Decahydroquinoline Ring 13C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (-)-Serralongamine A and Structural Reassignment and Synthesis of (-)-Huperzine K and (-)-Huperzine M (Lycoposerramine Y).

Analysis of 13C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the decahydroquinoline core to be established. A relatively simple predictive set of chemical shift combinations is reported, providing a tool for the challenging stereochemical assignment of phlegmarine-type alkaloids. Based on the chemical shifts in their NMR spectroscopic profiles, the alkaloids huperzine K and huperzine M, formally reported as cis derivatives, were structurally reassigned as trans-decahydroquinolines. The NMR spectroscopic data for huperzine M were identical to those reported for lycoposerramine Y and, hence, also implied the configurational reassignment of the latter. The revised structures of the above alkaloids were confirmed by enantioselective total synthesis. Additionally, the synthesis of (-)-serralongamine A via a common intermediate precursor is reported.

Supramolecular Assembly of DNA-Phenanthrene Conjugates into Vesicles with Light-Harvesting Properties.

Vesicle-shaped supramolecular polymers are formed by self-assembly of a DNA duplex containing phenanthrene overhangs at both ends. In the presence of spermine, the phenanthrene overhangs act as sticky ends linking the DNA duplexes together. In aqueous solution, the assembly leads to vesicles with a diameter in the range of 50-200 nm. Fluorescence measurements show that the assembled phenanthrene units act as light-harvesting complexes and transfer absorbed energy to an acceptor, such as pyrene or Cy3, which can either be directly added to the polymer or attached via a complementary DNA strand. The presence of DNA in the nanostructures allows the construction of light-harvesting vesicles that are amenable to derivatization with different functional groups.

Self-assembly of a redox-active bolaamphiphile into supramolecular vesicles.

The synthesis and self-assembly of a water-soluble bolaamphiphilic cyclopenta[hi]aceanthrylene derivative is described. Self-assembly in aqueous medium leads to the formation of supramolecular vesicles with intense absorption bands over an extended range of the UV/vis spectral region and a narrow HOMO-LUMO bandgap of 1.65 eV.

Radical Cyclization of Alkene-Tethered Ketones Initiated by Hydrogen-Atom Transfer.

An unprecedented C-C coupling reaction between alkenes and ketones by hydrogen-atom transfer, using Fe(acac)3 and PhSiH3 in EtOH, is described. This mild protocol features high site selectivity and allows the construction of sterically congested structures containing tertiary alcohols and quaternary centers. The overall process introduces a novel strategic bond disconnection for ring-closing reactions.

Appropriate antibiotic use reduces length of hospital stay.

Objectives: To define appropriate antibiotic use in hospitalized adults treated for a bacterial infection, we previously developed and validated a set of six generic quality indicators (QIs) covering all steps in the process of antibiotic use. We assessed the association between appropriate antibiotic use, defined by these QIs, and length of hospital stay (LOS). Methods: An observational multicentre study in 22 hospitals in the Netherlands included 1890 adult, non-ICU patients using antibiotics for a suspected bacterial infection. Performance scores were calculated for all QIs separately (appropriate or not), and a sum score described performance on the total set of QIs. We divided the sum scores into two groups: low (0%-49%) versus high (50%-100%). Multilevel analyses, correcting for confounders, were used to correlate QI performance (single and combined) with (log-transformed) LOS and in-hospital mortality. Results: The only single QI associated with shorter LOS was appropriate intravenous-oral switch (geometric means 6.5 versus 11.2 days; P < 0.001). A high sum score was associated with a shorter LOS in the total group (10.1 versus 11.2 days; P = 0.002) and in the subgroup of community-acquired infections (9.7 versus 10.9 days; P = 0.007), but not in the subgroup of hospital-acquired infections. We found no association between performance on QIs and in-hospital mortality or readmission rate. Conclusions: Appropriate antibiotic use, defined by validated process QIs, in hospitalized adult patients with a suspected bacterial infection appears to be associated with a shorter LOS and therefore positively contributes to patient outcome and healthcare costs.

Synthesis of (±)-Serralongamine A and the Revised Structure of Huperzine N.

A revised structure for the Lycopodium alkaloid huperzine N is proposed and confirmed by synthesis. The key synthetic steps involve an epimerization of a cis-5-oxodecahydroquinoline to the corresponding trans isomer and a coupling, followed by a diastereoselective hydrogenation using Wilkinson's catalyst to incorporate the pyridylmethyl moiety. This route allowed the alkaloid serralongamine A to be synthesized for the first time, and two additional steps led to the revised structure of huperzine N, both products bearing an unusual decahydroquinoline stereostructure.

Asymmetric Synthesis of Octahydroindoles via a Domino Robinson Annulation/5-Endo Intramolecular Aza-Michael Reaction.

A straightforward, two-step asymmetric synthesis of octahydroindoles has been developed on the basis of two complementary strategies: (i) an organocatalyzed Michael reaction followed by a tandem Robinson-aza-Michael double cyclization catalyzed by PS-BEMP, and (ii) a diastereoselective cyclization, which formally constitutes a remote 1,6 asymmetric induction mediated by PS-BEMP. This allowed the construction of complex octahydroindoles with up to four stereocenters, excellent enantioselectivities (up to 95% ee), and complete diastereoselective control in a single-pot operation. DFT calculations were performed to understand the origin of this effect.

Light-Harvesting Nanotubes Formed by Supramolecular Assembly of Aromatic Oligophosphates.

A 2,7-disubstituted phosphodiester-linked phenanthrene trimer forms tubular structures in aqueous media. Chromophores are arranged in H-aggregates. Incorporation of small quantities of pyrene results in the development of light-harvesting nanotubes in which phenanthrenes act as antenna chromophores and pyrenes as energy acceptors. Energy collection is most efficient after excitation at the phenanthrene H-band. Fluorescence quantum yields up to 23 % are reached in pyrene doped, supramolecular nanotubes.

Quality indicators to measure appropriate antibiotic use in hospitalized adults.

BACKGROUND: An important requirement for an effective antibiotic stewardship program is the ability to measure appropriateness of antibiotic use. The aim of this study was to develop quality indicators (QIs) that can be used to measure appropriateness of antibiotic use in the treatment of all bacterial infections in hospitalized adult patients. METHODS: A RAND-modified Delphi procedure was used to develop a set of QIs. Potential QIs were retrieved from the literature. In 2 questionnaire mailings with an in-between face-to-face consensus meeting, an international multidisciplinary expert panel of 17 experts appraised and prioritized these potential QIs. RESULTS: The literature search resulted in a list of 24 potential QIs. Nine QIs describing recommended care at patient level were selected: (1) take 2 blood cultures, (2) take cultures from suspected sites of infection, (3) prescribe empirical antibiotic therapy according to local guideline, (4) change empirical to pathogen-directed therapy, (5) adapt antibiotic dosage to renal function, (6) switch from intravenous to oral, (7) document antibiotic plan, (8) perform therapeutic drug monitoring, and (9) discontinue antibiotic therapy if infection is not confirmed. Two QIs describing recommended care at the hospital level were also selected: (1) a local antibiotic guideline should be present, and (2) these local guidelines should correspond to the national antibiotic guidelines. CONCLUSIONS: The selected QIs can be used in antibiotic stewardship programs to determine for which aspects of antibiotic use there is room for improvement. At this moment we are testing the clinimetric properties of these QIs in 1800 hospitalized patients, in 22 Dutch hospitals.

Amidation reactions from the direct coupling of metal carboxylate salts with amines.

A general method for the synthesis of amides involving the direct coupling of alkali metal carboxylate salts with amines is described. Amidation of a wide variety of carboxylate salts with either free amines or their ammonium hydrochloride salts can be achieved using HBTU as a coupling agent in combination with Hünig's base. The reaction is highly efficient and is generally complete in as little as 1-2 h, giving the products in good to excellent yields. The protocol is valuable for the coupling of carboxylates for which the corresponding carboxylic acids or acyl chlorides are unstable, less conveniently manipulated/isolated, or are not commercially available. For example, the coupling of amines and α-amino acids with lithium 5-bromo-1H-pyrrole-2-carboxylate, whose corresponding acid that is prone to decarboxylation, allowed for the synthesis of 5-bromo-1H-pyrrole-2-carboxamides, which are analogues of the pyrrole-2-aminoimidazole marine alkaloids. The protocol can be combined with other reactions in a sequenced fashion, as exemplified by the synthesis of acetylenic amides, in a one-pot procedure, via the coupling of a lithium carboxylate salt formed initially by the addition of carbon dioxide to a lithiated terminal alkyne.

Development of quality indicators for antimicrobial treatment in adults with sepsis.

BACKGROUND: Outcomes in patients with sepsis are better if initial empirical antimicrobial use is appropriate. Several studies have shown that adherence to guidelines dictating appropriate antimicrobial use positively influences clinical outcome, shortens length of hospital stay and contributes to the containment of antibiotic resistance.Quality indicators (QIs) can be systematically developed from these guidelines to define and measure appropriate antimicrobial use. We describe the development of a concise set of QIs to assess the appropriateness of antimicrobial use in adult patients with sepsis on a general medical ward or Intensive Care Unit (ICU). METHODS: A RAND-modified, five step Delphi procedure was used. A multidisciplinary panel of 14 experts appraised and prioritized 40 key recommendations from within the Dutch national guideline on antimicrobial use for adult hospitalized patients with sepsis (http://www.swab.nl/guidelines). A procedure to select QIs relevant to clinical outcome, antimicrobial resistance and costs was performed using two rounds of questionnaires with a face-to-face consensus meeting between the rounds over a period of three months. RESULTS: The procedure resulted in the selection of a final set of five QIs, namely: obtain cultures; prescribe empirical antimicrobial therapy according to the national guideline; start intravenous drug therapy; start antimicrobial treatment within one hour; and streamline antimicrobial therapy. CONCLUSION: This systematic, stepwise method, which combined evidence and expert opinion, led to a concise and therefore feasible set of QIs for optimal antimicrobial use in hospitalized adult patients with sepsis. The next step will entail subjecting these quality indicators to an applicability test for their clinimetric properties and ultimately, using these QIs in quality-improvement projects. This information is crucial for antimicrobial stewardship teams to help set priorities and to focus improvement.

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/).

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.

Urological and nephrological findings of renal ectopia.

PURPOSE: Urological characteristics of renal ectopia have been addressed previously but little is known about the functional consequences. We sought to study renal function, blood pressure, proteinuria and urological abnormalities in children with renal ectopia. As a secondary objective, we compared these parameters between simple and crossed ectopia. MATERIALS AND METHODS: For this retrospective, single center, observational study we reviewed case documents and radiological records. We also analyzed longitudinal data on blood pressure, proteinuria and kidney function. RESULTS: Renal ectopia was diagnosed in 41 cases, of which 26 (63%) were simple renal ectopia, ie unilateral pelvic kidney. In 32% of patients the diagnosis was made during prenatal screening. Median patient age was 0.24 years at diagnosis and 7.7 years at the most recent control visit. Associated urological abnormalities were found in 66% of patients. Voiding cystourethrography was performed in all patients, with vesicoureteral reflux shown in 13. In 8 of 10 cases with unilateral reflux the condition manifested in the orthotopic kidney. The relative function of the ectopic kidney on dimercapto-succinic acid scan was 38%, and in 22% of patients glomerular filtration rate was less than 90 ml per minute per 1.73 m(2). Albuminuria and proteinuria were absent in most cases. Longitudinal analysis of blood pressure, glomerular filtration rate and albuminuria revealed a stable course for all parameters. No substantial difference was observed between simple and crossed renal ectopia. CONCLUSIONS: Our data suggest no adverse effects on blood pressure or kidney function in children with renal ectopia. However, periodic followup seems warranted, at least until young adulthood.

Approach to cis-Phlegmarine Alkaloids via Stereodivergent Reduction: Total Synthesis of (+)-Serratezomine E and Putative Structure of (-)-Huperzine N.

A unified strategy for the synthesis of the cis-phlegmarine group of alkaloids is presented, leading to the first synthesis of serratezomine E (1) as well as the putative structure of huperzine N (2). A contrasteric hydrogenation method was developed based on the use of Wilkinson's catalyst, which allowed the facial selectivity of standard hydrogenation to be completely overturned. Calculations were performed to determine the mechanism, and structures for huperzines M and N are reassigned.

[Comprehensive quality indicators for measuring hospital antibiotic use]. / Generieke kwaliteitsindicatoren voor antibioticagebruik in het ziekenhuis.

As in other countries, the growing resistance to antimicrobial drugs is also taking place in the Netherlands; the primary cause being the total consumption of antibiotics. Given the steady decline in the discovery of new antimicrobials, better use of agents currently available is warranted. Guidelines describing appropriate antimicrobial therapy play an important role; however, such guidelines are not optimally used in daily practice. Quality indicators can be used to assess the quality of antibiotic treatment and evaluate the impact of interventions aimed at improving care. Quality indicators used for evaluating treatment of infections of the respiratory and urinary tracts are developed previously. A comprehensive set of indicators that could be used to assess the quality of hospital antibiotic use for all bacterial infections has not yet been developed. A new project has recently been started in the Netherlands called 'The development of Reliable generic quality Indicators for the optimalisation of ANTibiotic use in the hospital' (RIANT study) for developing such a set of comprehensive indicators.