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Abstract: Gilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3-tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Ketamine, a N-methyl-D-aspartate (NMDA) antagonist, is used for treatment-resistant depression (TRD). Recent studies have shown that there are increased levels of pro-inflammatory cytokines in individuals with major depressive disorder (MDD) and those with higher levels of oxidative stress markers have a decreased or null response to conventional antidepressants. Glutathione (GSH) as an antioxidant adjuvant to ketamine has not been well studied. This double-blind study with 30 patients divided into 2 groups of 15 each, aimed to determine if GSH, added to standard ketamine infusion (GSH+K), rendered better outcomes in MDD patients versus patients receiving ketamine infusions with a normal saline placebo (K+NS). There were significant drops in BDI-II scores from day 1 to day 14, PHQ- scores from day 1 to day 14 and PHQ-9 scores day 14 to day 28, suggesting the overall treatment was effective. There were no statistically significant differences between the groups over time. However, a sustained improvement in depressive symptoms was observed for 14 days post-infusion in both groups., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest, (Copyright © 2024. Published by Elsevier B.V.)

Background: Anesthetic gases have been known to cause damage when inhaled over long periods of time. Modern safety measures have been put in place to reduce the risk to anesthesia providers, however there is continued lack of information on providers experiencing short term effects (lethargy, fatigue, headache, slowed cognitive ability, nausea, and mucosal irritation) thereby leading to long-term sequalae (sister chromatid exchanges, micronuclei, chromosomal aberrations, and comet assays)., Method: A thirteen item, multiple choice survey was sent to 3,000 anesthesia providers, of which 463 completed the survey. A Chi-square test of independence was used to determine the association between gas exposure and participant self-reported symptoms. A Spearman's Correlation test was also utilized to interpret this data since both frequency of smelling gas and frequency of symptoms were ordinal variables for which Spearman's rho correlation was the appropriate measure of association., Results: The major findings were that as the frequency of smelling anesthetic gas increased, so too did the frequency of self-reported headaches and fatigue. Spearman's rho = .148 and .092. P value = .002 and .049, respectively., Conclusion: There have been many efforts to decrease the risk of exposure of anesthesia providers to anesthetic gases. While there is a decrease in reported exposures, indications of possible long-term effects remain a concern in anesthesia providers. Potential implications of exposure could lead to chromosomal aberrations, sister chromatid exchanges, comet assays, spontaneous abortions, and genotoxic effects., (© 2022. The Author(s).)

Equine piroplasmosis (EP) has historically been of minor concern to UK equine practitioners, primarily due to a lack of competent tick vectors. However, increased detection of EP tick vector species in the UK has been reported recently. EP screening is not currently required for equine importation, and when combined with recent relaxations in movement regulations, there is an increased risk regarding disease incursion and establishment into the UK. This study evaluated the prevalence of EP by both serology and PCR among 1242 UK equine samples submitted for EP screening between February and December 2016 to the Animal and Plant Health Agency and the Animal Health Trust. Where information was available, 81.5 per cent of submissions were for the purpose of UK export testing, and less than 0.1 per cent for UK importation. Serological prevalence of EP was 8.0 per cent, and parasite DNA was found in 0.8 per cent of samples. A subsequent analysis of PCR sensitivity in archived clinical samples indicated that the proportion of PCR-positive animals is likely to be considerably higher. The authors conclude that the current threat imposed by UK carrier horses is not adequately monitored and further measures are required to improve national biosecurity and prevent endemic disease., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. Laboratory diagnosis of haematological malignancies is dependent on combining several technologies, including morphology, immunophenotyping, cytogenetics and molecular genetics correlated clinical details and classification according to the current WHO guidelines. The concept of the Specialised Integrated Haematological Malignancy Diagnostic Services (SIHMDS) has evolved since the UK National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) in 2003 and subsequently various models of delivery have been established. As part of the 2016 update to the NICE IOG, these models were systematically evaluated and recommendations produced to form the basis for quality standards for future development of SIHMDS. We provide a summary of the systematic review and recommendations. Although the recommendations pertain to the UK National Health Service (NHS), they have relevance to the modern delivery of diagnostic services internationally., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan-3-amine] is a high-affinity and highly selective ligand at α3β4 nicotinic cholinergic receptors (nAChRs) that was reported to decrease nicotine self-administration in rats. It was initially reported to be an antagonist at rat α3β4 nAChRs heterologously expressed in HEK293 cells. Here we compared AT-1001 actions at rat and human α3β4 and α4β2 nAChRs similarly expressed in HEK 293 cells. We found that, as originally reported, AT-1001 is highly selective for α3β4 receptors over α4β2 receptors, but its binding selectivity is much greater at human than at rat receptors, because of a higher affinity at human than at rat α3β4 nAChRs. Binding studies in human and rat brain and pineal gland confirmed the selectivity of AT-1001 for α3β4 nAChRs and its higher affinity for human compared with rat receptors. In patch-clamp electrophysiology studies, AT-1001 was a potent partial agonist with 65-70% efficacy at both human and rat α3β4 nAChRs. It was also a less potent and weaker (18%) partial agonist at α4β2 nAChRs. Both α3β4 and α4β2 nAChRs are upregulated by exposure of cells to AT-1001 for 3 days. Similarly, AT-1001 desensitized both receptor subtypes in a concentration-dependent manner, but it was 10 and 30 times more potent to desensitize human α3β4 receptors than rat α3β4 and human α4β2 receptors, respectively. After exposure to AT-1001, the time to recovery from desensitization was longest for the human α3β4 nAChR and shortest for the human α4β2 receptor, suggesting that recovery from desensitization is primarily related to the dissociation of the ligand from the receptor., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonist-mediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, site-directed mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Psychosocial assessment prior to haematopoietic stem cell transplants (HSCT) can help to identify patients at risk of impaired health-related quality of life (HRQOL) post-transplant. According to the response-shift model, certain antecedents and mechanisms, along with changes in internal standards, values or conceptualizations of HRQOL, facilitate adjustment to changes in health circumstances. This study sought to explore the role of psychosocial variables in adjustment to compromised HRQOL following HSCT, from the theoretical basis of the response-shift model., Methods: Semi-structured interviews were conducted with 28 patients (15 women, 13 men; 22-71 years), post-HSCT. Time since transplant ranged from 1 month to 28 years. Verbatim transcripts were analysed using template analysis., Results: Patients provided narrative examples of changing their values and internal standards. Optimism, social support, social comparisons, changing expectations and setting goals were identified as important in managing threats to HRQOL., Conclusions: The response-shift model is a useful theoretical basis for exploring HRQOL in HSCT patients. Response shifts and psychosocial variables may help patients to cope and enabling them to experience good HRQOL despite the negative effects of HSCT. Understanding the adjustment processes has implications for patient care.

Leptospira have a worldwide distribution and include important zoonotic pathogens yet diagnosis and differentiation still tend to rely on traditional bacteriological and serological approaches. In this study a 1.3 kb fragment of the rrs gene (16S rDNA) was sequenced from a panel of 22 control strains, representing serovars within the pathogenic species Leptospira interrogans, Leptospiraborgpetersenii, and Leptospirakirschneri, to identify single nucleotide polymorphisms (SNPs). These were identified in the 5' variable region of the 16S sequence and a 181 bp PCR fragment encompassing this region was used for speciation by Denaturing High Performance Liquid Chromatography (D-HPLC). This method was applied to eleven additional species, representing pathogenic, non-pathogenic and intermediate species and was demonstrated to rapidly differentiate all but 2 of the non-pathogenic Leptospira species. The method was applied successfully to infected tissues from field samples proving its value for diagnosing leptospiral infections found in animals in the UK., (Crown Copyright 2010. Published by Elsevier India Pvt Ltd. All rights reserved.)

Between 1969 and 1999, 420 patients (age > 60 years) with newly diagnosed AML were managed at St Bartholomew's Hospital (SBH), London, UK. Sixty-nine percent of patients received therapy with curative intent Eighty-eight patients (31%) of the latter achieved complete remission (CR), representing an overall CR rate of 21%. Treatment failure due to early death (ED) and resistant disease (RD) occurred in 50 and 19%, respectively. With median follow up of 11 years, actuarial survivals at 1,3 and 5 years were 20, 7 and 4%, respectively, the median survival of the entire cohort was 2 months. For patients who achieved CR, median survival was significantly better than that of patients in whom treatment failed (14 vs. 6 months). Over the 30 years, CR rate and the relative incidence of RD both increased from 13 to 45%, and 3 to 27%, respectively, whilst ED rate reduced from 84 to 27%. Multivariate analysis showed that treatment era, hepatosplenomegaly and increasing age predicted for reduced CR rate and OS. Although elderly patients with AML are characterised by a poor response to intensive chemotherapy, significant improvements in supportive care and the delivery of intensive treatment have led to improved CR rates and OS. New therapeutic strategies and a greater awareness of prognostic factors may further improve clinical outcome in this important group of patients.