Background
This study highlights the multiple sources of delay along a hip fracture clinical pathway. The national recommendation is that ‘patients with a hip fracture should be admitted within 4 ...hours of arrival at the Emergency Department to which they first presented’.
Methods
Granular analysis and process mapping of all available hospital and ‘Irish Hip Fracture Database’ data for a 2-month period were used to highlight and compare causes of delay.
Discussion
We identified numerous sources of delay, occurring at every point along the pathway, emphasising the complexity of providing acute integrated care. There was no single stage that persistently contributed to the delay in the patient pathway. The focus is now to achieve marginal gains in each area. Increased staff and resources to the front line are a clear solution but this is complex to achieve.
β-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper ...folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies. By using native top-down mass spectrometry, we located two potentially covalently modified lysines. We obtained the first crystal structure, at 2.2 Å resolution, of a GCase with a noniminosugar modulator covalently bound, and were able to identify the exact lysine residue modified (Lys346) and reveal an allosteric binding site. GCase dimerization was induced by our modulator binding, which was observed by native mass spectrometry, its crystal structure, and size exclusion chromatography with a multiangle light scattering detector. Finally, the dimer form was confirmed by negative staining transmission electron microscopy studies. Our newly discovered allosteric site and observed GCase dimerization provide a new mechanistic insight into GCase and its noniminosugar modulators and facilitate the rational design of novel GCase modulators for Gaucher's disease and Parkinson's disease.
Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their ...contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.
We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.
Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (<1% each), they were prominent in regional epidemics, including in east and southeast Asia, west and central Africa, Middle East and north Africa, and eastern Europe and central Asia. In addition, in 2010-15, central Africa (21·3% 243 041 of 1 143 531), west Africa (15·5% 838 476 of 5 419 010), east Africa (12·6% 591 140 of 4 704 986), and Latin America (9·6% 153 069 of 1 586 605) had high proportions of URFs.
HIV-1 recombinants are increasingly prominent in global and regional HIV epidemics, which has important implications for the development of an HIV vaccine and the design of diagnostic, resistance, and viral load assays. Continued and improved surveillance of the global molecular epidemiology of HIV is crucial.
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The coordination of pyridyl-tetrazole derivatives containing ester substituents, at either the N-1 or N-2 position of the tetrazole ring, with copper(II) chloride results in the formation of either ...1:1 or 1:2 copper to ligand complexes, depending on the ligand. However, when the ester functionality is changed to a carboxylate group, the resulting complexation reactions yield metal–organic frameworks, which vary dramatically depending on reaction conditions. For example, in complex 4 shown, each copper(II) ion is in a distorted octahedral geometry and a key feature of the molecular structure is that one of the L3A ligand (O1/O2/N12/N22) behaves in both a bridging (using O2/N12/N22) and chelating (via N12/N22) fashion while the second L3A ligand (O3/O4/N32/N42) is only involved in binding through its carboxylate group. Display omitted
•First structural characterisation of copper complexes of pyridyl-tetrazole derivatives containing ester or carboxylate arms.•Formation of coordination polymers and metal–organic frameworks.•Complexes show increase in fluorescence compared to ligands alone.
The coordination of pyridyl-tetrazole derivatives containing ester substituents, at either the N-1 or N-2 position of the tetrazole ring, with copper(II) chloride results in the formation of either 1:1 or 1:2 copper to ligand complexes, depending on the ligand. However, when the ester functionality is changed to a carboxylate group, the resulting complexation reactions yield metal–organic frameworks. The resulting structures vary dramatically in pore size, depending on both reaction solvents and position of carboxylate group on the tetrazole ring. Despite the presence of sodium cations in the reaction mixtures, no sodium incorporation was ever observed in any of the complexes. This report represents the first attempts at producing copper(II) complexes of the N-1 and N-2 carboxylate derivative of this ligand.
Coordination reactions of 2-(6″-bromohexyl)-(1-tetrazol-5-yl)pyridine (L2) and 2-(6″-bromohexyl)-(2-tetrazol-5-yl)pyridine (L3) with CuCl2·2H2O, Co(SCN)2 and Fe(ClO4)2·H2O yielded strongly coloured ...solids Cu(II)(L2)Cl22 (1), Cu(II)(L3)Cl22 (2), Co(II)(L2)2(NCS)2 (3), Co(II)(L3)2(NCS)2 (4), Fe(II)(L2)2(H2O)2(ClO4)2 (5) and Fe(II)(L3)2(H2O)2(ClO4)2 (6), containing high-spin metal centres for the Co(II) and Fe(II) compounds. X-ray crystal structures were obtained for complexes 1–5.
The reaction of 2-(2H-tetrazol-5-yl)pyridine (L1) with 1,6-dibromohexane results in formation of the isomers 2-(6″-bromohexyl)-(1-tetrazol-5-yl)pyridine (L2) and 2-(6″-bromohexyl)-(2-tetrazol-5-yl)pyridine (L3). Coordination reactions of L2 and L3 with CuCl2·2H2O, Co(SCN)2 and Fe(ClO4)2·H2O yielded the strongly coloured solids Cu(II)(L2)Cl22 (1), Cu(II)(L3)Cl22 (2), Co(II)(L2)2(NCS)2 (3), Co(II)(L3)2(NCS)2 (4), Fe(II)(L2)2(H2O)2(ClO4)2 (5) and Fe(II)(L3)2(H2O)2(ClO4)2 (6), containing high-spin metal centres for the Co(II) and Fe(II) compounds. X-ray crystal structures were obtained for complexes 1–5. In each complex, ligands L2 and L3 coordinate to the metal centre through the pyridyl N atom and the 1-N site of the tetrazole ring, and the pyridyl–tetrazole ligand remains planar in all cases except 3. Complexes 1 and 2 comprise a central Cu2Cl2 dimeric core with Cu(II) in an essentially square-pyramidal coordination environment. Complexes 3 and 4 contain Co(II) in a distorted octahedral coordination environment. In 3, the pyridyl and tetrazole rings of L2 are twisted with respect to each other and the complex adopts a puckered conformation in its equatorial plane. Complex 5 contains water molecules coordinated to Fe(II) in the axial sites, which form hydrogen bonds to the perchlorate counter anions.
The MII complexes of 2-(2H-tetrazol-5-yl)pyridine derivatives, containing either an n-bromoalkyl (n=3, 4, 6 or 8) or and n-alkyl (n=4, 6 or 8) pendant arm at either the 1-N (L2) or 2-N (L3) position ...of the tetrazole ring, have been studied.
The reaction of 2-(2H-tetrazol-5-yl)pyridine (L1) with 1,n-dibromoalkane (n=3, 4, 6 or 8) results in the formation of the isomers 2-(n″-bromoalkyl-(1-tetrazol-5-yl)pyridine (L2A-D) and 2-(n″-bromoalkyl-(2-tetrazol-5-yl)pyridine (L3A-D). The reaction of L1 with 1-bromoalkanes also resulted in the formation of isomeric materials, namely 2-(n″-alkyl-(1-tetrazol-5-yl)pyridine (L4A-C) and 2-(n″-alkyl-(2-tetrazol-5-yl)pyridine (L5A-C). Complexation reactions of these ligands with the transition metal salts CuCl2·2H2O, Co(NCS)2, NiCl2·2H2O and ZnCl2 were carried out in methanol and resulted in complexes containing a 1:1 metal:ligand stoichiometry except in the cases of the cobalt complexes where a 1:2 metal:ligand stoichiometry was obtained. The 1H NMR spectra of the zinc complexes showed that the ligands containing the pendant arm in the 2-N position of the tetrazole ring bind the zinc ion more strongly than those containing the pendant arm in the 1-N position. The X-ray structures of two cobalt salts, Co(L5A)2(NCS)2 and Co(L5C)2(NCS)2, are also discussed.
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