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Acute myeloid leukemia (AML) is a heterogeneous disease of impaired myeloid differentiation and a caricature of normal hematopoiesis. Leukemic stem cells (LSCs) are responsible for long-term clonal propagation in AML just as hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis. LSCs are often resistant to standard chemotherapy and are responsible for clinical relapse. Although AML is highly heterogeneous, determinants of stemness are prognostic for AML patient survival and can predict AML drug sensitivity. Therefore, one way to overcome challenges preventing efficacious treatment outcomes is to target LSC stemness. Metabolomic and lipidomic studies of serum and cells from AML patients are emerging to complement genomic, transcriptomic, epigenetic, and proteomic data sets to characterize and stratify AML. Recent studies have shown the value of fractionating LSCs versus blasts when characterizing metabolic pathways and implicate the importance of lipid balance to LSCs function. As more extensive metabolic studies coupled to functional in vivo assays are conducted on highly purified HSCs, bulk AML, and LSCs, the similarities and differences in lipid homeostasis in stem-like versus more mature AML subtypes as well as from normal HSCs are emerging. Here, we discuss the latest findings from studies of lipid function in LSCs, with a focus on sphingolipids (SLs) as stemness/lineage fate mediators in AML, and the balance of fatty acid anabolism and catabolism fueling metabolic flexibility and drug resistance in AML. We also discuss how designing successful strategies to target lipid vulnerabilities and improve AML patient survival should take into consideration the hierarchical nature of AML.

Gene therapies can be envisioned for many disorders where conventional therapies fall short. Lysosomal Storage Disorders (LSDs) are inherited, mostly monogenic, disorders resulting from deficient lysosomal enzyme or co-factor activity. Existing standard-of-care treatments for LSDs are expensive and can negatively impact quality-of-life. They also may not be sufficiently efficacious. LSDs are particularly amenable to gene therapy as modified cells can secrete functional enzyme that can also correct unmodified cells. Gene therapies may thus be able to provide sustained long-term correction for LSD patients.We highlight recent advances and discuss advantages/disadvantages of gene therapies with a focus on lentiviral and adeno-associated virus vectors currently in clinical trials for LSDs. We also mention promising strategies that are close to clinical testing. We emphasize protocols usingGene therapy is still in its infancy with respect to LSDs. However, efficacy and safety has been demonstrated in numerous pre-clinical studies, and promising clinical results suggest that gene therapy treatment for several LSDs is a real possibility.

Farber disease (FD) is a rare monogenic lysosomal storage disorder caused by mutations in ASAH1 that results in a deficiency of acid ceramidase (ACDase) activity and the abnormal systemic accumulation of ceramide species, leading to multi-system organ failure involving neurological decline and retinopathy. Here we describe the effects of rAAV-mediated ASAH1 over-expression on the progression of retinopathy in a mouse model of FD (Asah1

We identified 11 common recommendations to deliver best care for musculoskeletal (MSK) pain.1 Recommendation 1, that MSK pain care is patient centred, is the cornerstone for best care. Yet patient-centred care is often undervalued, under-recognised, undertrained and considered less important than technical skills/knowledge. Greater attention to patient-centredness improves patient and practitioner outcomes and reduces costs.2 3 A paradigm shift is needed in which patient-centred skills are learnt with the same rigour as technical skills (eg, patient physical examination procedures). However, clinicians and high-performance professionals are often unsure of how the patient centredness of their practice can be improved. The simplest step is for clinicians to improve the effectiveness of their communication. Patient-centred care incorporates each individual’s context, knowledge, needs, values, goals and preferences into shared decision-making about management.4 Achieving this relies on effective communication,4 which elicits the patient’s concerns, within their unique context, leading to a partnership in management. This process is individualised, interactive, dynamic and evolves over the patient’s journey. Communication is also not just about the patient interview. It includes how clinicians approach the physical examination, how they engage and empower the patient in shared decision-making and arrive …

BackgroundTime-based-targets for emergency department length-of-stay were introduced in England in 2000; followed by Canada, Ireland, New Zealand, and Australia after emergency department crowding was associated with poor quality of care and increased mortality.ObjectivesThe aim of the systematic review was to evaluate qualitative literature to investigate how implementing time-based-targets for emergency department length-of-stay has influenced the quality of care of patients.MethodsSystematic review of qualitative studies that described knowledge, attitudes to or experiences regarding a time-based-target for emergency department length-of-stay. Searches were conducted in Cochrane library, Medline, Embase, CInAHL, Emerald, ABI/Inform, and Informit. Individual studies were evaluated using the Critical Appraisal Skills Programme tool. Individual study findings underwent thematic analysis. Confidence in findings was assessed using the Confidence in the Evidence from Reviews of Qualitative research approach.ResultsThe review included thirteen studies from four countries, incorporating 617 interviews. Themes identified were: quality of care, access block and overcrowding, patient experience, staff morale and workload, intrahospital and interdepartmental relationships, clinical education and training, gaming, and enablers and barriers to achieving targets. The confidence in findings is moderate or high for most themes. More patient and junior doctor perspectives are needed.ConclusionsEmergency time-based-targets have impacted on the quality of emergency patient care. The impact can be both positive and negative and successful implementation depends on whole hospital resourcing and engagement with targets.FundingThe Australasian College for Emergency Medicine provided administrative support for the study, no funding was received.RegistrationPROSPERO CRD42019107755 (prospective)

Objective To compare methods of assessment of the burden of primary care-type ED (PCTED) presentations against clinical assessment by general practitioners (GPs) in ED. Methods A cross-sectional study involving clinical assessment of patients presenting to four EDs in Western Australia. The GPs assessed patients who were likely to be discharged home from ED, and considered whether they could be managed in general practice. Patient presentations were defined by the GPs as: PCTED; PCTED if additional primary care resources were available; or not PCTED. Results GP researchers determined that 80% of patients assessed were PCTED presentations, with one-third of these considered PCTED presentations if additional resources were available. A high proportion of identified PCTED presentations included categories excluded by previous methods. Analysis of linked data found the cohort assessed to be of lower urgency, younger, and with a shorter length of stay than the average patient being discharged from ED. After accounting for potential bias, it is suggested that 20-40% of all ED presentations could be PCTED presentations. Conclusions Previous methods determining the burden of PCTED presentations have not been validated. Many presentations excluded by previous methods were identified as manageable in general practice by GPs clinically assessing patients in ED. Improved validation of criteria used to identify PCTED presentations will enable appropriately designed interventions to reduce such events.