Synthesis of pentafluorosulfanyl (SF5) containing aromatic amino acids.

Herein, a series of aromatic pentafluorosulfanyl (SF5) containing amino acids are reported. A Negishi cross-coupling strategy utilising a catalyst system of Pd(dba)2 and SPhos afforded the aforementioned SF5 amino acids in yields between 32% and 42%. Two dipeptides utilising both the amine and carboxylic functionalities of the synthesised SF5 containing amino acids were prepared, demonstrating their compatibility with common amide/peptide coupling reagents and strategies.

International comparison of liver transplant programmes: differences in indications, donor and recipient selection and outcome between Italy and UK.

BACKGROUND & AIMS: Comparing liver transplant (LT) programmes internationally can improve outcomes by stimulating cross-national learning. Yet, comparison of crude outcomes, by using registry data, is limited by missing data, not allowing proper risk-adjustment for donor- and recipient-related factors. The objective of this study was to compare two European LT programmes based on high-quality national longitudinal databases prospectively collected in Italy and UK respectively. METHODS: We undertook a multicentre, international cohort study including all adults who underwent a first single organ LT in Italy (N = 1480) and the UK (N = 1003) between June 2007 and May 2009. RESULTS: Italian donors were much older compared to the UK ones. Hepatitis C virus infection and hepatocellular carcinoma had higher prevalence in the Italian cohort compared to the UK one (47.5% vs. 23.1%, and 47.2% vs. 17.1% respectively). Centres' volume differed significantly, with five centres out of seven in UK vs. only two out of 20 in Italy performing >60 transplants per year. No national strategies to drive the donor-recipient matching were identified in both countries. After appropriate adjustment, a higher risk of early transplant loss was identified in the Italian cohort, whereas no differences were found in the 3-year survival rates. CONCLUSIONS: International comparison of LT programmes provides the opportunity for benchmarking between heterogeneous healthcare systems and should ideally become a vital part of national quality assurance programmes. This requires the implementation of a standardized methodology for data collection to appropriately weigh each country's patient case-mix and donor and recipients risk factors.

A direct method for the synthesis of orthogonally protected furyl- and thienyl- amino acids.

The synthesis of unnatural amino acids plays a key part in expanding the potential application of peptide-based drugs and in the total synthesis of peptide natural products. Herein, we report a direct method for the synthesis of orthogonally protected 5-membered heteroaromatic amino acids.

Impact of the new fast track kidney allocation scheme for declined kidneys in the United Kingdom.

INTRODUCTION: A "new" fast track kidney allocation scheme (FTKAS) was implemented in the UK in 2012 for offering of previously declined kidneys. We evaluated the impact of the FTKAS in utilization of declined kidneys and outcome. METHODS: Adult renal transplant centers were surveyed. Overall utilization was evaluated using National Health Service Blood and Transplant (NHSBT) data. Outcome of FTKAS kidneys in our center was analyzed. RESULTS: Centers cited graft, patient outcome concerns, and inadequate logistical support for their non-FTKAS participation. In the first year of the scheme, 266 kidneys were offered through the FTKAS, 158 were transplanted in 10 centers (59%). In comparison, 166 kidneys were offered through previous system over five yr (2006-2011), and 65 were utilized in 59 transplants (39%). In our center, 42 kidneys were transplanted in 39 recipients. One-yr graft and patient survival were both 95%. Results were comparable to a matched group of kidney transplants during the same periods allocated via the standard scheme. CONCLUSIONS: The FTKAS has led to effective utilization of the declined kidneys with outcome comparable to kidneys allocated through the standard scheme. Non-participation based on outcome concerns is mostly subjective while logistical issues need to be addressed.

Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study.

BACKGROUND: Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death. METHODS: We used the UK transplant registry to select a cohort of first-time recipients (aged ≥ 18 years) of deceased-donor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with χ tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors. FINDINGS: 6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1·14, 95% CI 0·95-1·36, p=0·16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceased-donor kidneys (2·35, 1·85-3·00, p<0·0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0·30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2·36, 1·39-4·02, p for interaction=0·004). INTERPRETATION: Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy. FUNDING: UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.

Novel fluorinated lipopeptides from Bacillus sp. CS93 via precursor-directed biosynthesis.

While attempting to improve production of fluoro-iturin A in Bacillus sp. CS93 new mono- and di-fluorinated fengycins were detected in culture supernatants by (19)F NMR and tandem mass spectrometry, after incubation of the bacterium with 3-fluoro-L-tyrosine. The fluorinated amino acid was presumably incorporated in place of one or both of the tyrosyl residues in fengycin. Investigations to generate additional new fluorinated derivatives were undertaken using commercially available fluorinated phenylalanines and 2-fluoro- and 2,3-difluoro-tyrosine that were synthesised by Negishi cross-coupling of iodoalanine and fluorinated bromo-phenols. The anti-fungal activity of the fluorinated lipopeptides was assayed against Trichophyton rubrum and found to be similar to that of the non-fluorinated metabolites.

The discard of deceased donor kidneys in the UK.

It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002-3 to 12% in 2011-12. A national offering system for hard-to-place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31-80) yr. Kidneys had been offered to a median of 3 (1-12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard-to-place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.

Renal function and cardiovascular outcomes after living donor nephrectomy in the UK: quality and safety revisited.

OBJECTIVE: To determine renal function and cardiovascular outcomes after living donor nephrectomy (LDN). Living donor kidney transplantation has become established as the treatment of choice for end-stage renal failure. Benefits to the recipient have to be balanced against perioperative and long-term health risks to the donor. SUBJECTS/PATIENTS AND METHODS: The UK Transplant Registry (UKTR) was used to identify 4586 living donors who had donated a kidney for transplantation in the UK between 2001 and 2008. This study was conducted with the consent and support of the NHS Blood and Transplant (NHSBT) Kidney and Pancreas Research Group. RESULTS: The mean glomerular filtration rate (GFR) fell from 103 mL/min/1.73 m(2) before LDN to 58 mL/min/1.73 m(2) 1 year after LDN. At 1 year after LDN 60% of donors had a GFR of <60 mL/min/1.73 m(2). A GFR of <60 mL/min/1.73 m(2) after LDN was associated with older age, females, lower GFR before LDN, White ethnicity, earlier LDN period, unrelated donor type and body mass index of >25 kg/m(2). Over a 2-year period after LDN there was an overall mortality rate of 0.39%, cardiovascular death in one patient (mortality rate of 0.02%) and a major cardiovascular event rate of 0.44%. CONCLUSION: In this study we show that mild renal dysfunction is common after LDN; however, due to the short duration of follow-up we are unable to comment on whether this subsequently leads to an increased risk of developing of cardiovascular disease.

UK Renal Registry 16th annual report: chapter 4 demography of patients waitlisted for renal transplantation in the UK: national and centre-specific analyses.

INTRODUCTION: For suitable patients, renal transplantation is considered the optimal modality of renal replacement therapy, with availability of donor organs limiting the number of transplants undertaken. The 2006 kidney allocation policy was developed to ensure equity of allocation to patients on the transplant waiting list, whilst still achieving a good donor/recipient match. This study aims to describe the characteristics of the kidney transplant waiting list and variations in median waiting times. METHODS: Demographics and clinical characteristics of all patients listed for a kidney only transplant in the UK on 1st January 2011 were examined. Renal unit variations were explored. Patients listed between January 2006 and December 2009 were included in analysis of waiting times to transplant. RESULTS: At the beginning of 2011, there were 6,699 patients registered active for kidney only transplant in UK; a prevalence rate of 107 pmp. The median age of prevalent listed patients was 53 years, with 8% aged 70 or above. Of the patients listed, 84% had started renal replacement therapy (RRT), 59% were male, 28% were from ethnic minorities, 50% had blood group type O, 28% were defined as difficult to HLA match and 23% were highly sensitised (calculated HLA antibody reaction frequency 85%). Median waiting time to transplant was 38 months. Waiting time was shorter for White patients (36 months) compared to Asian or Black patients (46 months), and was doubled in highly sensitised compared to un-sensitised patients. CONCLUSIONS: Intercentre variation was observed in the rate of wait-listing and in the proportion of listed patients across different ethnic groups, age, blood groups and level of sensitisation. This may reflect differences in baseline population characteristics as well as individual centre practice patterns. Median waiting times differ significantly across blood groups, degree of sensitisation and ethnic group.

Communication: Autodetachment versus internal conversion from the S1 state of the isolated GFP chromophore anion.

The anionic form of p-hydroxybenzylidene-2,3-dimethylimidazolinone (HBDI) has been extensively employed as a model of the chromophore of the green fluorescence protein. The bright S1 excited state HBDI(-) has a measured lifetime of 1.4 ps in the gas-phase and is dominated by two non-radiative decay mechanisms: internal conversion and autodetachment into the neutral continuum. Here, time-resolved photoelectron spectroscopy has been used to determine the yields of these two channels from which the lifetime for autodetachment was found to be ∼30 ps.

Demonstration of universal parametric entangling gates on a multi-qubit lattice.

We show that parametric coupling techniques can be used to generate selective entangling interactions for multi-qubit processors. By inducing coherent population exchange between adjacent qubits under frequency modulation, we implement a universal gate set for a linear array of four superconducting qubits. An average process fidelity of ℱ = 93% is estimated for three two-qubit gates via quantum process tomography. We establish the suitability of these techniques for computation by preparing a four-qubit maximally entangled state and comparing the estimated state fidelity with the expected performance of the individual entangling gates. In addition, we prepare an eight-qubit register in all possible bitstring permutations and monitor the fidelity of a two-qubit gate across one pair of these qubits. Across all these permutations, an average fidelity of ℱ = 91.6 ± 2.6% is observed. These results thus offer a path to a scalable architecture with high selectivity and low cross-talk.

UK National Registry Study of Kidney Donation After Circulatory Death for Pediatric Recipients.

BACKGROUND: Donation after circulatory death (DCD) kidney transplantation has acceptable renal allograft survival in adults but there are few data in pediatric recipients. The aim of this study was to determine renal allograft outcomes for pediatric recipients of a DCD kidney. METHODS: Data were collected from the UK Transplant Registry held by National Health Service Blood and Transplant. Kidney transplants performed for pediatric recipients (age, <18 years) in the United Kingdom from 2000 to 2014 were separated into DCD, donation after brain death (DBD), and living donor (LD) transplants, analyzing 3-year patient and renal allograft survival. RESULTS: One thousand seven hundred seventy-two kidney only transplants were analyzed. Twenty-one (1.2%) of these were from DCD donors, 955 (53.9%) from DBD donors, and 796 (44.9%) from LDs. Patient survival is 100% in the DCD group, 98.7% in the DBD group, and 98.9% in the LD group. Three-year renal allograft survival was 95.2% in the DCD group, 87.1% in the DBD group, and 92.9% in the LD group. There was no significant difference in 3-year renal allograft survival between the DCD and DBD groups (P = 0.42) or DCD and LD groups (P = 0.84). For DCD, the primary nonfunction rate was 5% and delayed graft function was 25%. CONCLUSIONS: Children receiving a DCD kidney transplant have good renal allograft survival at 3-year follow-up, comparable to those receiving a kidney from a DBD donor or a LD. This limited evidence encourages the use of selected DCD kidneys in pediatric transplantation, and DCD allocation algorithms may need to be reviewed in view of this.

The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants.

BACKGROUND: ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. METHODS: The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. RESULTS: For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. CONCLUSIONS: Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients.

BACKGROUND: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized. RESULTS: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03). CONCLUSIONS: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA-matched LD kidney transplant is available.

Multidisciplinary Approach to an Extended Pressure Sore at the Lumbosacral Area.

A pressure sore wound is often extensive or complicated by local infection involving adjacent soft tissue and bone. In this case, a regional flap after simple debridement is not adequate. Here, we present a case of an extensive pressure sore in the sacral area with deep tissue infection. A 43-year-old female patient with a complicated sore with deep tissue infection had a presacral abscess, an iliopsoas abscess, and an epidural abscess in the lumbar spine. After a multidisciplinary approach performed in stages, the infection had subsided and removal of the devitalized tissue was possible. The large soft tissue defect with significant depth was reconstructed with a free latissimus dorsi musculocutaneous flap, which was expected to act as a local barrier from vertical infection and provide tensionless skin coverage upon hip flexion. The extensive sacral sore was treated effectively without complication, and the deep tissue infection completely resolved. There was no evidence of donor site morbidity, and wheelchair ambulation was possible by a month after surgery.

Excited state dynamics of the isolated green fluorescent protein chromophore anion following UV excitation.

A combined frequency-, angle-, and time-resolved photoelectron spectroscopy study is used to unravel the excited state dynamics following UV excitation of the isolated anionic chromophore of the green fluorescent protein (GFP). The optically bright S3 state, which is populated for hv > 3.7 eV, is shown to decay predominantly by internal conversion to the S2 state that in turn autodetaches to the neutral ground state. For hv > 4.1 eV, a new and favorable autodetachment channel from the S2 state becomes available, which leads to the formation of the neutral in an excited state. The results indicate that the UV excited state dynamics of the GFP chromophore involve a number of strongly coupled excited states.

1H detected (13)C echo planar imaging.

Cyclic J cross polarisation (CYCLCROP) is a sensitive method for the noninvasive monitoring of (13)C distributions and fluxes. The PRAWN rotating frame Hartmann-Hahn mixing sequence ameliorates problems associated with sensitivity to Hartmann-Hahn mismatch and reduces RF power deposition. The combination of CYCLCROP with echo planar imaging (EPI) for spatial encoding of the proton detected carbon signal allows efficient use of the available signal to be made, permitting a significant improvement in the temporal resolution of any study. We report here on some initial experiments to demonstrate the feasibility of echo planar proton detected (13)C imaging using CYCLCROP based upon the PRAWN module, including the application of the technique to the measurement of transport and accumulation of (13)C-labelled sucrose in a castor bean seedling. Two methods that can be used to eliminate the effect of the J-splitting in the EP images are presented. In addition, a fast, image-based B(1) field-mapping method which may be used to quantitatively map the low frequency RF field in a dual resonant ((13)C/(1)H) probe is presented. The technique utilises the above described imaging method, permitting fully quantitative, 64x64 axial field maps to be generated in about a minute.

Strategies for expanding the UK pool of potential intestinal transplant donors.

BACKGROUND: The pool of suitable donors and listed recipients for intestinal transplantation is small, resulting in difficulties in donor-to-recipient matching and significant mortality on the waiting list. This study aims to help define the pool of potential donors for intestinal transplantation and propose methods for an increased utilization of donor bowels in the United Kingdom. METHODS: Data on bowel offering from 657 donors after brain stem death (DBD) and on 46 patients on the active intestinal transplant list over 12 months from 14 April 2011 were obtained from the UK Transplant Registry. RESULTS: Family consent for bowel donation was lower than for the other transplantable organs. Only 57% of bowels from DBD donors with consent and meeting the bowel offering criteria were offered for transplantation. A lack of suitable recipients was the most common reason cited for not offering. Only 10% of offered bowels were accepted and transplanted by centers. Donor size discrepancy and human leukocyte antigen incompatibility were common reasons for declining offers of the bowel. There was a scarcity of young and small donors compared with the number of young and small patients requiring a transplant. Two patients who were on the active list during the time period died. CONCLUSIONS: An increased awareness of bowel donation is needed to improve the low offering rate of bowels from DBD donors. A more robust UK bowel allocation system and a formalized European-wide intestinal donor organ sharing program should lead to an increased utilization of available donor bowels and a lower waiting list mortality rate.

Distribution of ABO blood group antibody titers in pediatric patients awaiting renal transplantation: implications for organ allocation policy.

BACKGROUND: Blood group-incompatible transplantation is one strategy used when a potential recipient does not have a compatible living donor. Current practice includes desensitization strategies to reduce antibody titers. However, when antibodies are low, in cardiac transplantation in neonates for example, no desensitization is required. This study is the first to examine the distribution of ABO blood group antibody titers in a population of pediatric patients on the deceased-donor renal transplantation waiting list. METHODS: All patients from two pediatric nephrology centers active on the national deceased-donor waiting list had antibody titers (total immunoglobulin load) measured. A simulation modeling the effect of allocating blood group-incompatible deceased-donor kidneys to those patients with titers of 16 or lower was developed. RESULTS: Twenty-four children were screened; eight (33.3%) had titers of either anti-A or anti-B antibodies of 8 or lower. A further three (12.5%) had either an anti-A or anti-B antibody titer of 16. Blood group A or B patients had lower antibody levels than blood group O patients. In blood group O patients, levels of anti-A antibodies were higher than anti-B antibodies (Wilcoxon signed rank test, P=0.028). The simulation model showed that a change in organ allocation policy would increase pediatric transplant activity by 2.2% and reduce the median waiting time for a transplant. CONCLUSION: This allocation strategy may be of particular benefit to those pediatric patients who have been on the deceased-donor waiting list for a long time or those with a high calculated reaction frequency.

Organ allocation in the United Kingdom.

Organ allocation procedures in the United Kingdom are monitored on a regular basis. Changes are frequently made to improve equity of access and outcomes, based on the performance of a current scheme and simulations of alternatives. This article summarizes current arrangements for the allocation of kidneys, livers and cardiothoracic organs, and illustrates the monitoring process. A new national pancreas allocation scheme is outlined and forthcoming developments in the allocation of livers and DCD donor kidneys are summarized.