Implementing risk-based approaches to improve drinking water quality in small water supplies in the Nordic region - barriers and solutions.

Small water supplies face similar problems worldwide, regardless of ownership or management type. Non-compliance with water quality regulations is more frequent in small supplies than in large ones, as are waterborne disease outbreaks. The new European Union Drinking Water Directive requires risk-based approach (RBA) to secure water safety as is recommended in the World Health Organization's Guidelines for drinking water quality through 'water safety plans'. This is already in regulation in the Nordic countries, although less used in small supplies. In this research, we explore the challenges, barriers and possible solutions to implementing RBA and improving compliance in small supplies. This was achieved by conducting and analysing interviews with 53 stakeholders from all eight Nordic countries to produce recommendations for action by the different implicated actors. Our findings suggest the centrality of governmental policy, including support for continuous training, provision of simple RBA guidelines and increasing cooperation in the water sector. The Nordic experience reflects global challenges with small water supplies and the trend towards systematic preventive management epitomized in the framework for drinking water safety advocated by the World Health Organization since 2004.

A potent IκB kinase-ß inhibitor labeled with carbon-14 and deuterium.

3-Amino-4-(1,1-difluoro-propyl)-6-(4-methanesulfonyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide (1) is a potent IκB Kinase-ß (IKK-ß) inhibitor. The efficient preparations of this compound labeled with carbon-14 and deuterium are described. The carbon-14 synthesis was accomplished in six radiochemical steps in 25% overall yield. The key transformations were the modified Guareschi-Thorpe condensation of 2-cyano-(14) C-acetamide and a keto-ester followed by chlorination to 2,6-dichloropyridine derivative in one pot. The isolated dichloropyridine was then converted in three steps in one pot to [(14) C]-(1). The carbon-14 labeled (1) was isolated with a specific activity of 54.3 mCi/mmol and radiochemical purity of 99.8%. The deuterium labeled (1) was obtained in eight steps and in 57% overall chemical yield using 4-hydroxypiperidine-2,2,3,3,4,5,5,6,6-(2) H9 . The final three steps of this synthesis were run in one pot.

Metabolic switching of BILR 355 in the presence of ritonavir. I. Identifying an unexpected disproportionate human metabolite.

11-Ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy] ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355) is an inhibitor of the human immunodeficiency virus-1. BILR 355 exhibited a nonlinear pharmacokinetic profile and low exposure after oral administration to humans. This article describes the in vitro metabolism of BILR 355, which is correlated with the in vivo nonlinearity findings. Our in vitro studies had demonstrated that BILR 355 was extensively metabolized by cytochrome P450 3A. Thus, BILR 355 was concomitantly administered with ritonavir (RTV) in an attempt to boost systemic exposure, which did occur in humans. In addition, the expectation was that the overall metabolism of BILR 355 would be decreased with concomitant administration of RTV. Subsequent metabolite profiling was performed using human plasma samples obtained from clinical phase Ib studies with concomitant administration of BILR 355 and RTV. A total of 18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development.

A 6 degrees-of-freedom haptic milling simulator for surgical training of vertebral operations.

In the research presented here, the aim has been to develop a haptic milling simulator for surgical training of vertebral operations. One central goal has been to create a simulator that gives the user a realistic impression of contacts with, and milling of, a virtually represented bone tissue model. A new 6 degrees-of-freedom haptic algorithm for milling is implemented together with new 6 degrees-of-freedom haptic device.

Lung cancer research and its citation on clinical practice guidelines.

BACKGROUND: The impact of medical research is usually judged on the basis of citations in the serial literature. A better test of its utility is through its contribution to clinical practice guidelines (CPGs) on how to prevent, diagnose, and treat illness. This study aimed to compare the parameters of lung cancer research papers with those cited as references in lung cancer CPGs from 16 countries, and the Cochrane Collaboration. These comparisons were mainly based on bibliographic data compiled from the Web of Science (WoS). METHODOLOGY: We examined 7357 references (of which 4491 were unique) cited in a total of 77 lung cancer CPGs, and compared them with 73,214 lung cancer papers published in the WoS between 2004 and 2018. RESULTS: References used by lung CPGs were much more clinical than the overall body of research papers on this cancer, and their authors predominantly came from smaller northern European countries. However, the leading institutions whose papers were cited the most on these CPGs were from the USA, notably the MD Anderson Cancer Center in Texas, the Memorial Sloan Kettering Cancer Center, New York, and the Mayo Clinic in Rochester, Minnesota. The types of research cited by the CPGs were primarily clinical trials, as well as three treatment modalities (chemotherapy, radiotherapy and surgery). Genetics, palliative care and quality of life were largely neglected. The median time gap between papers cited on a lung CPG and its publication was 3.5 years longer than for WoS citations. CONCLUSIONS: Analysis of the references on CPGs allows an alternative means of research evaluation, and one that may be more appropriate for clinical research than citations in academic journals. Own-country references show the direct contribution of research to a country's health care, and other-country references show the esteem in which this research has been held internationally.

Status of risk-based approach and national framework for safe drinking water in small water supplies of the Nordic water sector.

Reliable safe water supply is a pillar of society and a key to public health. The Nordic countries have an abundance of clean fresh water as a source for drinking water supplies. They have followed developments in safeguarding water, both the recommendations of the World Health Organization framework for safe drinking water and European legislation. Worldwide, including the Nordic countries, small water supplies are less compliant with water safety regulation. The forthcoming EU directive on drinking water require risk-based approaches and improved transparency on water quality. This research looks at the Nordic frameworks for safe water supply, with emphasis on risk-based approaches and smaller systems. We analyzed the legal frameworks for safe water, the structure of the water sector across the Nordic countries and explored how prepared these countries are to meet these requirements. Our findings show that, while legal requirements are mostly in place, delivery of information to the public needs to be improved. Most Nordic countries are in the process of implementing risk-based management in large and medium size water supplies, whereas small supplies are lagging. We conclude that a key to success is increased training and support for small supplies. We suggest wider adoption of the Nordic model of cooperation with benchmarking of safe water for all to transfer knowledge between the countries. This work provides insights into challenges and opportunities for the Nordic countries and provides insights relevant to countries worldwide in their effort towards realization of SDG Target 6.1.

Enzymatic one-pot route to telechelic polypentadecalactone epoxide: synthesis, UV curing, and characterization.

In an enzymatic one-pot procedure immobilized lipase B from Candida antarctica was used to synthesize semicrystalline diepoxy functional macromonomers based on glycidol, pentadecalactone, and adipic acid. By changing the stoichiometry of the building blocks, macromonomers of controlled molecular weight from 1400 to 2700 g mol(-1) could be afforded. The enzyme-catalyzed reaction went to completion (conversion >or=95%) within 24 h at 60 degrees C. After removal of the enzyme, the produced macromonomers were used for photopolymerization without any purification. The macromonomers readily copolymerized cationically with a cycloaliphatic diepoxide (Cyracure UVR-6110; CA-dE) to high conversion. The cross-linked copolymers formed a durable film with a degree of crystallinity depending on the macromonomer size and amount of CA-dE used, without CA-dE the macromonomers homopolymerized only to a low degree. Combined with CA-dE conversions of 85-90% were determined by FT-Raman spectroscopy. The films became more durable once reinforced with CA-dE, increasing the cross-link density and reducing the crystallinity of the PDL segments in the films.

(31)P solid state NMR study of structure and chemical stability of dichlorotriphenylphosphorane.

Solid state (31)P NMR spectroscopy was used to examine, monitor and quantify the compound integrity of the chemical reagent dichlorotriphenylphosphorane. Comparison was also made with solution (31)P NMR spectra which showed that this highly reactive species could be observed in dry benzene prior to conversion to the hydrolyzed product. This is the first reported solid state NMR study of the stability and reactivity of dichlorotriphenylphosphorane and the first account of its observation and comparison in the solution state. In the solid state, the ionic and covalent forms for dichlorotriphenylphosphorane were observed along with hydrolyzed products, however, the degree of hydrolysis was dependent upon the rotor packing conditions. Calculation of the relative percent composition of dichlorotriphenylphosphorane with hydrolyzed product was made for samples prepared in air versus under nitrogen atmosphere. This information was critical in adjusting the amount of reagent used in chemical development syntheses and scale up laboratories. All hydrolyzed products were identified, based upon chemical comparisons with spectra of pure materials.

Cervicocephalic kinesthetic sensibility and postural balance in patients with nontraumatic chronic neck pain--a pilot study.

BACKGROUND: Although cervical pain is widespread, most victims are only mildly and occasionally affected. A minority, however, suffer chronic pain and/or functional impairments. Although there is abundant literature regarding nontraumatic neck pain, little focuses on diagnostic criteria. During the last decade, research on neck pain has been designed to evaluate underlying pathophysiological mechanisms, without noteworthy success. Independent researchers have investigated postural balance and cervicocephalic kinesthetic sensibility among patients with chronic neck pain, and have (in most cases) concluded the source of the problem is a reduced ability in the neck's proprioceptive system. Here, we investigated cervicocephalic kinesthetic sensibility and postural balance among patients with nontraumatic chronic neck pain. METHODS: Ours was a two-group, observational pilot study of patients with complaints of continuous neck pain during the 3 months prior to recruitment. Thirteen patients with chronic neck pain of nontraumatic origin were recruited from an institutional outpatient clinic. Sixteen healthy persons were recruited as a control group. Cervicocephalic kinesthetic sensibility was assessed by exploring head repositioning accuracy and postural balance was measured with computerized static posturography. RESULTS: Parameters of cervicocephalic kinesthetic sensibility were not reduced. However, in one of six test movements (flexion), global repositioning errors were significantly larger in the experimental group than in the control group (p < .05). Measurements did not demonstrate any general impaired postural balance, and varied substantially among participants in both groups. CONCLUSION: In patients with nontraumatic chronic neck pain, we found statistically significant global repositioning errors in only one of six test movements. In this cohort, we found no evidence of impaired postural balance.Head repositioning accuracy and computerized static posturography are imperfect measures of functional proprioceptive impairments. Validity of (and procedures for using) these instruments demand further investigation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN96873990.

Imaging single DNA molecules for high precision NIPT.

Cell-free DNA analysis is becoming adopted for first line aneuploidy screening, however for most healthcare programs, cost and workflow complexity is limiting adoption of the test. We report a novel cost effective method, the Vanadis NIPT assay, designed for high precision digitally-enabled measurement of chromosomal aneuploidies in maternal plasma. Reducing NIPT assay complexity is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays or sequencing. The primary objective of this study was to assess the Vanadis NIPT assay with respect to analytical precision and clinical feasibility. Analysis of reference DNA samples indicate that samples which are challenging to analyze with low fetal-fraction can be readily detected with a limit of detection determined at <2% fetal-fraction. In total of 286 clinical samples were analysed and 30 out of 30 pregnancies affected by trisomy 21 were classified correctly. This method has the potential to make cost effective NIPT more widely available with more women benefiting from superior detection and false positive rates.

A haptic VR milling surgery simulator--using high-resolution CT-data.

A haptic virtual reality milling simulator using high resolution volumetric data is presented in this paper. We discuss the graphical rendering performed from an iso-surface generated using marching cubes with a hierarchical storage method to optimize for fast dynamic changes to the data during the milling process. We also present a stable proxy-based haptic algorithm used to maintain a tip position on the surface avoiding haptic fall-through.

Haptic simulation of the milling process in temporal bone operations.

A VR-simulation system for educating surgeons of the temporal bone milling processes is presented in this paper. E.g. the milling process that occurs during the removal of certain cancer tumors in the brain. The research project is recently started up and this paper is an introduction to the bone milling simulation topic. We present how the graphical rendering of the temporal bone is done. Acquired data are managed using the Marching cubes algorithm to perform a visual representation. A re-production of iso-surfaces will represent the material removal occurred during the milling process. Force models are discussed and will be implemented in the H3D API, which is used to control the virtual simulation and collision detection. Equipment, implementation and future work are also presented in the paper.

Iodotrimethylsilane-Promoted 1,4-Addition of Copper Acetylides to alpha,beta-Unsaturated Ketones and Aldehydes.

In the presence of iodotrimethylsilane (TMSI) and lithium iodide in tetrahydrofuran, the otherwise unreactive copper acetylides add to enones present as s-trans conformers to provide good yields of the silyl enol ethers of beta-acetylido carbonyl compounds. Typically good substrates are 2-cyclopentenone, 2-cyclohexenone, alpha,beta-unsaturated aldehydes, and beta-alkoxy-alpha-enones. Copper acetylide reagents prepared from CuI and an alkynyllithium give considerably higher yields than those prepared from CuBr or CuCN. Iodotrimethylsilane is by far the most efficient silane, although trimethylsilyl triflate is useful in some cases.

[2,3]-Sigmatropic rearrangements of 2-phosphineborane 2-propen-1-ols: rapid access to enantioenriched diphosphine monoxide derivatives.

Hydrophosphination of secondary propargylic alcohols generates phosphine-containing allylic alcohols that undergo facile [2,3]-sigmatropic rearrangements with chlorophosphines, furnishing highly enantioenriched, crystalline diphosphine monoxides. The configuration at the newly formed stereocenter is opposite to that expected based on prior studies, and an ab initio computational evaluation of the possible transition states was performed to help explain the stereochemical course of the reaction.

Hydrophosphination of propargylic alcohols and amines with phosphine boranes.

The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphine- borane complexes are described. The reactions proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric secondary phosphines, furnishing air-stable phosphineborane-amines and alcohols in good yields. Utilization of chiral propargylic substrates and unsymmetrical secondary phosphineboranes leads to diastereomeric P-chiral products that can be separated by fractional crystallization or chromatography. Initial applications of these new P-X species to asymmetric catalysis are detailed.

Practical synthesis of unsymmetrical ureas from isopropenyl carbamates.

A very convenient method for the synthesis of unsymmetrical ureas is described, based on isopropenyl carbamates. The synthetic efficiency of traditional methods for urea formation, such as use of phosgene or alkyl and aryl carbamates, is limited by the formation of symmetrical urea side products or reaction reversibility. Isopropenyl carbamates react with amines cleanly and irreversibly and give unsymmetrical ureas in high yield and purity. This method is ideal for the rapid synthesis of compound libraries.

Electronic control of chiral quaternary center creation in the intramolecular asymmetric heck reaction.

The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.