Diquat Derivatives: Highly Active, Two-Dimensional Nonlinear Optical Chromophores with Potential Redox Switchability

In this article, we present a detailed study of structure−activity relationships in diquaternized 2,2′-bipyridyl (diquat) derivatives. Sixteen new chromophores have been synthesized, with variations in the amino electron donor substituents, π-conjugated bridge, and alkyl diquaternizing unit. Our aim is to combine very large, two-dimensional (2D) quadratic nonlinear optical (NLO) responses with reversible redox chemistry. The chromophores have been characterized as their PF_6^− salts by using various techniques including electronic absorption spectroscopy and cyclic voltammetry. Their visible absorption spectra are dominated by intense π → π^* intramolecular charge-transfer (ICT) bands, and all show two reversible diquat-based reductions. First hyperpolarizabilities β have been measured by using hyper-Rayleigh scattering with an 800 nm laser, and Stark spectroscopy of the ICT bands affords estimated static first hyperpolarizabilities β_0. The directly and indirectly derived β values are large and increase with the extent of π-conjugation and electron donor strength. Extending the quaternizing alkyl linkage always increases the ICT energy and decreases the E_(1/2) values for diquat reduction, but a compensating increase in the ICT intensity prevents significant decreases in Stark-based β_0 responses. Nine single-crystal X-ray structures have also been obtained. Time-dependent density functional theory clarifies the molecular electronic/optical properties, and finite field calculations agree with polarized HRS data in that the NLO responses of the disubstituted species are dominated by ‘off-diagonal’ β_(zyy) components. The most significant findings of these studies are: (i) β_0 values as much as 6 times that of the chromophore in the technologically important material (E)-4′-(dimethylamino)-N-methyl-4-stilbazolium tosylate; (ii) reversible electrochemistry that offers potential for redox-switching of optical properties over multiple states; (iii) strongly 2D NLO responses that may be exploited for novel practical applications; (iv) a new polar material, suitable for bulk NLO behavior

Exome Sequencing and Genetic Testing for MODY

Context: Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. Objective: The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. Research Design and Methods: We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. Results: On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0–4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Conclusion: Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Factors predicting the use of therapeutic hypothermia and survival in unconscious out-of-hospital cardiac arrest patients admitted to the ICU

Introduction: Therapeutic hypothermia (TH) after out-of-hospital cardiac arrest (OHCA) was adopted early in Norway. Since 2004 the general recommendation has been to cool all unconscious OHCA patients treated in the intensive care unit (ICU), but the decision to cool individual patients was left to the responsible physician. We assessed factors that were associated with use of TH and predicted survival. Method: We conducted a retrospective observational study of prospectively collected cardiac arrest and ICU registry data from 2004 to 2008 at three university hospitals. Results: A total of 715 unconscious patients older than 18 years of age, who suffered OHCA of both cardiac and non-cardiac causes, were included. With an overall TH use of 70%, the survival to discharge was 42%, with 90% of the survivors having a favourable cerebral outcome. Known positive prognostic factors such as witnessed arrest, bystander cardio pulmonary resuscitation (CPR), shockable rhythm and cardiac origin were all positive predictors of TH use and survival. On the other side, increasing age predicted a lower utilisation of TH: Odds Ratio (OR), 0.96 (95% CI, 0.94 to 0.97); as well as a lower survival: OR 0.96 (95% CI, 0.94 to 0.97). Female gender was also associated with a lower use of TH: OR 0.65 (95% CI, 0.43 to 0.97); and a poorer survival: OR 0.57 (95% CI, 0.36 to 0.92). After correcting for other prognostic factors, use of TH remained an independent predictor of improved survival with OR 1.91 (95% CI 1.18-3.06; P < 0.001). Analysing subgroups divided after initial rhythm, these effects remained unchanged for patients with shockable rhythm, but not for patients with non-shockable rhythm where use of TH and female gender lost their predictive value. Conclusions: Although TH was used in the majority of unconscious OHCA patients admitted to the ICU, actual use varied significantly between subgroups. Increasing age predicted both a decreased utilisation of TH as well as lower survival. Further, in patients with a shockable rhythm female gender predicted both a lower use of TH and poorer survival. Our results indicate an underutilisation of TH in some subgroups. Hence, more research on factors affecting TH use and the associated outcomes in subgroups of post-resuscitation patients is needed

Assessing biological stability in a porous groundwater aquifer of a riverbank filtration system: combining traditional cultivation-based and emerging cultivation-independent in situ and predictive methods

Riverbank filtration systems are important drinking water resources. Aquifers of riverbank filtration systems are subjected to considerable dynamics concerning the quantity and quality of the infiltrating water. The microbiological quality is mainly jeopardized by faecal contamination of the main river. Besides, water quality can be impacted by growth of natural water-borne bacteria due to the input of nutrients resulting in the proliferation of opportunistic pathogens, impairment of odour and taste or bio-corrosion. The occurrence of such phenomena indicates a biological instability. For highly dynamic riverbank filtration systems, it is thus of high relevance to assess the biological stability of the groundwater resource. In the present study, we applied a holistic, two-tiered concept of in situ and predictive methods to assess the biostability of the aquifer in a bank filtration system of the Danube River. We applied traditional cultivation-based and selected cultivation-independent methods—including cultivation on yeast extract and R2A agar, determination of total cell counts via fluorescence microscopy and flow cytometry, leucine incorporation and 16S rRNA gene amplicon sequencing—at critical control points along the infiltration path from the river to the abstraction well. The concentration of organic nutrients and the hydrological variability were the main controlling factors driving the biological stability of the groundwater body. Wells situated at greater distance displayed significantly lower dissolved organic carbon concentrations and a dampened hydrological influence in comparison to the well situated next to the river. Apparent discrepancies between the methods used indicated a different indicator function of the cultivation-based and cultivation-independent approaches. For complex systems, we thus recommend this new holistic concept for assessing biostability by combining in situ as well as predictive parameters and using cultivation-based and cultivation-independent methods.Flussuferfiltrationssysteme sind wichtige Trinkwasserressourcen. Die Aquifere von Uferfiltrationssystemen sind einer erheblichen Dynamik in Bezug auf die Menge und Qualität des infiltrierenden Wassers unterworfen. Die mikrobiologische Qualität wird hauptsächlich durch die fäkale Verunreinigung des Hauptflusses gefährdet. Darüber hinaus kann die Wasserqualität durch das Wachstum natürlicher wasserbürtiger Bakterien aufgrund von Nährstoffeinträgen beeinträchtigt werden, was zur Vermehrung opportunistischer Krankheitserreger, zur Beeinträchtigung von Geruch und Geschmack oder zur Biokorrosion führen kann. Das Auftreten solcher Phänomene deutet auf eine biologische Instabilität hin. Für hochdynamische Uferfiltrationssysteme ist es daher von großer Bedeutung, die biologische Stabilität der Grundwasserressource zu bewerten. In der vorliegenden Studie wurde ein ganzheitliches, zweistufiges Konzept aus In-situ- und Vorhersage-Methoden angewandt, um die biologische Stabilität des Aquifers in einem Uferfiltrationssystem der Donau zu bewerten. Wir wendeten traditionelle kultivierungsbasierte und ausgewählte kultivierungsunabhängige Methoden – einschließlich Kultivierung auf Hefeextrakt und R2A-Agar, Bestimmung der Gesamtzellzahl mittels Fluoreszenzmikroskopie und Durchflusszytometrie, Leucin-Inkorporation und 16S rRNA-Genamplikon-Sequenzierung – an kritischen Kontrollpunkten entlang des Infiltrationspfads vom Fluss zum Entnahmebrunnen an. Die Konzentration der organischen Nährstoffe und die hydrologische Variabilität waren die wichtigsten Einflussfaktoren für die biologische Stabilität des Grundwasserkörpers. Brunnen in größerer Entfernung wiesen deutlich niedrigere Konzentrationen an gelöstem organischem Kohlenstoff und einen gedämpften hydrologischen Einfluss im Vergleich zum Brunnen in Flussnähe auf. Offensichtliche Diskrepanzen zwischen den verwendeten Methoden deuten auf eine unterschiedliche Indikatorfunktion der kultivierungsbasierten und kultivierungsunabhängigen Ansätze hin. Für komplexe Systeme empfehlen wir daher dieses neue ganzheitliche Konzept zur Bewertung der Biostabilität durch die Kombination von In-situ- und Vorhersage-Parametern und die Verwendung kultivierungsbasierter und kultivierungsunabhängiger Methoden.49050011FTI—Forschungs‑, Technologie- und Innovationsprogramm NiederösterreichWiener Wasser (MA 31

Science of The Total Environment / Spatiotemporal analysis of bacterial biomass and activity to understand surface and groundwater interactions in a highly dynamic riverbank filtration system

Characterization of surface water groundwater interaction in riverbank filtration (RBF) systems is of decisive importance to drinking water utilities due to the increasing microbial and chemical contamination of surface waters. These interactions are commonly assessed by monitoring changes in chemical water quality, but this might not be indicative for microbial contamination. The hydrological dynamics of the infiltrating river can influence these interactions, but seasonal temperature fluctuations and the supply of oxygen and nutrients from the surface water can also play a role. In order to understand the interaction between surface water and groundwater in a highly dynamic RBF system of a large river, bacterial abundance, biomass and carbon production as well as standard chemical parameters were analyzed during a 20 month period under different hydrological conditions. In the investigated RBF system, groundwater table changes exhibited striking dynamics even though flow velocities were rather low under regular discharge conditions. Bacterial abundance, biomass, and bacterial carbon production decreased significantly from the river towards the drinking water abstraction well. The cell size distribution changed from a higher proportion of large cells in the river, towards a higher proportion of small cells in the groundwater. Although biomass and bacterial abundance were correlated to water temperatures and several other chemical parameters in the river, such correlations were not present in the groundwater. In contrast, the dynamics of the bacterial groundwater community was predominantly governed by the hydrogeological dynamics. Especially during flood events, large riverine bacteria infiltrated further into the aquifer compared to average discharge conditions. With such information at hand, drinking water utilities are able to improve their water abstraction strategies and react quicker to changing hydrological conditions in the RBF system.(VLID)469955

Cardiac arrest as a reportable condition: A cohort study of the first 6 years of the Norwegian out-of-hospital cardiac arrest registry

Objectives The Norwegian Cardiac Arrest Registry (NorCAR) was established in 2013 when cardiac arrest became a mandatory reportable condition. The aim of this cohort study is to describe how the world’s first mandatory, population-based cardiac arrest registry evolved during its first 6 years. Setting Norway has a total population of 5.3 million inhabitants with a population density that varies considerably. All residents are assigned a unique identifier number, giving nationally approved registries access to information about all births and deaths in the country. Data in the registry are entered by data processors; public employees with close links to the emergency medical services. All data processors undergo a standardised training and meet for yearly retraining and updates. Participants All events of cardiac arrest where bystanders or healthcare professionals have started cardiopulmonary resuscitation or performed defibrillation are included into the NorCAR. Primary and secondary outcome measures Since the establishment of the registry, the number of reporting health trusts, the number of reported events and the corresponding population at risk were followed year by year. Outcome is measured as changes in inclusion rate, incidence per 100 000 inhabitants and survival to 30 days after cardiac arrest. Results In total, 14 849 cases were registered over 6 years, between 2013 and 2018. The number of health trusts reporting rose steadily from 2013. Within 3 years, all trusts reported to the registry with an increasing number of events reported; going from 1101 to 3400 per year. The prevalence of bystander cardiopulmonary resuscitation increased slightly, but the population incidence of survival did not change. Conclusion Declaring cardiac arrest as a reportable condition and close follow-up of all reporting areas is essential when building a national registry

Cardiac arrest as a reportable condition: A cohort study of the first 6 years of the Norwegian out-of-hospital cardiac arrest registry

Objectives The Norwegian Cardiac Arrest Registry (NorCAR) was established in 2013 when cardiac arrest became a mandatory reportable condition. The aim of this cohort study is to describe how the world’s first mandatory, population-based cardiac arrest registry evolved during its first 6 years. Setting Norway has a total population of 5.3 million inhabitants with a population density that varies considerably. All residents are assigned a unique identifier number, giving nationally approved registries access to information about all births and deaths in the country. Data in the registry are entered by data processors; public employees with close links to the emergency medical services. All data processors undergo a standardised training and meet for yearly retraining and updates. Participants All events of cardiac arrest where bystanders or healthcare professionals have started cardiopulmonary resuscitation or performed defibrillation are included into the NorCAR. Primary and secondary outcome measures Since the establishment of the registry, the number of reporting health trusts, the number of reported events and the corresponding population at risk were followed year by year. Outcome is measured as changes in inclusion rate, incidence per 100 000 inhabitants and survival to 30 days after cardiac arrest. Results In total, 14 849 cases were registered over 6 years, between 2013 and 2018. The number of health trusts reporting rose steadily from 2013. Within 3 years, all trusts reported to the registry with an increasing number of events reported; going from 1101 to 3400 per year. The prevalence of bystander cardiopulmonary resuscitation increased slightly, but the population incidence of survival did not change. Conclusion Declaring cardiac arrest as a reportable condition and close follow-up of all reporting areas is essential when building a national registry