0.05) or showing a trend (p < 0.08) on multivariate analysis were used for the WBRT-30-NSCLC. Patient scores were derived by adding factor scores (6-month survival rates divided by 10). WBRT-30-NSCLC was compared to other scores for intracerebral metastases from NSCLC., Results: On multivariate analysis, age (p = 0.005), KPS (p < 0.001), systemic treatment (p = 0.018), and metastasis outside the brain (p < 0.001) were significant; number of intracerebral metastases (p = 0.075) showed a trend. Four groups were designed (912, 1317, 1820, and 22 points) with 6-month survival rates of 3, 26, 65, and 100%. Positive predictive value (PPV) to predict death ≤ 6 months after WBRT was 97% (updated DS-GPA classification 86%, Rades-NSCLC 88%), and PPV to predict survival ≥ 6 months was 100% (updated DS-GPA 78%, Rades-NSCLC 74%)., Conclusions: The WBRT-30-NSCLC appeared very precise in identifying patients with intracerebral metastases from NSCLC dying ≤ 6 months or surviving ≥ 6 months. It appeared more precise than previous scores and can support physicians developing personalized treatment regimens.

Background Previous survival scores for breast cancer patients with cerebral metastases were developed in cohorts receiving heterogeneous treatments, which could have introduced selection biases. A new instrument (WBRT-30-BC) was created from 170 patients receiving whole-brain radiotherapy (WBRT) alone with 30 Gy in 10 fractions. Methods Characteristics showing significant associations (p < 0.05) with overall survival (OS) or a trend (p < 0.08) on multivariate analysis were used for the WBRT-30-BC. For each characteristic, 6-month OS rates were divided by 10. These scoring points were added for each patient (patient scores). The WBRT-30-BC was compared to the diagnosis- specific graded prognostic assessment (DS-GPA) classification and Rades-Score for breast cancer regarding positive predictive values (PPVs) to identify patients dying within 6 months and patients surviving at least 6 months following WBRT. Results On multivariate analysis, Karnofsky performance score (KPS) was significant (risk ratio [RR]: 2.45, p < 0.001). In addition, extra-cerebral metastatic disease (RR: 1.52, p = 0.071) and time between breast cancer diagnosis and WBRT (RR: 1.37, p = 0.070) showed a trend. Based on these three characteristics, four predictive groups were designed: 7-9, 10-12, 13-15 and 16 points. Six-month OS rates were 8%, 41%, 68% and 100% (p < 0.001). PPVs to identify patients dying within 6 months were 92% (WBRT-30-BC), 84% (DS-GPA) and 92% (Rades-Score). PPVs to identify patients surviving for at least 6 months were 100% (WBRT-30-BC), 74% (DS-GPA) and 68% (Rades-Score). Conclusions The WBRT-30-BC appeared very accurate in predicting death ≤ 6 months and survival ≥ 6 months of breast cancer patients receiving WBRT. It was superior to previous instruments in predicting survival ≥ 6 months.

Background/aim: Existing survival scores for patients with brain metastases were created in heterogeneously treated cohorts. A new score was developed in 56 patients with brain metastases from colorectal cancer treated with 10×3 Gy of whole-brain radiotherapy (WBRT)., Patients and Methods: Factors found significantly associated with survival (p<0.05) or showing a trend (p<0.08) were included in the tool. The new WBRT-30-CRC was compared to diagnosis-specific graded prognostic assessment (DS-GPA) classification for gastrointestinal cancers., Results: The WBRT-30-CRC included four prognostic groups: 3-4, 5-6, 7-9 and 10 points. Six-month survival rates were 0%, 15%, 38% and 80%. PPV of the 3-4 points-group predicting death ≤6 months was 100% (91% for DS-GPA of 0.0-1.0). PPV of the 10 points-group predicting survival ≥6 months was 80% (0% DS-GPA of 3.5-4.0, 33% DS-GPA of 3.0-4.0)., Conclusion: The WBRT-30-CRC appeared very precise in identifying patients with brain metastases from colorectal cancer dying ≤6 months or surviving ≥6 months., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: A new tool for estimating survival of patients receiving whole-brain radiotherapy (WBRT) for intracerebral metastases from renal cell carcinoma (RCC) was created., Patients and Methods: The new WBRT-30-RCC was developed in 34 patients homogeneously treated with 30 Gy in 10 fractions of WBRT and compared to updated diagnosis-specific graded prognostic assessment DS-GPA and Dziggel score for predicting death within 6 months and survival for at least 6 months following WBRT., Results: WBRT-30-RCC included three groups with 6-month survival rates of 6.7% for those with 8-10 points, 38.5% for those with 12-14 points and 66.7% for those with 16-18 points. Positive predictive values (PPV)s for predicting death within 6 months were 93.3% using WBRT-30-RCC, 77.3% using updated DS-GPA and 93.7% using the Dziggel score. PPVs for predicting survival for at least 6 months were 66.7%, 50.0% and 50.0%, respectively., Conclusion: WBRT-30-RCC was more precise than the other scores in predicting survival for at least 6 months, although all three scores were not optimal. For predicting death within 6 months, WBRT-30-RCC and Dziggel score were similarly accurate and superior to the updated DS-GPA., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In 2015, the German Medical Association (Bundesärztekammer) issued new guidelines on the diagnosis of the "irreversible loss of brain function" (ILBF). ILBF replaced the colloquial term "brain death" in order to leave the notion that concepts of death might vary such as "cardiac death" or "apparent death" and stress the objective medical-scientific matter. The German Transplantation Law describes ILBF as "the final, irreversible loss of all function of the cerebrum, cerebellum, and brainstem." The new guidelines are to be followed closely. They demand higher qualifications of physicians involved in the diagnosis of ILBF and emphasize at the same time the interdisciplinary approach and the mandatory involvement of at least one specialist in the neurological field. Several technical methods were added as additional tools to support the ILBF diagnosis such as CT-angiography and duplex ultrasound of brain and neck vessels. The new guidelines thereby raise the impact of demonstrating complete cerebral circulatory arrest but leave other options to prove irreversibility. Many procedures, such as the apnea test, were specified in more detail. This article summarizes the new features of the new guideline with a practical overview on who must be involved in the diagnosis of ILBF, how often, how the diagnosis is achieved stepwise from stage I to III and how it is secured as well as what technical methods may be involved at what stage of the procedure.

Background/aim: The interval between diagnostic imaging and whole-brain radiotherapy (WBRT) had no significant impact on survival in our previous study of WBRT for brain metastases. Since median survival time was only 2 months, a potentially negative impact by delaying treatment could have been missed. Therefore, we performed an additional analysis of patients surviving at least 4 months following irradiation., Patients and Methods: The interval between diagnosis of brain metastases and WBRT and ten other factors were retrospectively analyzed for survival in 191 patients surviving 4 months or longer following WBRT., Results: On univariate analyses, Eastern Cooperative Oncology Group (ECOG) performance score of 0-1, 1-3 brain metastases and absence of extra-cerebral metastases were significantly associated with longer survival, whereas the interval from diagnostic imaging to WBRT was not. On multivariate analysis, ECOG performance score remained significant, and extra-cerebral metastases showed a trend towards a longer survival., Conclusion: The interval between diagnostic imaging and WBRT didn't have a significant impact on patients surviving 4 months or longer. Depending on the need for symptom relief, WBRT may be postponed for very important reasons such as obtaining a multidisciplinary tumor board decision or definitive histology., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Diagnosis-specific scoring systems developed for predicting survival of patients with cerebral metastases from malignant melanoma (MM) were evaluated., Patients and Methods: The new whole-brain radiotherapy (WBRT)-30-MM was created in homogeneously treated patients receiving 10×3 Gy of WBRT for cerebral metastases from MM. It consisted of three groups with significantly different 6-month survival rates of 0% (3-5 points), 30% (7 points) and 52% (9 points) (p=0.001). The WBRT-30-MM was compared to three other scores created for cerebral metastases from MM, including first updated DS-GPA classification, Dziggel-Score and Sehmisch-Score., Results: Positive predictive values (PPVs) for predicting death ≤6 months after WBRT were 100% (WBRT-30-MM), 77% (DS-GPA), 69% (Dziggel-Score) and 73% (Sehmisch-Score). PPVs for predicting survival ≥6 months were 52%, 38%, 63% and 75%, respectively., Conclusion: WBRT-30-MM was the most accurate instrument for predicting death ≤6 months. For predicting survival ≥6 months, Sehmisch-Score was most accurate, although all existing scorring systems appeared suboptimal for this purpose., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Diagnosis-specific survival scores including a new score developed in 157 patients with brain metastases from small-cell lung cancer (SCLC) receiving whole-brain radiotherapy (WBRT) with 30 Gy in 10 fractions (WBRT-30-SCLC) were compared. Three prognostic groups were designed based on the 6-month survival probabilities of significant or almost significant factors, (age, performance score, number of brain metastases, extra-cerebral metastasis). Six-month survival rates were 6% (6⁻11 points), 44% (12⁻14 points) and 86% (16⁻19 points). The WBRT-30-SCLC was compared to three disease-specific scores for brain metastasis from SCLC, the original and updated diagnosis-specific graded prognostic assessment DS-GPA classifications and the Rades-SCLC. Positive predictive values (PPVs) used to correctly predict death ≤6 months were 94% (WBRT-30-SCLC), 88% (original DS-GPA), 88% (updated DS-GPA) and 100% (Rades-SCLC). PPVs to predict survival ≥6 months were 86%, 75%, 76% and 100%. For WBRT-30-SCLC and Rades-SCLC, differences between poor and intermediate prognoses groups and between intermediate and favorable prognoses groups were significant. For both DS-GPA classifications, only the difference between poor and intermediate prognoses groups was significant. Of these disease-specific tools, Rades-SCLC appeared to be the most accurate in identifying patients dying ≤6 months and patients surviving ≥6 months after irradiation, followed by the new WBRT-30-SCLC and the DS-GPA classifications.

Background/aim: Many patients with brain metastases receive whole-brain radiotherapy (WBRT). An important question is whether a delay between diagnosis of brain metastases and treatment impairs the patient's prognosis., Patients and Methods: This retrospective study investigated the impact of the interval between diagnosis of brain metastases and WBRT plus ten additional factors on overall survival (OS) in 573 patients. Prospective trials cannot be performed due to ethical concerns., Results: On univariate analyses, age (p<0.001), performance status (p<0.001), controlled primary tumor (p=0.047), metastases outside the brain (p<0.001) and completion of WBRT (p<0.001) were associated with OS. The interval between diagnosis and WBRT had no significant impact (p=0.84). On multivariate analysis, age (p=0.047), performance status (p<0.001), metastases outside the brain (p=0.029) and completion of WBRT (p<0.001) maintained significance., Conclusion: WBRT may be postponed for good reasons (multidisciplinary coordination of treatment, missing histology). OS was significantly associated with previously identified factors, which demonstrates consistency of the present data., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.

Layered Fe II -Fe III hydroxide chloride (chloride green rust, GR Cl ) has high reactivity toward reducible pollutants such as chlorinated solvents. However, this reactive solid is prone to dissolution, and hence loss of reactivity, during storage and handling. In this study, adsorption of silicate (Si) to GR Cl was tested for its ability to minimize GR Cl dissolution and to inhibit reduction of carbon tetrachloride (CT). Silicate adsorbed with high affinity to GR Cl yielding a sorption maximum of 0.026 g of Si/g of GR Cl . In the absence of Si, the pseudo-first-order rate constant for CT dehalogenation by GR Cl was 2.1 h -1 , demonstrating very high reactivity of GR Cl but with substantial Fe II dissolution up to 2.5 mM. When Si was adsorbed to GR Cl , CT dehalogenation was blocked and Fe II dissolution extent was reduced by a factor of 28. The addition of glycine (Gly) was tested for reactivation of the Si-blocked GR Cl for CT dehalogenation. At 30 mM Gly, partial reactivation of the GR Cl was observed with pseudo-first-order rate constant for CT reduction of 0.075 h -1 . This blockage and reactivation of GR Cl reactivity demonstrates that it is possible to design a switch for GR Cl to control its stability and reactivity under anoxic conditions.

Plants produce a multitude of metabolites that contribute to their fitness and survival and play a role in local adaptation to environmental conditions. The effects of environmental variation are particularly well studied within the genus Plantago ; however, previous studies have largely focused on targeting specific metabolites. Studies exploring metabolome-wide changes are lacking, and the effects of natural environmental variation and herbivory on the metabolomes of plants growing in situ remain unknown. An untargeted metabolomic approach using ultra-high-performance liquid chromatography-mass spectrometry, coupled with variation partitioning, general linear mixed modeling, and network analysis was used to detect differences in metabolic phenotypes of Plantago major in fifteen natural populations across Denmark. Geographic region, distance, habitat type, phenological stage, soil parameters, light levels, and leaf area were investigated for their relative contributions to explaining differences in foliar metabolomes. Herbivory effects were further investigated by comparing metabolomes from damaged and undamaged leaves from each plant. Geographic region explained the greatest number of significant metabolic differences. Soil pH had the second largest effect, followed by habitat and leaf area, while phenological stage had no effect. No evidence of the induction of metabolic features was found between leaves damaged by herbivores compared to undamaged leaves on the same plant. Differences in metabolic phenotypes explained by geographic factors are attributed to genotypic variation and/or unmeasured environmental factors that differ at the regional level in Denmark. A small number of specialized features in the metabolome may be involved in facilitating the success of a widespread species such as Plantago major into such wide range of environmental conditions, although overall resilience in the metabolome was found in response to environmental parameters tested. Untargeted metabolomic approaches have great potential to improve our understanding of how specialized plant metabolites respond to environmental change and assist in adaptation to local conditions.

Intensive human activities, in particular agricultural and industrial production have led to heavy metal accumulation in the peri-urban agricultural soils of China threatening soil environmental quality and agricultural product security. A combination of spatial analysis (SA), Pb isotope ratio analysis (IRA), input fluxes analysis (IFA), and positive matrix factorization (PMF) model was successfully used to assess the status and sources of heavy metals in typical peri-urban agricultural soils from a rapidly developing region of China. Mean concentrations of Cd, As, Hg, Pb, Cu, Zn and Cr in surface soils (0-20 cm) were 0.31, 11.2, 0.08, 35.6, 44.8, 119.0 and 97.0 mg kg -1 , respectively, exceeding the local background levels except for Hg. Spatial distribution of heavy metals revealed that agricultural activities have significant influence on heavy metal accumulation in the surface soils. Isotope ratio analysis suggested that fertilization along with atmospheric deposition were the major sources of heavy metal accumulation in the soils. Based on the PMF model, the relative contribution rates of the heavy metals due to fertilizer application, atmospheric deposition, industrial emission, and soil parent materials were 30.8%, 33.0%, 25.4% and 10.8%, respectively, demonstrating that anthropogenic activities had significantly higher contribution than natural sources. This study provides a reliable and robust approach for heavy metals source apportionment in this particular peri-urban area with a clear potential for future application in other regions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background/aim: Patients with cerebral metastases from gynecological cancer who receive whole-brain irradiation (WBI) alone require personalized therapy. This study contributes to personalized care by creating an instrument to predict 6-month survival probability., Patients and Methods: In 49 patients, six pre-treatment variables, namely age, Eastern Cooperative Oncology Group performance score (ECOG-PS), primary tumor type, number of cerebral metastases, metastasis outside the brain, and interval between diagnosis of gynecological cancer and WBI, were analyzed for survival., Results: Of the six pre-treatment variables, ECOG-PS was significantly associated with survival (p=0.014) and metastasis outside the brain showed a trend for association (p=0.096). Six-month survival rates divided by 10 resulted in scores of 0, 2 or 7 points for ECOG-PS and of 2 or 7 points for metastasis outside the brain. Scores for individual patients were 2, 4, 7, 9 or 14 points. Three groups were created, those with 2-7, 9 and 14 points, with 6-month survival rates of 10%, 53% and 100%, respectively (p=0.004)., Conclusion: An instrument was designed to predict the 6-month survival of patients receiving WBI for cerebral metastases from gynecological cancer and facilitate personalized care., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Non-typhoidal Salmonella (NTS) are foodborne pathogens of global public health significance. The aim of this study was to subtype a collection of 85 NTS originating from poultry farms in Uganda, and to evaluate a subgroup of phenotypically resistant isolates for common antimicrobial resistance genes and associated integrons. All isolates were subtyped by pulsed-field gel electrophoresis (PFGE). Phenotypically resistant isolates ( n = 54) were screened by PCR for the most relevant AMR genes corresponding to their phenotypic resistance pattern, and all 54 isolates were screened by PCR for the presence of integron class 1 and 2 encoding genes. These genes are known to commonly encode resistance to ampicillin, tetracycline, ciprofloxacin, trimethoprim, sulfonamide and chloramphenicol. PFGE revealed 15 pulsotypes representing 11 serotypes from 75 isolates, as 10 were non-typable. Thirty one (57.4%) of the 54 resistant isolates carried at least one of the seven genes ( bla TEM-1, cmlA, tetA, qnrS, sul1, dhfrI, dhfrVII) identified by PCR and six (11%) carried class 1 integrons. This study has shown that a diversity of NTS-clones are present in Ugandan poultry farm settings, while at the same time similar NTS-clones occur in different farms and areas. The presence of resistance genes to important antimicrobials used in human and veterinary medicine has been demonstrated, hence the need to strengthen strategies to combat antimicrobial resistance at all levels., Competing Interests: The authors declare no conflict of interest.

Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity., (Copyright © 2017 The Author(s).)

A novel zinc (Zn) fertilizer concept based on Zn-doped layered double hydroxides (Zn-doped Mg-Fe-LDHs) has been investigated. Zn-doped Mg-Fe-LDHs were synthesized, their chemical composition was analyzed, and their nutrient release was studied in buffered solutions with different pH values. Uptake of Zn by barley (Hordeum vulgare cv. Antonia) was evaluated in short- (8 weeks), medium- (11 weeks), and long-term (28 weeks) experiments in quartz sand and in a calcareous soil enriched with Zn-doped Mg-Fe-LDHs. The Zn release rate of the Zn-doped Mg-Fe-LDHs was described by a first-order kinetics equation showing maximum release at pH 5.2, reaching approximately 45% of the total Zn content. The Zn concentrations in the plants receiving the LDHs were between 2- and 9.5-fold higher than those in plants without Zn addition. A positive effect of the LDHs was also found in soil. This work documents the long-term Zn release capacity of LDHs complying with a release-on-demand behavior and serves as proof-of-concept that Zn-doped Mg-Fe-LDHs can be used as Zn fertilizers.

Inhibition of bromo and extra-terminal (BET) bromodomains, including BRD4, has emerged as a new exciting epigenetic target for oncology, in particular. Recently, novel alternatives to the traditional use of reversible small molecules have emerged, including proteolytic targeting BET agents and irreversible binding inhibitors. These alternatives to reversible inhibitors may offer some advantage and can be used as tools to further decipher the underlying biology. Supportive pre-clinical data have these novel approaches bound for clinical development in the near future., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chinese greenhouse vegetable production can cause eutrophication of fresh waters due to heavy use of fertilizers. To address this, phosphorus (P) leaching was compared between two major greenhouse vegetable soils from Jiangsu Province, Southeast China: clayey and acid-neutral Guli Orthic Anthrosols and sandy and alkaline Tongshan Ustic Cambosols. A total of 20 intact soil columns were collected based on differences in total P content varying between 1360 and 11,220 mg kg -1 . Overall, six leaching experiments were carried out with collection of leachates over 24 h. Very high P concentrations, with a mean of 3.43 mg L -1 , were found in the leachates from P rich Tongshan soils. In contrast, P leaching from fine-textured but less P rich Guli soils rarely exceeded the suggested environmental P threshold of 0.1 mg L -1 . Strong linear correlations were found between different soil test P measures (STPs) or degree of P saturations (DPSs) and dissolved reactive P (DRP) for Tongshan soil columns. The correlations with Olsen P (r 2  = 0.91) and DPS based on MehlichIII extractable calcium (DPS M3-Ca ) (r 2  = 0.87) were the most promising. An Olsen P value above 41 mg kg -1 or a DPS M3-Ca above 3.44% led to DRP leaching exceeding 0.1 mg L -1 . Accordingly, more than 80% of Tongshan soils resulted in DRP leaching exceeding the environmental P threshold. In conclusion P rich alkaline sandy soils used for greenhouse vegetable production are at high risk of P mobilization across China., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Layered Fe II -Fe III hydroxides (green rusts, GRs) are promising reactants for reductive dechlorination of chlorinated solvents due to high reaction rates and the opportunity to inject reactive slurries of the compounds into contaminant plumes. However, it is necessary to develop strategies that reduce the formation of toxic byproducts such as chloroform (CF). In this study, carbon tetrachloride (CT) dehalogenation by the chloride form of GR (GR Cl ) was tested in the presence of glycine (GLY) and other selected amino acids. GLY, alanine (ALA), and serine (SER) all resulted in remarkable suppression of CF formation with only ∼10% of CF recovery while sarcosine (SAR) showed insignificant effects. For two nonamino acid buffers, TRIS had little effect while HEPES resulted in a 40 times lower rate constant compared to experiments in which no buffer was added. The Fe II complexing properties of the amino acids and buffers caused variable extents of GR Cl dissolution which was linearly correlated with CF suppression and dehalogenation rate. We hypothesize that the CF suppression seen for amino acids is caused by stabilization of carbene intermediates via the carbonyl group. Different effects on CF suppression and CT dehalogenation rate were expected because of the different structural and chemical properties of the amino acids.

In the rainy season, rice growing areas in Vietnam often become flooded by up to 1.5 m water. The floodwater brings contaminants from cultivated areas, farms and villages to the rice fields resulting in widespread contamination. In 2012 and 2013, the inorganic and organic contaminants in floodwater was investigated in Thanh Hoa and Hue. Water samples were taken at 16 locations in canals, paddy fields and rivers before and during the flood. In total, 940 organic micro-pollutants in the water samples were determined simultaneously by GC-MS method with automatic identification and quantification system (AIQS), while ICP-MS was used for determination of ten trace elements in the samples. The concentrations of 277 organic micro-pollutants and ten elements (As, Cu, Cd, Cr, Co, Pb, Zn, Fe, Mn, Al) ranged from 0.01 to 7.6 μg L -1 and 0.1 to 3170 μg L -1 , respectively, in the floodwater. Contaminants originated from industrial sources (e.g. PAH) were detected at low concentrations, ranged from 0.01 to 0.18 μg L -1 , while concentrations of pollutants originated from domestic sources (e.g. sterols, pharmaceuticals and personal care products and pesticides) were ranged from 0.01 to 2.12 μg L -1 . Isoprocarb had the highest detection frequency of 90%, followed by isoprothiolane (88%) and fenobucarb (71%). The results indicated that contaminants in floodwater come from untreated wastewater from villages, and the agricultural activities are the major sources of increased pesticides resuspended in the floodwater in this study.