Rethinking the transfusion pathway in myelodysplastic syndromes: Study protocol for a novel randomized feasibility n-of-1 trial of weekly-interval red cell transfusion in myelodysplastic syndromes.

BACKGROUND: Anemia in myelodysplastic syndromes (MDS) is associated with poorer health-related quality of life (HRQoL) and physical function, and is frequently treated with transfusions. The current common practice of transfusing multiple red blood cells (RBC) units every 2-4 weeks may result in peaks/troughs in hemoglobin (Hb) level, yet maintaining a stable Hb may better improve HRQoL. We describe a study protocol aiming to investigate the feasibility of weekly low-dose RBC transfusion in MDS patients, including assessing HRQoL and physical function outcomes. STUDY DESIGN AND METHODS: In this n-of-1 pilot study, patients receive two treatment arms, with randomly allocated treatment sequence: arm A (patient's usual transfusion schedule) and arm B (weekly transfusion, individualized per patient). To facilitate timely delivery of weekly transfusion, extended-matched RBCs are provided, with transfusion based upon the previous week's Hb/pre-transfusion testing results to eliminate delays of awaiting contemporaneous cross-matching. Primary outcome is the feasibility of delivering weekly transfusion. Secondary outcomes include HRQoL, functional activity measurements, RBC usage, and alloimmunization rates. A qualitative substudy explores patient and staff experiences. RESULTS: The trial is open in Australia, Netherlands, and UK. The first patient was recruited in 2020. Inter-country differences in providing RBCs are observed, including patient genotyping versus serological phenotyping to select compatible units. DISCUSSION: This pilot trial evaluates a novel personalized transfusion approach of weekly matched RBC transfusion and challenges the dogma of current routine pre-transfusion matching practice. Findings on study feasibility, HRQoL, and physical functional outcomes and the qualitative substudy will inform the design of a larger definitive trial powered for clinical outcomes.

Comparing transfusion practice at multiple hospitals using electronically collected and analysed data.

BACKGROUND: Comparisons of transfusion practice between organisations are time-consuming using manual methods for data collection. We performed a feasibility study to determine whether large-scale transfusion data from three English hospitals could be combined to allow comparisons of transfusion practice. METHODS: Clinical, laboratory and transfusion data from patients discharged between 1 April 2016 and 31 March 2017 were extracted from Patient Administration Systems (PAS), Laboratory Information Management Systems (LIMS), and electronic transfusion systems at three NHS hospitals, which are academic medical centres based in large cities outside London. A centralised database and business intelligence software were used to compare the data. RESULTS: The dataset contained 748 982 episodes of patient care with 91 410 blood components transfused. The study confirms the results of previous studies finding peaks in the ages of transfusion in the 0-4 years age range, in women of childbearing ages, and in males over 60 years. The number of components transfused per 1000 bed days was used as a standardised comparator. Red cell utilisation was 42.4, 40.4 and 49.5 units/1000 bed days and platelet utilisation 11.69, 7.76, and 11.66 units/1000 bed days. 60.5% (6848/11 310) of Group O D negative red cell units were transfused to non-group O D negative recipients. An analysis of component usage highlighted variations in practice, for example platelet usage for cardiac surgery varied from 2.4% to 7.3% across the three hospitals. CONCLUSION: This feasibility study demonstrates that large electronic datasets from hospitals can be combined to identify areas for targeted interventions to improve transfusion practice.

Asymmetric Induction in C-Alkylation of Tropane-Derived Enamines: Congruence Between Computation and Experiment.

Quantum chemical studies of C-ethylation of 1-methyl- and 1,4,4-trimethyl-tropane-derived enamines predict good (89:11 er, B3LYP) and high (98:2 er, B3LYP) levels, respectively, of asymmetric induction in the resulting α-alkylated aldehydes. The nonracemic tropanes were synthesized using Mannich cyclization strategies (Robinson-Schöpf and by way of a Davis-type N-sulfinyl amino bisketal, respectively), and ethylation of the derived enamines was found to support the predicted sense and magnitude of asymmetric induction (81:19 er and 95:5 er, respectively). A comparison of several computational methods highlights the robustness of predicted trends in enantioselectivity, enabling theory to guide synthesis.

C-alkylation of chiral tropane- and homotropane-derived enamines.

The synthesis and alkylation of chiral, nonracemic tropane- and homotropane-derived enamines is examined as an approach to enantioenriched α-alkylated aldehydes. The two bicyclic N auxiliaries, which differ by a single methylene group, give opposite senses of asymmetric induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines.

Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.

Determination of the phenoxyacid herbicides MCPA, mecoprop and 2,4-D in kidney tissue using liquid chromatography with electrospray tandem mass spectrometry.

An analytical method was developed to determine the phenoxyacid herbicides 2,4-D, MCPA and mecoprop in kidney tissue from animals where poisoning is suspected. Samples were Soxhlet extracted using diethyl ether and the extracts cleaned-up using anion exchange solid phase extraction cartridges. Analysis was performed using liquid chromatography with negative-ion electrospray tandem mass spectrometry (LC-MS/MS). The method was evaluated by analysing control kidney samples fortified at 1 and 5 mg/kg. Mean recoveries ranged from 82 to 93% with relative standard deviations from 3.2 to 19%. The limit of detection was estimated to be 0.02 mg/kg.

Left-sided Neck Swelling: An Unusual Presentation of a Rare Disease.

Pneumomediastinum describes air infiltrating into the soft tissues of the mediastinum. It may be classified as spontaneous or secondary. Spontaneous pneumomediastinum is a rare disease, which usually resolves without intervention. The acute onset of chest pain is the most common presenting complaint.  This article presents a case of spontaneous pneumomediastinum in a 19-year-old man with a short history of rapidly enlarging, painless swelling to the left side of his neck, followed by a discussion of the literature. The diagnosis was made following chest x-ray (CXR) and computed tomography (CT). There was no history of any precipitating event or any risk factors. He was managed conservatively and discharged with outpatient follow-up.  Management of spontaneous pneumomediastinum continues to vary and may benefit from the development of guidelines to standardise management in the future.

Determination of imidazole and triazole fungicide residues in honeybees using gas chromatography-mass spectrometry.

An analytical method employing clean up by high-performance gel permeation chromatography (HPGPC) and solid-phase extraction (SPE) on Florisil cartridges was developed to determine residues of eleven imidazole and triazole ergosterol-biosynthesis-inhibiting (EBI) fungicides in honeybee samples. Detection was by means of gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode. The method was validated by fortifying control samples at levels of 0.01 and 0.05 micro g/bee. Mean recoveries for each analyte except imazalil were between 79 and 99% with relative standard deviations of 12.3% or less. Mean recoveries of imazalil were 51% at 0.01 micro g/bee and 81% at 0.05 micro g/bee. Limits of detection for the analytes investigated ranged from 0.005 to 0.001 micro g/bee.

Incidents of bee poisoning with pesticides in the United Kingdom, 1994-2003.

For over 20 years, the UK Agriculture Departments have monitored the direct effects of pesticides on beneficial insects, mainly honeybees (Apis mellifera, L.) and bumblebees (Bombus terrestris, L.), as part of the Wildlife Incident Investigation Scheme (WIIS). The Central Science Laboratory (CSL) has contributed to WIIS by providing the required laboratory skills for the determination of bee diseases and the expert analytical experience necessary to determine low-level pesticide residues and interpret these results. The results from WIIS form part of the pesticide regulatory process coordinated by the Pesticides Safety Directorate (PSD) and are published each year. This paper has reviewed the data from WIIS over the 10 year period from 1994 to 2003. The overall trend is that suspected poisoning incidents, reported by beekeepers and the general public, have declined from 56 incidents per year to 23 incidents per year. The number of these incidents that have been attributed to pesticide poisoning has also declined, from 25 incidents to five incidents per year. The possible reasons for these changes and the circumstances involved in the bee poisoning incidents are discussed. However, the source of the pesticide in bee poisoning incidents is often uncertain and the likely cause of these incidents and any trends over time are also discussed.

Development of a cell culture/ELISA assay to detect anticoagulant rodenticides and its application to analysis of rodenticide treated grain.

This study describes a generic biological screening assay designed to detect anticoagulant rodenticides based on their inhibitory action on the vitamin K epoxide reductase protein complex, resulting in an accumulation of under-carboxylated prothrombin or proteins induced by vitamin K antagonism (PIVKA-II). A combined cell culture/ELISA assay was optimized to measure PIVKA-II production by the human hepatoma HepG2 cell line cultured in the presence of anticoagulant rodenticides. The specificity and sensitivity of the assay was validated using 41 grain extracts containing representative concentrations of rodenticide or appropriate nonrodenticide control compounds. In all cases, PIVKA-II produced by HepG2 cells in response to grain extracts spiked with rodenticides was detected by ELISA, while PIVKA-II was not detected in supernatants collected from cells exposed to nonrodenticide controls. This represents a novel, class-specific biological assay for the detection of anticoagulant rodenticides present in contaminated grain.

Analytical methods used in the United Kingdom Wildlife Incident Investigation Scheme for the detection of animal poisoning by pesticides.

The United Kingdom Wildlife Incident Investigation Scheme (WIIS) investigates cases of suspected poisoning of wildlife, honey bees, and companion animals by pesticides. Together with field inquiries and veterinary post-mortem examinations, the analytical procedures presented here provide a comprehensive approach to the investigation of these cases. The paper covers selection of animal tissues for analysis and methods suitable for the analysis of honey bees and for various types of bait. Seven multiresidue methods cover around 130 pesticides, and methods are also described for a further 8 compounds. These methods are currently used on samples submitted to the Scheme in England and Wales.

Stratospheric memory and skill of extended-range weather forecasts.

We use an empirical statistical model to demonstrate significant skill in making extended-range forecasts of the monthly-mean Arctic Oscillation (AO). Forecast skill derives from persistent circulation anomalies in the lowermost stratosphere and is greatest during boreal winter. A comparison to the Southern Hemisphere provides evidence that both the time scale and predictability of the AO depend on the presence of persistent circulation anomalies just above the tropopause. These circulation anomalies most likely affect the troposphere through changes to waves in the upper troposphere, which induce surface pressure changes that correspond to the AO.