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Cassarino, Marica, Úna Cronin, Katie Robinson, Rosie Quinn, Fiona Boland, Marie E. Ward, Rosa McNamara, et al. "Development and delivery of an allied health team intervention for older adults in the emergency department: A process evaluation." PLOS ONE 17, no. 5 (May 26, 2022): e0269117. http://dx.doi.org/10.1371/journal.pone.0269117.
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Background There is encouraging evidence that interdisciplinary teams of Health and Social Care Professionals (HSCPs) can enhance patient care in the Emergency Department (ED), especially for older adults with complex needs. However, no formal process evaluations of implementations of ED-based HSCP interventions are available. The study aimed to evaluate the development and delivery of a HSCP team intervention for older adults in the ED of a large Irish teaching hospital. Methods Using the Medical Research Council (MRC) Framework for process evaluations, we investigated implementation and delivery, mechanisms of impact, and contextual influences on implementation by analysing the HSCP team’s activity notes and participant recruitment logs, and by carrying out six interviews and four focus groups with 26 participants (HSCP team members, ED doctors and nurses, hospital staff). Qualitative insights were analysed thematically. Results The implementation process had three phases (pre-implementation, piloting, and delivery), with the first two described as pivotal to optimise care procedures and build positive stakeholders’ involvement. The team’s motivation and proactive communication were key to promote acceptability and integration in the ED (Theme 1); also, their specialised skills and interdisciplinary approach enhanced patient and staff’s ED experience (Theme 2). The investment and collaboration of multiple stakeholders were described as essential contextual enablers of implementation (Theme 4). Delivering the intervention within a randomised controlled trial fostered credibility but caused frustration among patients and staff (Theme 3). Discussion This process evaluation is the first to provide in-depth and practical insights on the complexities of developing and delivering an ED-based HSCP team intervention for older adults. Our findings highlight the importance of establishing a team of HSCPs with a strong interdisciplinary ethos to ensure buy-in and integration in the ED processes. Also, actively involving relevant stakeholders is key to facilitate implementation. Trial registration ClinicalTrials.gov, NCT03739515; registered on 12th November 2018.
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Avenoso, Daniele, Anne Bradshaw, Andrew Innes, Josu de la Fuente, Eduardo Olavarria, Jane F. Apperley, and Jiří Pavlů. "Microbial Contamination of Haematopoietic Stem Cell Products: A Single Centre Experience." Blood 128, no. 22 (December 2, 2016): 5741. http://dx.doi.org/10.1182/blood.v128.22.5741.5741.
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Abstract Bacterial contamination of haematopoietic stem cell products (HSCP) during collection and processing is a potential risk and has been described as cause of serious morbidity and mortality. The rate of contamination is reported in the range of 0 to 4.5% in peripheral blood progenitor cell (PBPC) apheresis to as high as 26% in bone marrow (BM) harvests. Systematic microbiological testing is an important component of the HSCP quality assessment and identification of the bacteria involved helps in the management of early infective complications. Here we report the rate of contaminated HSCP collected in a single transplant centre, our policy of the management of this complication and the relevant clinical outcomes. This is a retrospective study of prospectively collected results of microbiological analyses of 246 collections performed from January 2015 till December 2015. Stem cells were collected by BM harvesting under general anaesthesia (N=47) and by PBPC apheresis (N=199) using Optia separator system. BM harvest rather then PBPC was performed on donor request or with donor consent where BM was clinically preferable over PBPC transplant. (eg. red cell disorders). Samples of HSCP for bacterial cultures were taken pre processing, post processing, including post filtration and at defined intervals during complex procedures. Cryoprotectant is also tested to check that no contamination has occurred during manufacture of the freeze mix. Samples were cultured in BACTEC™ Lytic/10 Anaerobic/F culture vials (pre-reduced enriched Soybean-Casein Digest broth with CO2) and in anaerobic blood cultures; BACTEC Peds Plus™/F culture vials (enriched Soybean-Casein Digest broth with CO2) under aerobic conditions, both for 14 days. Organisms were specifically identified in all positive HSCP. Sixteen bacterial contaminations of HSCP were recorded (6.09% of total collections). The most frequent product contaminated was BM (N=15, 31.9%); only one PBPC apheresis product was positive (0.5%). The following bacteria were isolated: propionibacterium (N=7), coagulase negative staphylococcus (N=4), micrococcus (N=2), staphylococcus capitis (N=1), Staphylococcus epidermidis (N=2). Seven HSCP were not infused: one patient died before undergoing to transplant, two products have been collected as stem cell rescue in case of graft failure from allogeneic donors, four collections were stored for future use. Nine patients received contaminated HSCPs. After being contemporaneously alerted to the contamination, the clinical team performed daily blood cultures (BC). From these 9 patients only two minor clinical events were recorded; One, a non-neutropaenic fever on day +2 (S. Capitis cultured from HSCP, BC negative) and the other a positive BC (micrococcus cultured from both HSCP and BC) in a patient without fever or signs of infection. Both were treated with IV vancomycin on microbiology advice. These data showed a rate of bacterial contamination of HSCP comparable with reports from other groups. Moreover, at our centre no major clinical events were recorded after the infusion of contaminated HSCP. In this small study, the most frequent source of contaminated HSCP was BM and the most frequently isolated pathogens were skin commensals. No consensus exists on the requirement for antibiotics after the infusion of contaminated HSCP. Our experience supports a strategy of symptomatic management based on fevers or positive blood cultures with targeted antibiotics based on in vitro sensitivities rather than pre-emptive empirical treatment of all patients. Disclosures Apperley: Bristol Myers Squibb: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
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Singh, Abhishek K., Karin Golan, Mark J. Althoff, Ekaterina Petrovich-Kopitman, Ashley M. Wellendorf, Fatima Mohmoud, Mayla Bertagna, et al. "Bone Marrow Hematopoietic Connexin 43 Is Required for Mitotransfer and AMPK Dependent Mesenchymal Microenvironment Regeneration after Irradiation." Blood 132, Supplement 1 (November 29, 2018): 872. http://dx.doi.org/10.1182/blood-2018-99-118292.
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Abstract Hematopoietic stem cell/progenitor (HSCP) transplantation (HSCT) is routinely used for the treatment of cancer and inborn hematopoietic defects. The bone marrow (BM) microenvironment (ME) is a major regulator of hematopoietic function and fate. Clinical data supports osteoblastic regeneration after HSCT despite the inability of BM mesenchymal stem cells (BM-MSC) to engraft. Therefore, understanding the hematopoietic-dependent mechanisms controlling ME mesenchymal regeneration is expected to provide molecular targets for intervention in the context of HSCT. Hematopoietic connexin-43 (H-Cx43) mediates HSCP survival and efficient blood formation by scavenging damaging excess reactive oxygen species (ROS) through transfer to BM mesenchymal stromal cells (BM-MSC) after chemotherapy, preventing lethal hematopoietic failure (Taniguchi-Ishikwawa E et al., PNAS 2012), while the expression of Cx43 on BM-MSC regulates CXCL12 secretion and HSCP homeostasis (Schajnovitz A et al., Nat. Immunol., 2011). Since Cx43 is expressed in mitochondria, we hypothesized that H-Cx43 mediated ROS transfer upon stress depends on hematopoietic mitochondria transfer and uptake by the BM-MSC. We created chimeric mice by transplanting Vav1-CreTg/-, Cox8 mitochondrial localization signal-Dendra2Tg/- wild-type (mDendra2/WT) or Cx43fl/fl(mDendra2/Cx43Δ/Δ) HSCP to lethally irradiated, congenic WT mice and assessed the recovery of stromal cell regeneration via transfer of mitochondria to BM-MSC. H-Cx43Δ/Δchimeric mice have delayed lympho-hematopoietic recovery after irradiation or chemotherapy which can be reversed by restoration of hematopoietic Cx43 expression. H-Cx43Δ/Δchimeric mice exhibit decreased (~60-80%) and delayed colony-forming-unit-fibroblast (CFU-F) and osteoblast (CFU-Ob) regeneration and hematopoietic recovery. The delayed hematopoietic response in H-Cx43Δ/Δchimeras associated with ~40% reduction in mitochondrial transfer from HSCP to Lin-/CD45-/PDGFRα+/Sca1- BM stromal cells (MSC/P). Reverse transplantation experiments indicate that stromal Cx43 is dispensable for mitochondrial transfer from BM stroma to HSCP. Impaired mitochondrial uptake in H-Cx43Δ/Δchimeras associated with ~30-40% decreased mitochondrial ROS (mROS), membrane potential (MMP) and proliferation (assessed by in vivo BrdU uptake) of recipient MSC/P, suggesting that the transferred mitochondria reprogram the recipient mesenchymal progenitor metabolism. Defects of mitotransfer from H-Cx43Δ/ΔHSCP to BM MSC/P and in recipient BM MSC/P mitochondrial activity were recapitulated in in vitro co-cultures. Interestingly, intracellular [ATP] is upregulated (~2 fold) in MSC/P from chimeric H-Cx43Δ/ΔBM that received donor-derived mitochondria, as compared to donor mitochondria containing MSC/P from WTchimeras. Hemichannel opening causes loss of ATP, we therefore speculated that ATP released from MSC/P upon irradiation and transplantation is uptaken by HSPC, activating mitochondrial transfer as part of BM regeneration. Forced glycolysis-dependent restoration of [ATP] in MSC/P but not in HSCP enhances transfer of mitochondria from HSCP to MSC/P, suggesting that BM stromal [ATP] is an irradiation-responsive positive regulator of mitochondria transfer. Hemichannel-derived exogenous ATP suppresses AMPK activation, which regulates cellular metabolic homeostasis by modulating mitochondrial ROS, mitochondria dynamics and the fate of mitochondria. We found that MSC/P recipient of H-Cx43Δ/Δ mitochondria have increased AMPK activity as assessed by increased phosphorylation of AMPK and its downstream effectors ULK1 and ACC (~2-fold) when compared with MSC/P recipient of H-WT mitochondria, whereas MSC/P containing no donor-derived mitochondria from either chimeric mice are insensitive to the effect of Cx43 deficiency. In vivo administration of the AMPK inhibitor BML-275 dramatically increased the mitochondria transfer from HSCP to MSC/P in WT and H-Cx43Δ/Δ chimeras, and completely restores the negative effect of H-Cx43 deficiency on BM mesenchymal and hematopoietic regeneration. Our data indicate that hematopoietic mitochondrial Cx43 is required to control both mitochondrial transfer and BM ME energetic balance and regeneration after myeloablative irradiation. Disclosures No relevant conflicts of interest to declare.
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Trépel, Dominic, Manuel Ruiz-Adame, Marica Cassarino, Elayne Ahern, Collette Devlin, Katie Robinson, Íde O’Shaughnessy, Gerard McCarthy, Cian Corcoran, and Rose Galvin. "The cost effectiveness of early assessment and intervention by a dedicated health and social care professional team for older adults in the emergency department compared to treatment-as-usual: Economic evaluation of the OPTI-MEND trial." PLOS ONE 19, no. 6 (June 25, 2024): e0298162. http://dx.doi.org/10.1371/journal.pone.0298162.
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Background Over 65s are frequent attenders to the Emergency Department (ED) and more than half are admitted for overnight stays. Early assessment and intervention by a dedicated ED-based Health and Social Care Professionals (HSCP) team reduces ED length of stay and the risk of hospital admissions among older adults while improving patient health-related quality-of-life and satisfaction with care. This study aims to evaluate whether augmenting the treatment as usual for older adults admitted to ED is cost-effective. Methods and findings Cost-effectiveness analysis (CEA), conducted alongside the OPTI-MEND randomised controlled trial of 353 patients aged ≥65 with lower urgency complaints compared the effectiveness of early assessment and intervention by a dedicated HSCP team in the ED to treatment as usual (TAU). An economic analysis estimated the average cost per older adults randomised to the HSCP team, and compared to TAU, how contact with HSCP team changed health care use, and associated total costs, and estimated the effect of HSCP on Quality-Adjusted Life Years (QALYs). Within the OPTI-MEND trial, the average cost of a contact with the HSCP team during ED attendance is estimated to be €801 per patient. Compared to TAU, the incremental QALY of intervention is 0.053 (95% CI: 0.023 to 0.0826, p<0.0001). Accounting for cost savings because of contact with HSCP team, the average incremental saving in the total cost, compared to TAU, is -€6,128 (95% CI: -€9,217 to -€3,038, p<0.0001). Given the incremental health gains and significant cost savings, bootstrapped cost CEA suggests that dedicated HSCP care dominates over TAU for low urgency older adults attending the ED. Conclusions A dedicated HSCP team in the ED significantly improves overall health for lower acuity older adults and, by reducing inpatient length of stay, results in staggering cost savings. This economic evaluation conducted on the OPTI-MEND trial provides convincing evidence that HSCP should be adopted as part of treatment as usual in Irish EDs. Trial registration ClinicalTrials.gov, NCT03739515; registered on 12th November 2018. https://classic.clinicaltrials.gov/ct2/show/NCT03739515.
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Cassarino, Marica, Katie Robinson, Rosie Quinn, Fiona Boland, Marie E Ward, Rosa McNamara, Gerard McCarthy, Damien Ryan, Margaret O'Connor, and Rose Galvin. "138 The Role of Health and Social Care Professional Teams in the Emergency Department: A Qualitative Study of Key Stakeholders’ Views." Age and Ageing 48, Supplement_3 (September 2019): iii1—iii16. http://dx.doi.org/10.1093/ageing/afz102.27.
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Abstract Background Introducing Health and Social Care Professional (HSCP) teams to the emergency department (ED) has increasingly demonstrated benefits for ED patient and process outcomes. However, there is a dearth of research exploring the views of key ED stakeholders on the role of HSCP teams in care delivery the ED. This qualitative study investigated the perspectives of a wide range of ED stakeholders about HSCPs teams working in the ED. Methods A total of 65 participants including older adults who had recently attended the ED and their carers/relatives, ED doctors and nurses, HSCPs and pre-hospital staff participated in four World Café style focus groups and individual interviews across two Irish hospital sites. Written and audio-recorded data were transcribed and thematically analysed. Results Overall, participants expressed positive views on HSCPs working in teams in the ED, with benefits for patients, staff members and the hospital (Theme 1). Having an ED-based HSCP team was described as promoting effective and timely decision-making and a more integrated approach to patient care, particularly for frail older adults with complex needs (Theme 2). Barriers and enablers for effective implementation were identified at multiple levels (Theme 3) including the ED physical environment, (e.g., space and equipment), operational factors (e.g., working hours), and relations (e.g., patient-staff or staff-staff communication); factors at system level included availability of community resources and financial pressures. Conclusion Our study indicates overall acceptability of HSCPs working in teams in the ED and positive views on their contribution to enhance the quality care of older adults. However, a number of operational and relational factors need to be considered to ensure feasibility and effectiveness. This information is crucial to inform implementation.
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Cassarino, Marica, Úna Cronin, Katie Robinson, Rosie Quinn, Fiona Boland, Marie E. Ward, Rosa MacNamara, et al. "Implementing an allied health team intervention to improve the care of older adults in the emergency department: protocol for a process evaluation." BMJ Open 9, no. 7 (July 2019): e032645. http://dx.doi.org/10.1136/bmjopen-2019-032645.
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IntroductionHealth and social care professionals (HSCPs) have increasingly contributed to enhance the care of patients in emergency departments (EDs), particularly for older adults who are frequent ED attendees with significant adverse outcomes. For the first time, the effectiveness of a HSCP team intervention for older adults in the ED has been tested in a large randomised controlled trial (Clinicaltrials.gov,NCT03739515), providing an opportunity to explore the implementation process for this type of intervention. This protocol describes a process evaluation that will to investigate the implementation, delivery and impact of an HSCP team intervention in the ED.Methods and analysisUsing the Medical Research Council Framework for process evaluations, we will employ a mixed-methods approach to provide a description of the process of implementation and delivery of the HSCP intervention in the ED, evaluate its fidelity, dose and reach and explore the perceptions of key staff members in relations to the mechanisms and contexts of impact at the levels of individuals, physical environment, operations, communication and the broader hospital and healthcare system.Ethics and disseminationEthical approval for this study was received from the HSE Mid-Western Regional Hospital Research Ethics Committee (Ref: 103/18). All participants will be invited to read and sign a written consent form prior to participation. The results of this review will be disseminated through publication in a peer-review journal and presented at relevant conferences.
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Easterbrook, Kevin D., Mitchell A. Vona, Kiana Nayebi-Astaneh, Amanda M. Miller, and Hans D. Osthoff. "Measurement of Henry's law and liquid-phase loss rate constants of peroxypropionic nitric anhydride (PPN) in deionized water and in n-octanol." Atmospheric Chemistry and Physics 23, no. 1 (January 10, 2023): 311–22. http://dx.doi.org/10.5194/acp-23-311-2023.
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Abstract. The Henry's law solubility (HS) and liquid-phase loss rate constants (kl) of the tropospheric trace gas constituents peroxyacetic nitric anhydride (PAN; CH3C(O)O2NO2, commonly known as peroxyacetyl nitrate) and peroxypropionic nitric anhydride (PPN; C2H5C(O)O2NO2, also known as peroxypropionyl nitrate) in deionized (DI) water and of PPN in n-octanol were measured using a flow bubble apparatus at temperatures between 5.0 and 25.0 ∘C. For PAN in DI water, the observed values for HS,aq are consistent with the literature, whereas the solubility of PPN in DI water is slightly lower than literature values, ranging from HScp(PPN)aq = (1.49 ± 0.05) M atm−1 at 25.0 ∘C to HScp(PPN)aq = (7.01 ± 0.25) M atm−1 at 5.0 ∘C (stated uncertainties are at the 1σ level). The data are best described by ln(HScp(PAN)aq/[Matm-1]) = -(17.8±0.3) + (5620±85)/T and ln(HScp(PPN)aq/[Matm-1]) = -(19.5±1.7) + (5955±480)/T, where T is in kelvin. For n-octanol, the PPN solubility ranges from HScp(PPN)oct = (88±5)Matm-1 at 25.0 ∘C to HScpoct = (204±16)Matm-1 at 5.0 ∘C and is best described by ln(HScp(PPN)oct/[Matm-1]) = -(6.92±0.75) + (3390±320)/T. n-Octanol–water partition coefficients (KOW) for PPN were determined for the first time, ranging from 59 ± 4 at 25.0 ∘C to 29 ± 3 at 5.0 ∘C. Observed loss rate constants in DI water are consistent with recent literature and larger than the thermal dissociation rates for both PAN and PPN, consistent with a hydrolysis mechanism, whereas kl values in n-octanol are significantly smaller than gas-phase dissociation rate constants, likely owing to a “cage effect” in the organic liquid. The results imply that uptake of either PAN or PPN on cloud water and organic aerosol is negligible but that uptake of PPN may constitute an overlooked source of peroxy radicals in organic aerosol.
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McKerracher, L., S. Oresnik, T. Moffat, B. Murray-Davis, J. Vickers-Manzin, L. Zalot, D. Williams, DM Sloboda, and ME Barker. "Addressing embodied inequities in health: how do we enable improvement in women’s diet in pregnancy?" Public Health Nutrition 23, no. 16 (July 6, 2020): 2994–3004. http://dx.doi.org/10.1017/s1368980020001093.
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AbstractObjective:To disrupt cycles of health inequity, traceable to dietary inequities in the earliest stages of life, public health interventions should target improving nutritional wellbeing in preconception/pregnancy environments. This requires a deep engagement with pregnant/postpartum people (PPP) and their communities (including their health and social care providers, HSCP). We sought to understand the factors that influence diet during pregnancy from the perspectives of PPP and HSCP, and to outline intervention priorities.Design:We carried out thematic network analyses of transcripts from ten focus group discussions (FGD) and one stakeholder engagement meeting with PPP and HSCP in a Canadian city. Identified themes were developed into conceptual maps, highlighting local priorities for pregnancy nutrition and intervention development.Setting:FGD and the stakeholder meeting were run in predominantly lower socioeconomic position (SEP) neighbourhoods in the sociodemographically diverse city of Hamilton, Canada.Participants:All local, comprising twenty-two lower SEP PPP and forty-three HSCP.Results:Salient themes were resilience, resources, relationships and the embodied experience of pregnancy. Both PPP and HSCP underscored that socioeconomic-political forces operating at multiple levels largely determined the availability of individual and relational resources constraining diet during pregnancy. Intervention proposals focused on cultivating individual and community resilience to improve early-life nutritional environments. Participants called for better-integrated services, greater income supports and strengthened support programmes.Conclusions:Hamilton stakeholders foregrounded social determinants of inequity as main factors influencing pregnancy diet. They further indicated a need to develop interventions that build resilience and redistribute resources at multiple levels, from the household to the state.
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Chen, Yung-Hui, Cindy Jones, Amy Bannatyne, and Maria Horne. "P207: Pilot testing of the Health and Social Care Professionals’ Knowledge & Attitudes towards Later Life Sexuality (HSCP-KALLS) instrument." International Psychogeriatrics 35, S1 (December 2023): 148. http://dx.doi.org/10.1017/s104161022300282x.
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Objective:Due to a lack of validated assessment instruments, this study aimed to pilot test the newly developed Health and Social Care Professionals’ Knowledge & Attitudes Towards Later Life Sexuality (HSCP-KALLS) instrument. The HSCP-KALLS instrument is designed to assess health and social care professionals’ knowledge (46 items) and attitudes (40 items) towards later life sexuality including components related to dementia, sex worker services and Lesbian, Gay, Bisexual, Transgender, Intersex or Queer/Questioning (LGBTIQ+).Methods:A group of health and social care professionals (n = 22) and Healthcare-related educator (n = 2) were invited to complete the HSCP-KALLS instrument. Feedback on items phrasing and the experience of completing the instrument was sought.Results:Written feedback regarding either phrase of items or use of the instrument was not specifically addressed by participants. A high level of internal consistency was revealed for both the knowledge and attitude items (α = 0.84 & 0.88, respectively). A decent level of knowledge (M=39.75, SD=4.90) and positive attitudes (M=161.04, SD=13.50) towards later life sexuality were demonstrated by participants. Participants had greater knowledge on items related to ageing, intimacy, and sexuality (95%), with a lower level of knowledge on items related to sexuality diversity (e.g., LGBTIQ+). Providing more trainings about later life sexuality was frequently addressed in the knowledge written feedback. Participants generally demonstrated positive attitudes towards later life sexuality. However, a high proportion of ambivalent responses were noted on some attitude items (e.g., A9 & A18) that participants indicated in written feedback that their responses would depend on circumstances.Conclusion:Preliminary reliability and feasibility of using the HSCP-KALLS instrument has been encouraging, with further testing in large samples now, required to robustly establish psychometric properties. Supporting later life sexuality is essential and the use of HSCP-KALLS instrument can inform and identify professional development needs of health and social care professionals to improve care provision for older people by supporting their expression of sexuality in healthcare settings.
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Adel, Heba Mohamed. "ICT, information sharing and a new hybrid lean-agile performance: Empirical evidence from automotive hierarchical supply chains." International Journal of Technology Management & Sustainable Development 19, no. 2 (June 1, 2020): 221–45. http://dx.doi.org/10.1386/tmsd_00023_1.
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The purpose of this study was to investigate the direct and indirect effects of information and communication technology (ICT) on a hybrid lean-agile supply chain performance (HSCP) in terms of leanness, agility and leagility of automotive supply chains (SCs) in Egypt. A conceptual framework was proposed and tested using questionnaires, which were filled through face-to-face interviews. A mixed-methods approach was used to achieve a comprehensive understanding of research relationships. The population was 101 international organizations in Egyptian automotive industry within its three sub-sectors (manufacturers of auto-feeding and automotive industries and distributors). Structural equation modelling was used to examine the proposed relationships. Results indicated that ICT positively/significantly affects both SC integration (SCI) and HSCP. SCI positively/significantly affects SC information sharing (SCIS). SCIS affects HSCP in terms of mass customization and postponement positively/significantly. The three sub-sectors are using a new blended SC strategy that hybridizes attributes of each approach according to the SC node’s position. This article adds value to the current debate on the applicability of implementing a blended lean-agile SC strategy by integrating two main lines of management research (leagility approach and hybridized lean-agile manufacturing systems) into one new hybrid approach. It is the first study that investigated empirically the direct/indirect ICT–HSCP relationships of multiple nodes in a heterogeneous market. It maps the hierarchical auto SCs of an emerging market. It provides automotive SC players with practical insights on using ICT for better SCI and SCIS and choosing the appropriate aspects of leanness, agility and leagility based on the organization’s position across its SC.
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Elefant, Felice, and Karen B. Palter. "Tissue-specific Expression of Dominant Negative MutantDrosophila HSC70 Causes Developmental Defects and Lethality." Molecular Biology of the Cell 10, no. 7 (July 1999): 2101–17. http://dx.doi.org/10.1091/mbc.10.7.2101.
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The Drosophila melanogaster HSC3 andHSC4 genes encode Hsc70 proteins homologous to the mammalian endoplasmic reticulum (ER) protein BiP and the cytoplasmic clathrin uncoating ATPase, respectively. These proteins possess ATP binding/hydrolysis activities that mediate their ability to aid in protein folding by coordinating the sequential binding and release of misfolded proteins. To investigate the roles of HSC3(Hsc3p) and HSC4 (Hsc4p) proteins during development, GAL4-targeted gene expression was used to analyze the effects of producing dominant negatively acting Hsc3p (D231S, K97S) and Hsc4p (D206S, K71S) proteins, containing single amino acid substitutions in their ATP-binding domains, in specific tissues ofDrosophila throughout development. We show that the production of each mutant protein results in lethality over a range of developmental stages, depending on the levels of protein produced and which tissues are targeted. We demonstrate that the functions of both Hsc3p and Hsc4p are required for proper tissue establishment and maintenance. Production of mutant Hsc4p, but not Hsc3p, results in induction of the stress-inducible Hsp70 at normal temperatures. Evidence is presented that lethality is caused by tissue-specific defects that result from a global accumulation of misfolded protein caused by lack of functional Hsc70. We show that both mutant Hsc3ps are defective in ATP-induced substrate release, although Hsc3p(D231S) does undergo an ATP-induced conformational change. We believe that the amino acid substitutions in Hsc3p interfere with the structural coupling of ATP binding to substrate release, and this defect is the basis for the mutant proteins’ dominant negative effects in vivo.
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Cassarino, Marica, Katie Robinson, Dominic Trépel, Íde O’Shaughnessy, Eimear Smalle, Stephen White, Collette Devlin, et al. "Impact of assessment and intervention by a health and social care professional team in the emergency department on the quality, safety, and clinical effectiveness of care for older adults: A randomised controlled trial." PLOS Medicine 18, no. 7 (July 28, 2021): e1003711. http://dx.doi.org/10.1371/journal.pmed.1003711.
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Background Older adults frequently attend the emergency department (ED) and experience high rates of adverse events following ED presentation. This randomised controlled trial evaluated the impact of early assessment and intervention by a dedicated team of health and social care professionals (HSCPs) in the ED on the quality, safety, and clinical effectiveness of care of older adults in the ED. Methods and findings This single-site randomised controlled trial included a sample of 353 patients aged ≥65 years (mean age = 79.6, SD = 7.01; 59.2% female) who presented with lower urgency complaints to the ED a university hospital in the Mid-West region of Ireland, during HSCP operational hours. The intervention consisted of early assessment and intervention carried out by a HSCP team comprising a senior medical social worker, senior occupational therapist, and senior physiotherapist. The primary outcome was ED length of stay. Secondary outcomes included rates of hospital admissions from the ED; hospital length of stay for admitted patients; patient satisfaction with index visit; ED revisits, mortality, nursing home admission, and unscheduled hospital admission at 30-day and 6-month follow-up; and patient functional status and quality of life (at index visit and follow-up). Demographic information included the patient’s gender, age, marital status, residential status, mode of arrival to the ED, source of referral, index complaint, triage category, falls, and hospitalisation history. Participants in the intervention group (n = 176) experienced a significantly shorter ED stay than the control group (n = 177) (6.4 versus 12.1 median hours, p < 0.001). Other significant differences (intervention versus control) included lower rates of hospital admissions from the ED (19.3% versus 55.9%, p < 0.001), higher levels of satisfaction with the ED visit (p = 0.008), better function at 30-day (p = 0.01) and 6-month follow-up (p = 0.03), better mobility (p = 0.02 at 30 days), and better self-care (p = 0.03 at 30 days; p = 0.009 at 6 months). No differences at follow-up were observed in terms of ED re-presentation or hospital admission. Study limitations include the inability to blind patients or ED staff to allocation due to the nature of the intervention, and a focus on early assessment and intervention in the ED rather than care integration following discharge. Conclusions Early assessment and intervention by a dedicated ED-based HSCP team reduced ED length of stay and the risk of hospital admissions among older adults, as well as improving patient satisfaction. Our findings support the effectiveness of an interdisciplinary model of care for key ED outcomes. Trial registration ClinicalTrials.gov NCT03739515; registered on 12 November 2018.
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O'Shaughnessy, Íde, Stephan White, Eimear Smalle, Marica Cassarino, Katie Robinson, Rosie Quinn, Boland Fiona, et al. "106 Optimising Early Assessment and Intervention by Health and Social Care Professions in the ED: Preliminary Findings from the OPTIMEND RCT." Age and Ageing 48, Supplement_3 (September 2019): iii1—iii16. http://dx.doi.org/10.1093/ageing/afz102.24.
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Abstract Background Older adults are frequent users of emergency services and demonstrate high rates of adverse outcomes following emergency care. There is some evidence to suggest that Health and Social Care Professions (HSCP) teams working in the emergency department (ED) can enhance the care of older adults but the quality of these studies is mixed. This randomised controlled trial (Trial registration: NCT03739515) explores the impact of early assessment and intervention by an ED-based HSCP team on the quality, safety and cost-effectiveness of care of older adults. Methods Consecutive ED attendees aged ≥65 years were considered eligible for inclusion to the trial and were screened for eligibility based on pre-defined inclusion criteria. Participants were randomised to either early assessment/intervention by interdisciplinary team comprising a senior occupational therapist, senior physiotherapist and senior medical social worker or usual care. Primary outcomes included: ED length of stay and hospital admission rates. Secondary outcomes included: patient satisfaction, function, quality of life, incidence of ED re-visits, hospital admissions, nursing home admission, healthcare utilisation and mortality at 30-day and 6-month follow-up Results Considering the first 140 participants, the intervention group spent significantly shorter time in the ED than the control group (7.5 vs. 15.2 median hours, p<0.001) and experienced lower admission rates (18.6% vs. 64.3%). At 30-day follow up, healthcare utilisation rates were higher in the intervention than control group (77.2% vs. 61.4%, p=0.04). There were no significant differences between the groups regarding satisfaction with their ED visit, function, quality of life of incidence of adverse outcomes at 30 days. Our cost-effectiveness analysis is ongoing. Conclusion Preliminary findings from our trial indicates that HSCPs working in the ED can contribute to improved older patients’ care by reducing their duration of stay in the ED and increasing rates of discharge home. Participant recruitment and six month follow-up is continuing.
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Desappan, Venkatesh, and Jaisankar Viswanathan. "High thermal stability of aliphatic polyurethanes prepared from sesame and peanut oil and their kinetic parameters." European Journal of Chemistry 9, no. 2 (June 30, 2018): 126–37. http://dx.doi.org/10.5155/eurjchem.9.2.126-137.1703.
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Thermo-responsive vegetable oil-based polyurethanes were successfully prepared by poly-condensation reaction in the mixture of polyol and hexamethylene diisocynate. The functionality and high molecular weight of the polyurethanes were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Carbon Nuclear Resonance Spectroscopy (13C NMR), and Gel Permeation Chromatography. The viscosity of the polyols was characterized by Rheometry and flow rate of the polyols were derived from power law model. The kinetic and thermodynamic parameters of synthesized polyurethanes HSCP and HPCP were calculated from by TG curve. Five different mass loss temperature was obtained in the TGA curve of HSCP and HPCP, which corresponded to the decomposition of the physically observed NH and C=O formed between polyol and diisocyanate, respectively. The average value of the activation energy calculated by Murray and White, Coats and Redfern, Doyle’s, and Freeman-Carroll’s method. The success of the investigated different vegetable oil-based polyurethanes, in comparison with the activation energy of the Freeman-Carroll’s method to determine the thermal stability and the lifetime prediction of the peanut and sesame oil-based polyurethanes is 1.87×105 and 1.27×104 s-1.
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Gong, Shun, and Yalei Wang. "Investigating lubrication performance in HSCP with sliding-frictional pairs of stepped bearings." International Journal of Computational Materials Science and Surface Engineering 12, no. 1 (2024): 81–94. http://dx.doi.org/10.1504/ijcmsse.2024.139019.
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Luna-Sánchez, Sandra Elizabeth, Judith L. Gibbons, María del Pilar Grazioso, Francisco José Ureta Morales, and Claudia García de la Cadena. "Social Axioms Mediate Gender Differences in Gender Ideologies Among Guatemalan University Students." Journal of Cross-Cultural Psychology 53, no. 1 (November 5, 2021): 21–42. http://dx.doi.org/10.1177/00220221211049543.
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Gender role ideologies are embedded in cultural values and assumptions about life. Women’s greater endorsement of egalitarian beliefs may stem from gender differences in world views as indexed by social axioms. The purpose of this study was to examine potential mediators of gender differences in gender ideologies among university students in Guatemala, a country where traditional views are prevalent. Participants, 2,134 university students from nine campuses in different regions of Guatemala (43% male, 85% emerging adults), completed a Social Axioms Scale, along with three culturally relevant measures of gender ideology: the Historic-Sociocultural Premises Scale (HSCP) and the Machismo Measure that taps both traditional machismo and caballerismo (gentlemanliness). Consistent with previous research in other countries, men held more traditional attitudes about gender and the family than did women on all measures. Gender differences on all scales were mediated by cynicism and religiosity. Fate control mediated the gender differences in traditional machismo and the HSCP. These findings suggest that Guatemalan women and men through socialization, cultural demands, and life experiences develop gender-specific ways of viewing the world, and their attitudes about gender roles are shaped by those worldviews. The achievement of gender equality, a U.N. sustainable development goal, may require attention to the underlying world views of women and men.
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Armstrong, Richard N., Mariana Benicio, Houtan Moshiri, Hongbing Li, Bozana Zlateska, Olga I. Gan, Eric R. Lechman, John E. Dick, and Yigal Dror. "Erythropoiesis Failure in Diamond-Blackfan Anemia Starts at the Oligopotent Common Myeloid and Megakaryocyte-Erythroid Progenitor Stage." Blood 136, Supplement 1 (November 5, 2020): 37. http://dx.doi.org/10.1182/blood-2020-143103.
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Diamond-Blackfan anemia (DBA) is a hereditary bone marrow failure disorder that is characterized by erythropoiesis failure and chronic anemia and is frequently associated with physical malformations. Considered a ribosomopathy, most patients harbor pathogenic mutations in one of at least 22 large or small ribosomal protein genes in an autosomal dominant manner, however rarer cases involving mutations in GATA1, TSR2 and EPO have also been described. A recent study of the architecture of the human hematopoietic hierarchy throughout development (Notta et al, Science 2016) showed that, after birth, unipotent progenitors can derive directly from multipotent progenitors without intermediate differentiation into oligopotent progenitors. Critically, this work identified novel progenitors for which the abundance, clonal capacity and progenitor function is currently unknown in many benign and malignant hematological disorders. Specifically, multipotent, common myeloid and megakaryocyte-erythroid progenitors (MPP, CMP and MEP) were found to be functionally heterogeneous and could be subdivided (F1, F2 and F3 subtypes) based on the combination of CD71 and BAH1 expression. We hypothesized that in-depth analysis of these novel and previously reported progenitors will better elucidate hematopoiesis in DBA, providing insights in to DBA pathogenesis and erythropoietic failure. Using flow cytometry, we quantified the frequencies of 11 hematopoietic stem and progenitor cell (HSPC) populations: HSC, MPP F1-F3, CMP F1-F3, MEP F1-F3 and granulocyte-monocyte progenitors (GMP), from the BM specimens of 8 DBA patients harboring ribosomal protein mutations and 6 healthy age-matched control donors. To characterize the function of HSPCs in DBA we then utilized a highly sensitive and quantitative single-cell in-vitro stromal feeder-based differentiation assay that supports the expansion and lineage commitment of single HSCPs towards mature cell types (myeloid, erythroid and megakaryocytes) with progeny immunophenotyping and quantification by flow cytometry. Our refined quantification of HSPCs by flow cytometry showed that the defect of erythropoiesis in DBA patients starts at the CMP/MEP compartment. Namely, CMP-F2 and CMP-F3 as well as MEP-F2 and MEP-F3 sub-populations that are predicted to form erythroid cells were significantly reduced in DBA patients compared to healthy aged-matched individuals (Figure 1A-B). In contrast, CMP/MEP-F1 sub-populations that are predicted to form only myeloid cells (BAH1-/CD71-) showed no significant difference compared to healthy controls. Importantly, the multipotent compartment (HSC and MPP) did not significantly differ from that of healthy controls. Functional analysis of F2/F3 CMP/MEP HSCP sub-populations in single-cell colony assays showed that they have a high propensity to produce erythroid progeny in healthy control samples (Figure 1C). In contrast, in DBA patients these HSCPs had limited erythroid forming potential, but maintain a high propensity to develop myeloid colonies (Figure 1D). To our knowledge this is the first study that the HSCP sub-populations F1/F2/F3 HSCP fractions have been analyzed in DBA. Collectively, these data indicate that the hematopoietic defect in DBA occurs in erythroid-producing CMP/MEP populations. Our data show that these sub-populations are both reduced and dysfunctional in DBA patients and we suggest these abnormalities lead to the pure red cell aplasia seen in these patients. Figure 1: DBA patients have reduced CMP and MEP sub-populations that behave dysfunctional in-vitro. A-B) DBA patients have reduced CMP-F2/3 (A) and MEP-F2/3 (B) sub-populations in their bone marrow. C) CMP F2-F3 and MEP F2-F3 have a high propensity to produce erythroid cell types in healthy controls. D) Single-cells isolated from the CMP-F2/3 and MEP-F2 population of DBA patients produced proportionally fewer erythroid and greater myeloid colonies in in-vitro colony assays (plot shows the mean respective proportions from all healthy controls and DBA patients tested, each N=5). Disclosures Dick: Bristol-Myers Squibb/Celgene: Research Funding.
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Ross, Lisa. "Glasgow City HSCP Complex Needs Service - Personalised and Person-Centred Health and Care." International Journal of Integrated Care 22, S3 (November 4, 2022): 398. http://dx.doi.org/10.5334/ijic.icic22204.
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Cox, Marie, Fiona Haughey, and Niamh Leonard. "Safer Patient Mealtimes: An interdisciplinary Educational Initiative for HSCP students in a neurorehabilitation setting." International Journal of Integrated Care 17, no. 5 (October 17, 2017): 513. http://dx.doi.org/10.5334/ijic.3833.
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Park, Y., M. F. J. Taylor, and R. Feyereisen. "Voltage-gated sodium channel genes hscp and hDSC1 of Heliothis virescens F. genomic organization." Insect Molecular Biology 8, no. 2 (May 1999): 161–70. http://dx.doi.org/10.1046/j.1365-2583.1999.820161.x.
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Marrinan, Eileen M., Richard A. Labrie, and John B. Mulliken. "Velopharyngeal Function in Nonsyndromic Cleft Palate: Relevance of Surgical Technique, Age at Repair, and Cleft Type." Cleft Palate-Craniofacial Journal 35, no. 2 (March 1998): 95–100. http://dx.doi.org/10.1597/1545-1569_1998_035_0095_vfincp_2.3.co_2.
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Objective The goal of this study was to determine the relative importance of surgical technique, age at repair, and cleft type for velopharyngeal function. Design This was a retrospective study of patients operated on by two surgeons using different techniques (von Langenbeck and Veau-Wardill-Kilner [VY]) at Children's Hospital, Boston, MA. Patients We included 228 patients who were at least 4 years of age at the time of review. Patients with identifiable syndromes, nonsyndromic Robin sequence, central nervous system disorders, communicatively significant hearing loss, and inadequate speech data were excluded. Main Outcome Measure Need for a pharyngeal flap was the measure of outcome. Results Pharyngeal flap was necessary in 14% of von Langenbeck and 15% of VY repaired patients. There was a significant linear association (p = .025) between age at repair and velopharyngeal insufficiency (VPI). Patients with an attached vomer, soft cleft palate (SCP), and unilateral cleft lip/palate (UCLP) had a 10% flap rate, whereas those with an unattached vomer, hard/soft cleft palate (HSCP), and bilateral cleft lip/palate (BCLP) had a 23% flap rate (p = .03). Age at repair was critical for the unattached-vomer group (p = .03) but was not statistically significant for the attached-vomer group (p = .52). Conclusions Surgical technique was not a significant variable either in aggregate or for the Veau types. Patients in the earliest repair group (8-10 months) were the least likely to require a pharyngeal flap. Early repair was more critical for HSCP and BCLP patients. There was no correlation between velopharyngeal insufficiency and Veau hierarchy. The attached vomer/levator muscle complex may be a more important predictor of surgical success than the anatomic extent of cleft.
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Wu, Limei, Qiqi Lin, Zhilin Ma, Fabliha Chowdhury, Md Habibul Mazumder, and Wei Du. "Mesenchymal COX2-Derived PGD2 Activates an ILC2-Treg Axis to Promote Proliferation of Normal and Malignant HSPCs." Blood 134, Supplement_1 (November 13, 2019): 1208. http://dx.doi.org/10.1182/blood-2019-124144.
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Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD2 has recently emerged as a key regulator of tumor- and inflammation-associated functions. We previously reported that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) overexpressed COX-2 and secreted high levels of PGs including PGD2. Since little is known about the role of PGD2 in normal and malignant hematopoiesis, we prioritized this mesenchymal source of PG for further investigation. We observed that AML MSCs or normal MSCs overexpressing COX-2 promotes proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX-2 knockdown or TM30089, a specific antagonist of the PGD2 receptor CRTH2. Mechanistically, we demonstrate that PGD2-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. We further show that IL-5 but not IL-13 expands CD25+Foxp3+ IL5Ra+ T regulatory cells (Tregs) and promotes HSCP proliferation. Disruption of the PGD2-activated ILC2-Treg axis by specifically blocking the PGD2 receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of Lin-CD127+CRTH2+ ILC2s and CD4+CD25+IL5Ra+ Tregs promotes malignant HSCP proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD2 promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this PGD2-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases. Disclosures No relevant conflicts of interest to declare.
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Keogh, Fiona, Tom Pierse, and Eamon O'Shea. "96 Service Priorities for People with Dementia in Ireland: A Mixed Methods Study of Health Care Professionals." Age and Ageing 48, Supplement_3 (September 2019): iii17—iii65. http://dx.doi.org/10.1093/ageing/afz103.57.
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Abstract Background Public services for people with dementia living in the community face significant resource constraints. The aims of this study are to identify an optimum mix of services for six dementia case types and to gain a greater understanding of the resource allocation decision making process. Methods Irish datasets were used to identify dementia cases types representing 46% of cases in the datasets. Vignettes were prepared for six case types ranging from low to high dependency and needs. Carers, people with dementia and health and social care professionals (HSCPs) took part in mixed methods workshops. Initial findings for the HSCPs are reported here (N=23). HSCP participants firstly quantitatively identified an optimum care package for a set of six vignettes, then qualitatively discussed the needs and individual case factors that were driving service recommendations. The quantitative exercise was repeated with a budget constraint. The sessions finished with a discussion on service and case prioritisation. Results When no budget constraint is imposed, participants recommended the use of a wide range of services. Home help, in-home respite and day care services comprised 62% of spending in this scenario. When a budget constraint was imposed, participants focused on essential care and reduced services aimed at prevention, quality of life and carer support. Resources were not redistributed between cases (e.g. from low need to higher need cases) as a similar proportion of the budget was allocated to each of the cases in both scenarios. Conclusion People with dementia living in the community and their families have a wide range of health and social care needs. Optimum dementia care packages included a wide range of services to meet these needs. However, a budget constraint resulted in a much narrower range of services with consequent implications in terms of unmet need and a reactive rather than preventive approach to care.
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Grimley, Michael, Monika Asnani, Archana Shrestha, Sydney Felker, Carolyn Lutzko, Paritha I. Arumugam, Scott Witting, et al. "Early Results from a Phase 1/2 Study of Aru-1801 Gene Therapy for Sickle Cell Disease (SCD): Manufacturing Process Enhancements Improve Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-140963.
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Introduction: ARU-1801 is a gene therapy consisting of autologous CD34+ hematopoietic stem cells and progenitors (HSCPs) transduced with a lentiviral vector (LV) encoding a modified γ-globinG16D gene. Preclinical studies in SCD mice have shown that g-globinG16D binds α-globin with higher affinity; hence, the g-globinG16D LV produces 1.5-2x more HbF/vector copy number (VCN) than a g-globin LV. Preliminary studies also show greater reduction in reticulocytes in SCD mice expressing HbFG16D compared to those expressing the same level of HbF, suggesting that HbFG16D may have a more potent anti-sickling effect than HbF. We hypothesized a high potency anti-sickling globin would allow ARU-1801 to be effective with reduced intensity conditioning (RIC). RIC would result in lower toxicities and resource utilization compared to myeloablative approaches, allowing access of gene therapy to a broader group of SCD patients. We previously reported early data from patient 1 (P1) and 2 (P2) in the ongoing Phase 1/2 study (NCT02186418), who were treated with drug product (DP) from the initial ARU-1801 manufacturing process (Process I). We now present the long-term data on these patients and early data from P3, the first patient treated with our new manufacturing process (Process II). Methods: Adults with severe SCD, as defined by recurrent vaso-occlusive events (VOE) and acute chest syndrome deemed eligible were enrolled. Manufacturing process improvements in Process II included optimized timing of HSCP collection after plerixafor mobilization, LV production and improved HSCP transduction. Prior to DP infusion, all patients received a single dose of IV melphalan (140 mg/m2 BSA) and were weaned off transfusions 3-6 months after DP infusion. Patients were monitored for safety, engraftment, VCN, anti-sickling Hb (ASG) expression, and hematological and clinical manifestations of SCD. Levels of ASG (including HbFG16D) are presented as fractions of endogenous Hb. Results: As of 28 July 2020, data from 3 patients treated with ARU-1801 are available. P1 (34yr old) has HbSβ0- and P2 (24yr old) has HbSβ+ thalassemia (2-3% HbA). Both have 30 months (mo) post-transplant (PT) follow up. P3 (19yr old) has HbSS genotype with 6 mo PT follow up. ARU-1801 demonstrated a favorable safety profile with no treatment-related adverse events to date. Time to neutrophil engraftment (ANC ≥500) was 9, 7, and 7 days PT, and time to platelet recovery (Plt >50,000) was 12, 7, and 6 days PT, in P1, P2, and P3, respectively. Figure 1 shows HSPC dose, conditioning exposure and gene transfer; Figure 2 shows ASG over time. Using Process I, P1 has shown stable expression of 20% HbFG16D, 31% ASG and 31%à64% F-cells over 2.5 years, despite a low DP VCN of 0.2 and low HSPC dose of 1.4 x106 cell/kg. P2 received a higher cell dose of 7.1 x106 cell/kg with a DP VCN of 0.47 but had below target melphalan exposure, likely due to rapid clearance from hyperfiltration (GFR= 200 mL/min/1.73m2). Despite lower engraftment and HbFG16D level, P2 maintains stable total ASG of 22% at 30 mo due to a compensatory increase in HbF. Using Process II, P3 received DP of 6.8 x106 cells/kg with a VCN of 1.0, and demonstrated an engrafted VCN of 0.74, 71% F-cells and 91% F-reticulocytes at 6 mo. As P3 is being weaned off transfusions, HbFG16D is progressively rising, showing the selective advantage to HbFG16D-containing RBCs. P1 and P2 have maintained improvements in VOEs, no VOE in P3 so far (data will be presented). Conclusion: We show that engraftment of ARU-1801 and amelioration of disease is possible with RIC using IV melphalan, with persistent stable ASG expression and meaningful improvement in VOEs in P1 and P2. P1 shows stable HbFG16D and high ASG despite low, albeit stable VCN. P2 had lower HSCP engraftment, which we hypothesize was due to below target melphalan exposure. Nevertheless, significant clinical benefit was observed in P2 due to stable ASG of 22% at mo 30. It is likely that the presence of this amount of HbFG16D has provided enough ASG to prevent sickling/ineffective erythropoiesis, resulting in the preferential survival of HbF+HbFG16D-expressing RBC. Process II DP in P3 resulted in 2-4X higher engraftment of transduced HSCPs at 6 mo. Additional process enhancements are under development for future treated patients. ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD. Disclosures Asnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding. Lutzko:Aruvant Sciences: Patents & Royalties: pre-clinical vector development. Lo:Aruvant Sciences: Current Employment. Little:Aruvant Sciences: Current Employment. McIntosh:Aruvant: Current Employment, Current equity holder in private company. Malik:Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor - stem cell mobiliziation Melphalan - chemotherapy conditioning pre autologous transplant with ARU-1801
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Park, Yoonseong, and Martin F. J. Taylor. "A novel mutation L1029H in sodium channel gene hscp associated with pyrethroid resistance for Heliothis virescens (Lepidoptera: Noctuidae)." Insect Biochemistry and Molecular Biology 27, no. 1 (January 1997): 9–13. http://dx.doi.org/10.1016/s0965-1748(96)00077-x.
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Colgan, Caroline, Grainne Flanagan, Sinead Gallagher, Miriam Dolan, Paula Sheridan, Cathal McKeon, and Lorraine Daly. "205A Collaborative Health and Social Care (HSCP) Shared Assessment and Screening Process Improves Patient Outcomes in Acute Unscheduled Care." Age and Ageing 47, suppl_5 (September 1, 2018): v13—v60. http://dx.doi.org/10.1093/ageing/afy140.152.
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Martean, Melissa, Jennifer Malik, and Kevin Murray. "‘20 Minute Care Space’ for care home staff: Service-based evaluation." FPOP Bulletin: Psychology of Older People 1, no. 158 (April 2022): 31–37. http://dx.doi.org/10.53841/bpsfpop.2022.1.158.31.
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Health and social care staff wellbeing was highlighted as a priority in light of pressures during the Covid-19 pandemic (Duffy et al., 2020; Gray et al., 2021). The 20 Minute Care Space session was developed to facilitate self-care and connection among colleagues, based on compassion-focused principles (Association of Clinical Psychologists, 2020). Between February and September 2021, NHS Greater Glasgow and Clyde’s Care Home Liaison Psychology Service delivered 14 remote 20 Minute Care Space sessions via Microsoft Teams for care home staff across Glasgow City Health & Social Care Partnership (HSCP). A total of 88 care home staff and managers attended these sessions, and 32 completed evaluation forms. Findings are discussed in relation to attendance, awareness of self-care and connection to colleagues, alongside qualitative themes and facilitator reflections. The increasing recognition of the importance of self-care among health and social care staff, has resulted in funding being secured for two 8B Clinical Psychologist posts in NHS Greater Glasgow & Clyde (GG&C) to lead on staff support across the Health Board.
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Hellmich, Charlotte, Jayna J. Mistry, Jamie A. Moore, Aisha Jibril, Kristian M. Bowles, and Stuart A. Rushworth. "Mitochondrial Function Is Impaired in a Subset of Aged Haematopoietic Stem Cells in Response to Infection." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-140311.
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Introduction The burden of age-related diseases is steadily increasing as our population ages. A better understanding of the physiological changes that occur with age may provide an insight into the processes that promote disease development which in turn may help to identify potential targets for the management of these diseases. Haematopoietic stem cells (HSCs) play a vital role in the bone marrow response to infection and previous work has shown that emergency granulopoiesis is supported by increased mitochondrial function in HSCs (1). HSC numbers have previously been shown to increase with age whilst mitochondrial function is known to decline with age. Here we investigate how mitochondrial health changes in ageing HSCs and how this impacts on HSC function and their ability to respond to stress. Methods C57Bl/6 mice were aged to 18-24 months and 8-12-week-old mice were used as controls. Both aged and young mice were sacrificed, and their BM was isolated. Flow cytometry was used to measure numbers of HSCs and mitochondrial content and function using MitoTracker Green and TMRM. Seahorse metabolic flux analysis was used to assess metabolic changes in young and aged HSC populations. Next young and aged C57Bl/6 mice were treated with lipopolycaccharide (LPS) and sacrificed after 16 hours. Their BM was isolated HSC populations were quantified and mitochondrial health was assessed using flow cytometry. Finally, ABT-263 was used to deplete senescent cells in the BM microenvironment. C57Bl/6 mice were treated with 100mg/kg of ABT-263 or vehicle control by oral gavage for 17 days, they were then treated with 0.4mg/kg of LPS and sacrificed after 12 hours. They BM was isolated and analysed by flow cytometry as described above. Results In aged mice HSC numbers were increase and this was associated with an increase in mitochondrial content but a decrease in mitochondrial function. Levels of oxidative phosphorylation (OXPHOS) or glycolysis were not significantly changed in aged HSCs in a steady state. In response to infection, however, in aged mice HSC mitochondrial content and function was not shown to increase following LPS treatment when compared to HSCs from young mice. Moreover, LPS significantly increased OXPHOS in young HSCs whilst aged HSCs were shown to favour glycolysis. Finally, aged HSCs were shown to have increased expression of the anti-apoptotic protein BCL-XL but not BCL-2. In vitro analysis of aged HSC showed the BCL-XL inhibitor ABT-263 but not the BCL-2 inhibitor ABT-199 induced HSC apoptosis. Finally, to determine the effect of targeting BCL-XL on HSCs in vivo we treated aged animals with ABT-263 daily for 17 days and then treated these animals with LPS. Results show that treating aged animals with ABT-263 allowed the HSC to use OXPHOS instead of glycolysis in response to stress. Conclusion Aged HSCs have altered mitochondrial content and function and this impairs their ability to respond to infection through changes in OXPHOS. Instead aged HSC have increased reliance on glycolysis in response to LPS treatment, which is less efficient, and this may impact on HSC function. Targeting BCL-XL with ABT-263 allows elimination of aged HSCs within the BM, reverses some of the age-related mitochondrial changes observed and improves the HSCP ability to respond to stress. References 1. Mistry JJ, Marlein CR, Moore JA, Hellmich C, Wojtowicz EE, Smith JGW, et al. ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc Natl Acad Sci U S A. 2019;116(49):24610-9. Disclosures Bowles: AbbVie: Research Funding; Janssen: Research Funding. Rushworth:Janssen: Research Funding; AbbVie: Research Funding.
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Cook, Ailsa, and Gill Main. "System Wide Governance and Leadership: A New Governance Model to Rethink How Performance is Measured; How Integrated Services are Contracted, Funded and Co-ordinated and How Outcomes and Benefits are Assessed." International Journal of Integrated Care 23, S1 (December 28, 2023): 438. http://dx.doi.org/10.5334/ijic.icic23504.
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This workshop shares learning from the work of Midlothian Health and Social Care Partnership to develop a strategic governance and performance framework that supports person centred practice and assesses impact on outcomes for people.
It is widely recognised that for person centred approaches to be sustained, they need to go beyond practice and be embedded within the culture, systems and processes of health and social care organisations. This poses a challenge for traditional approaches to performance management, which tend to hold services accountable for delivering on easily measurable service outputs, rather than working in the flexible and outcome focused ways required to be person centred. In this workshop we share learning from work carried out by Midlothian Health and Social Care Partnership to align strategic governance and performance systems with their commitment to person centred practice and provide space for workshop participants to explore how they could put learning into practice.
Midlothian HSCP are responsible for delivering and commissioning integrated services and supports to a local population of about 93,000 people in Scotland. The partnership has been strongly committed to embedding person centred practice for many years and have established the ‘MidWay’ approach to having ‘Good Conversations’ and building relationships with people, where services facilitate change, rather than aim to fix it.
The partnership recognised that their strategic governance and performance approach was not aligned with this focus on person centred practice and outcomes for people. In 2020 they commissioned Matter of Focus to work with them to develop an outcome focused performance framework underpinned by the Matter of Focus approach and software OutNav. Over the past 2.5 years the framework has been tested and refined by diverse services and teams and is now being rolled out across the partnership.
The Matter of Focus approach is informed by contribution analysis and evidence to action approaches and enables organisations delivering complex change that is people based to evidence contribution to desired outcomes, rather than attribution. The approach and software is being used by more than 150 organisations internationally.
The workshop will be of interest to managers, leaders, researchers and policy makers looking to embed person centred practice at scale and to improve governance and performance management approaches.
The interactive workshop will involve: 5 minutes welcome and introductions; 10 minutes table discussion; 10 minute presentation on the Matter of Focus approach; 15 minute presentation on the framework and lessons learnt from Midlothian HSCP; 10 minute table discussions; 10 minutes feedback from tables, summary of take home messages and close.
The audience will be engaged through focused discussion questions at the tables. Take home messages will be captured from each table by the presenters in the final feedback session.
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Breda, Laura, Tyler E. Papp, Michael P. Triebwasser, Amir Yadegari, Megan T. Fedorky, Naoto Tanaka, Osheiza Abdulmalik, et al. "In vivo hematopoietic stem cell modification by mRNA delivery." Science 381, no. 6656 (July 28, 2023): 436–43. http://dx.doi.org/10.1126/science.ade6967.
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Hematopoietic stem cells (HSCs) are the source of all blood cells over an individual’s lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP–messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti–human CD117/LNP–based editing system yielded near-complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT.
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GAO, Xin, Philip Boulais, Masato Tanaka, Christopher Richard Marlein, and Paul S. Frenette. "Macrophage Transfer to HSCs Assigns Residence in Bone Marrow." Blood 134, Supplement_1 (November 13, 2019): 276. http://dx.doi.org/10.1182/blood-2019-123762.
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Hematopoietic stem cells (HSCs), residing at the apex of the hematopoietic hierarchy, are a rare and heterogeneous cell population. Although HSC subsets with various repopulation capacities and lineage bias have been identified, there is no available information about whether each HSC has an equal chance of being mobilized or whether there are specific pools of mobilizable or non-mobilizable HSCs in bone marrow (BM). Here, we identify a BM resident HSC subset based on the expression of the macrophage marker F4/80. Flow cytometry analysis revealed that F4/80 was expressed on 75% of HSCs (Lin- Sca1+cKit+CD150+CD34-; hereafter referred to as HSCM) in the BM. In competitive transplantation assays, HSCM exhibited significantly lower engraftment potential, but no lineage bias, compared to F4/80- HSCs (HSCM: 19.7±4.8%; F4/80- HSC: 37.1±4.5%, P<0.05). We next analyzed the ability of HSCM and F4/80- HSCs to be mobilized after G-CSF treatment and found that F4/80- HSCs, but not HSCM, were exclusively mobilized (F4/80- HSC: 5042±912.5; HSCM: 6.6±6.6 per mL blood, P<0.001). Similar selective mobilization was observed after administration of AMD3100 or macrophage depletion using clodronate liposomes. To confirm this observation in a genetic model, we crossed transgenic mice expressing Cre recombinase knocked into the Cd169 locus, a marker of BM macrophages (MΦ), with ROSA26-loxP-stop-loxP-tdTomato (CD169/Tomato). We found CD169/Tomato labelled a large fraction of HSCM (31.7±8.4%), in contrast to F4/80- HSCs which were largely unlabelled (2.1±1.2%). Remarkably, CD169/Tomato+ HSCs were not mobilized into the circulation after G-CSF treatment (CD169/Tomato- HSC: 4573±1416; CD169/Tomato+ HSC: 90.6±90.6 per mL blood, P<0.01). Although HSCs are reported to express Csf1r, the expression of macrophage markers on HSCs (F4/80 and CD169) was unexpected. To ascertain the expression origin, we transplanted CD169/Tomato+ and CD169/Tomato- sorted HSCs into lethally irradiated CD45.1 congenic mice. If HSCs expressed CD169, we would expect that donor HSC tomato expression would be retained. However, to our surprise, we found that the proportion of Tomato+ HSCs was higher in the CD169/Tomato- group, suggesting that F4/80 and CD169 expression may be acquired, rather than expressed within HSCs. Indeed, co-culture of TdTomato+ BM MΦ with GFP+ HSCs consistently revealed the acquisition of tdTomato (GFP+ TdTomato+: 9.9±1.9%). Transwell experiments revealed that cell contact was important as GFP+ cells did not show any TdTomato expression in the absence of direct cell contact (GFP+TdTomato+: 0%). To investigate the mechanism of HSC retention, we analyzed CXCR4 expression on HSCM and F4/80- HSC subsets. These analyses revealed that CXCR4 was expressed at higher expression levels on HSCM compared to F4/80- HSCs (HSCM: 79.4±9.1% CXCR4+;F4/80- HSC: 45.6±8.5% CXCR4+, P<0.001). In accordance with their increased CXCR4 expression, HSCM exhibited a 4.7-fold increase in pERK1/2 after CXCL12 stimulation, while CXCL12 only triggered a modest increase (1.5-fold) in pERK1/2 in F4/80- HSCs, suggesting that HSCM have a higher signaling response to CXCL12, and thus exhibit enhanced BM retention. To further confirm that the cell transfer occurred in vivo, we used xenografted mice in which human HSCs were transplanted into NOG mice. We found a significant presence of murine F4/80 on human CD34+ HSCs in xenografted huNOG mice, confirming the F4/80 transfer from host MΦ into human HSCs in vivo. To investigate further the mechanism of cell transfer, we carried out co-culture experiments of GFP+ lineage-depleted BM cells with TdTomato+ MΦ in the presence of inhibitors known to prevent cell transfer through membrane and cytoskeleton remodeling. Of all conditions tested, only the presence of the GAP junction inhibitor carbenoxolone (CBX) could inhibit the transfer of TdTomato from MΦ to GFP+ cells (control: 21.4±3.0%; CBX: 12.6±2.1%, P<0.001). Furthermore, treatment of wild-type mice with CBX led to a marked suppression of F4/80 transfer in vivo, similar to that observed in vitro, suggesting that GAP junctions are responsible for the direct transfer of cellular content from BM MΦ to HSCs. Our results thus identify a novel mechanism by which macrophages can assign HSC residence in BM. Manipulation of macrophage-mediated transfer may enhance the mobilizable HSC pool and provide a new method to improve HSC yields after mobilization. Disclosures Frenette: Cygnal Therapeutics: Equity Ownership; Ironwood Pharmaceuticals: Research Funding; Albert Einstein College of Medicine, Inc: Patents & Royalties; Pfizer: Consultancy.
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Holdreith, Nicholas, Grace Lee, Vemika Chandra, Carlo Salas Salinas, Peter Nicholas, Timothy S. Olson, and Wei Tong. "LNK (SH2B3) inhibition expands healthy and Fanconi anemia human hematopoietic stem and progenitor cells." Blood Advances 6, no. 3 (January 27, 2022): 731–45. http://dx.doi.org/10.1182/bloodadvances.2021004205.
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Abstract Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for a variety of hematological diseases. Allogenic HSCT requires hematopoietic stem cells (HSCs) from matched donors and comes with cytotoxicity and mortality. Recent advances in genome modification of HSCs have demonstrated the possibility of using autologous HSCT-based gene therapy to alleviate hematologic symptoms in monogenic diseases, such as the inherited bone marrow failure (BMF) syndrome Fanconi anemia (FA). However, for FA and other BMF syndromes, insufficient HSC numbers with functional defects results in delayed hematopoietic recovery and increased risk of graft failure. We and others previously identified the adaptor protein LNK (SH2B3) as a critical negative regulator of murine HSC homeostasis. However, whether LNK controls human HSCs has not been studied. Here, we demonstrate that depletion of LNK via lentiviral expression of miR30-based short hairpin RNAs results in robust expansion of transplantable human HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Importantly, LNK depletion enhances cytokine-mediated JAK/STAT activation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that LNK depletion expands primary HSPCs associated with FA. In xenotransplant, engraftment of FANCD2-depleted FA-like HSCs was markedly improved by LNK inhibition. Finally, targeting LNK in primary bone marrow HSPCs from FA patients enhanced their colony forming potential in vitro. Together, these results demonstrate the potential of targeting LNK to expand HSCs to improve HSCT and HSCT-based gene therapy.
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Brenet, Fabienne A., Pouneh Kermani, Shahin Rafii, and Joseph M. Scandura. "TGFβ Restores Hematopoietic Homeostasis After Chemotherapy." Blood 120, no. 21 (November 16, 2012): 2344. http://dx.doi.org/10.1182/blood.v120.21.2344.2344.
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Abstract Abstract 2344 Background: Hematopoietic stem cells (HSCs) are required for lifelong blood cell production and, to prevent exhaustion, the majority of HSCs are deeply quiescent during steady-state hematopoiesis. Paracrine factors produced by specialized bone marrow niche cells maintain HSC quiescence. Yet, evolution demands a rapid hematopoietic response to stressors such as infection, bleeding or toxin exposure. These triggers set off a remarkable adaptation in hematopoiesis that sacrifices HSPC quiescence, and the protection it affords, to meet an urgent need for new blood cell production. A great deal is known about how the HSPCs are mobilized during these periods of stress but mechanisms driving the return to steady-state hematopoiesis after stress have not been identified. Method/Results: Because TGFβ is one of few negative regulators of hematopoiesis, we measured the levels of active TGFβ and assessed the effects of its downstream signaling during hematopoietic recovery after chemotherapy. During late hematopoietic regeneration, as hematopoietic homeostasis is restored, the levels of active TGFβ spike in whole bone marrow and downstream signaling (as reported by Smad2 phosphorylation) increases in hematopoietic stem and progenitor cells (HSPCs). To assess how TGFβ signaling alters hematopoietic regeneration, we administered myelosuppressive chemotherapy to mice and then, during recovery, treated cohorts with either an antibody that specifically neutralizes active TGFβ (1D11), an isotype control antibody (13C4) or nothing at all. We found that TGFβ blockade accelerated blood count and bone marrow regeneration, and promoted HSCP self-renewal/proliferation by delaying the return of HSPCs to quiescence (G0). In contrast, TGFβ blockade during homeostasis elevates neither blood counts nor bone marrow cellularity and fails to induce HSPCs to emerge from quiescence. Conclusions: The de facto paradigm is that homeostasis is passively reestablished as stress mediators normalize. Our data strongly suggest that this paradigm is incorrect. Rather than being a passive process, it appears that steady-state hematopoiesis is actively reimposed. TGFβ pathway activation marks regenerating HSPCs returning to quiescence and this context-depending signaling helps reestablish homeostasis during recovery from chemotherapy. Together, our data demonstrate that myelosuppression does not drive hematopoiesis using only a cytokine-fueled gas pedal but also taps an active braking mechanism once sufficient recovery has been attained. More directly, our data strongly suggests that TGFb pathway inhibitors could be used to promote multi-lineage hematopoietic reconstitution. This finding significantly extends prior work in the field by opening the door to new, potentially superior, ways to modulate the hematopoietic adaptation to stress. Disclosures: No relevant conflicts of interest to declare.
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Dong, Fang, Haitao Bai, Shanshan Zhang, Xiaofang Wang, Jinhong Wang, Zhao Wang, Sha Hao, Tao Cheng, and Hideo Ema. "Early and Late Leukemic Stem Cells in Murine Leukemia Models." Blood 128, no. 22 (December 2, 2016): 1544. http://dx.doi.org/10.1182/blood.v128.22.1544.1544.
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Abstract Acute leukemia is uncontrolled proliferation of leukemic stem cells (LSCs). Murine models of leukemia suggest that LSCs arise from lineage-committed progenitor cells. However, whether LSCs also directly arise from long-term (LT) and short-term (ST) hematopoietic stem cells (HSCs) and other hematopoietic progenitor cells (HPCs) and whether differentiation potentials influence the leukemia types are poorly understood. In this study, we used two murine leukemia models (AML with MLL-AF9 fusion protein and T-ALL with Notch-1 intracellular domain, ICN-1). Two HSC and three HPC populations were sorted from B6 (CD45.1) mouse bone marrow (BM) by flow cytometry: HSC1, CD150+CD41-CD34-Lin-Sca-1+c-Kit+ (LSK) cells; HSC2, CD150-CD41-CD34-LSK cells; HPC1, CD150+CD41+CD34-LSK cells; HPC2, CD150+CD41+CD34+LSK cells; HPC3, CD150-CD41-CD34+LSK cells. HSC1, HSC2, HPC1, and HPC3 are enriched in LT-HSCs, ST-HSCs, repopulating common myeloid progenitors, and lymphoid-primed multipotent progenitors, respectively. 400-600 cells were sorted from each population, pre-stimulated for 24 hrs, and transduced with MLL-AF9 or ICN-1 retrovirus for another 24 hrs. Cells were mixed with 3-5 x 105 BM cells (CD45.2), and injected into the lethally irradiated mice (CD45.2). The recipient mice were monitored by detection of GFP+ cells in the peripheral blood (PB). When the recipient mice showed > 50% GFP+ cells in the PB or became ill, mice were killed and analyzed for leukemia. In the MLL-AF9 AML model, leukemia developed in all recipient mice injected with HSC1, 2, HPC1, 2, or 3 around 6 weeks after transplantation. Leukemic cells in PB and BM appeared positive for Mac-1/Gr-1, but negative for CD3 and B220. We detected a new LSC population in the BM: Lin-Mac-1+c-Kit+Sca-1+CD150-CD16/32+ cells. Both CD34-negative and CD34-positive cells were detected in this population. We named this population as "early LSCs" because it was phenotypically similar to ST-HSCs and/or LMPPs in normal mouse BM cells except Mac-1 expression. Early LSCs differed from previously identified LSCs (L-GMP) because they are Sca-1-positive. We now consider L-GMP as one of "late LSC" types. Early LSCs formed leukemic colonies in vitro and initiated the AML in serial transplantation. These results show the similar AML develops regardless of HSC and HPC types transduced. Both early and late LSCs likely play a role in establishment of AML. In the ICN-1 T-ALL model, leukemia developed in all recipient mice injected with HSC1, 2, HPC1, 2, or 3 around 4 weeks after transplantation. Most leukemic cells in PB and BM appeared positive for CD4/CD8, but negative for Mac-1/Gr-1 and B220. We did not detect early LSCs in BM. To identify late LSCs in BM, we injected the CD3+CD8+CD4- and CD3+CD8+CD4+ cells into the sub-lethally irradiated mice. T-ALL developed from both populations (median latency, 23 vs 35 days). These results show the similar T-ALL develops regardless of HSC and HPC types transduced. In this case, late LSCs can be directly generated without early LSCs from HSC or HPC populations. Taken together, we found that the similar types of leukemia develop regardless of different types of initiating cells in both models. We also found new LSC populations, early LSCs in the AML model and late LSCs in the T-ALL model. Both early and late LSCs were able to re-initiate leukemia after secondary transplantation. In conclusion, highly purified murine HSCs and HPCs were used for the first time to initiate leukemia. Both MLL-AF9 AML and ICN-1 T-ALL models suggest that gene mutations at all differentiation stages from HSCs to HPCs potentially induce the similar types of leukemia. Of note is that distinct lineage differentiation potentials of HSCs and HPCs do not affect leukemia types. More importantly, early LSCs may serve as the earliest event in leukemogenesis in AML. In the case of ALL, gene mutations seem carried over until reaching the developmental stage of late LSCs. Our results suggest that both early and late LSCs should be eradicated to achieve complete remission and prevent relapse. Disclosures No relevant conflicts of interest to declare.
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Park, Yoonseong, Daewoo Lee, Martin F. J. Taylor, Jonathan W. Holloway, James A. Ottea, Michael E. Adams, and René Feyereisen. "A Mutation Leu1029 to His in Heliothis virescens F. hscp Sodium Channel Gene Associated with a Nerve-Insensitivity Mechanism of Resistance to Pyrethroid Insecticides." Pesticide Biochemistry and Physiology 66, no. 1 (January 2000): 1–8. http://dx.doi.org/10.1006/pest.1999.2445.
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Taylor, P. R., and M. Scarlett. "The rotational spectra of HOCO(+), HOCS(+), HSCO(+), and HSCS(+)." Astrophysical Journal 293 (June 1985): L49. http://dx.doi.org/10.1086/184489.
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Szymansky, Annabell, Louisa-Marie Kruetzfeldt, Lukas C. Heukamp, Falk Hertwig, Jessica Theissen, Hedwig E. Deubzer, Eva-Maria Willing, et al. "Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing." Journal of Personalized Medicine 11, no. 8 (July 22, 2021): 691. http://dx.doi.org/10.3390/jpm11080691.
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For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for analyzing traditional and new molecular markers in routine diagnostics is an urgent clinical need. Here, we investigated targeted panel sequencing as a diagnostic approach to analyze all relevant genomic neuroblastoma risk markers in one assay. Our “neuroblastoma hybrid capture sequencing panel” (NB-HCSP) assay employs a technology for the high-coverage sequencing (>1000×) of 55 selected genes and neuroblastoma-relevant genomic regions, which allows for the detection of single nucleotide changes, structural rearrangements, and copy number alterations. We validated our assay by analyzing 15 neuroblastoma cell lines and a cohort of 20 neuroblastomas, for which reference routine diagnostic data and genome sequencing data were available. We observed a high concordance for risk markers identified by the NB-HSCP assay, clinical routine diagnostics, and genome sequencing. Subsequently, we demonstrated clinical applicability of the NB-HCSP assay by analyzing routine clinical samples. We conclude that the NB-HCSP assay may be implemented into routine diagnostics as a single assay that covers all essential covariates for initial neuroblastoma classification, extended risk stratification, and targeted therapy selection.
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Maiques-Díaz, Alba, Fu-Sheng Chou, Mark Wunderlich, Gonzalo Gómez López, Filipe V. Jacinto, Sandra Rodriguez-Perales, María José Larrayoz, et al. "Chromatin Modifications Induced by the AML1/ETO Fusion Protein Reversibly Silence Its Genomic Targets Through AML1 and Sp1 Binding Motifs." Blood 118, no. 21 (November 18, 2011): 2422. http://dx.doi.org/10.1182/blood.v118.21.2422.2422.
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Abstract Abstract 2422 The AML1/ETO fusion protein, which is present in 10% to 15% of cases of acute myeloid leukemia (AML), is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. Previous studies have shown that both histone H4 deacetylation and K9 trimethylation of histone H3 (H3K9me3), respectively catalyzed by enzymes such as histone deacetylase 1 (HDAC1) and lysine methyltransferase enzyme suppressor of variegation 3–9 homolog 1(SUV39H1), are direct AML1/ETO effects on specific locus, but to date no global analysis of the AML1/ETO functional repressive chromatin modifications have been performed. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1/ETO fusion gene (HSPC-AE) enabled us to identify 1168 AML1/ETO target genes, 103 of which were co-occupied by HDAC1 with a lost of hyperacetylation at histone H4, and 264 showed an increase H3K9me3 (p(X)<0.001; Normalized Log Ratio>0.7). We found a significant enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways (i.e. TGF-β and Wnt/β-catenin) in AML1/ETO epigenetically modified target gene sets. Among them we identified novel genes (i.e. CTCF, MAPK1, SIRT1, YES1, AML1, MLLT3, and RPS19) previously described to be involved on the hematopoietic development, which epigenetic repression could implicate relevant steps in AML development induced by t(8;21). Gene Set Enrichment Analysis (GSEA) showed that expression of the 103 AML1/ETO-HDAC1 and 264 AML1/ETO-H3K9me3 target genes is highly diminished on HSCP-AE cells compared to the normal HSPC (p<0.0001 and p<0.001 respectively), suggesting that transduction with AML1/ETO directly causes this transcriptional silencing by the induction of chromatin modifications. Individual analysis confirmed a significant downregulation (p< 0.0001) of 6 out of 7 selected candidate genes. Furthermore, by using a Cre-LoxP AML1/ETO system we showed that this transcriptional repression is reversible, as the expression levels of SIRT1, AML1, CTCF, RPS19, YES1, GSK3A and MAPK1 genes were significantly restored upon AML1/ETO knockout. The clinical importance of these target genes was further analyzed in a set of 15 t(8;21) AML primary samples. All genes were found downregulated on the primary samples compared to the control HSCP, although different levels of significance were observed between them. Interestingly, AML1 binding sites were absent on a large number of the 1168 AML1/ETO target genes identified, and a Sp1 binding site was found in over 50% of them. AML1/ETO association with other motifs (e.g. E-Box motifs) has been already described and, in fact, Sp1 transcription factor is essential in hematopoietic differentiation and is known to interact with AML1/ETO. A significant enrichment of Sp1 presence in all the promoters studied was confirmed in the HSPC-AE samples compared to normal HSPC (p<0.1).Therefore, this study provides a global analysis of AML1/ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA-binding pattern of AML1/ETO, suggesting a role for Sp1 targeted therapy in this leukemia subtype. Disclosures: No relevant conflicts of interest to declare.
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Shen, Hongmei, Hui Yu, Paulina H. Liang, Haizi Cheng, Richard XuFeng, Youzhong Yuan, Peng Zhang, Clayton A. Smith, and Tao Cheng. "An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells." Blood 119, no. 15 (April 12, 2012): 3629–37. http://dx.doi.org/10.1182/blood-2011-08-373621.
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Abstract Ultimate success of hematopoietic stem cell transplantation (HSCT) depends not only on donor HSCs themselves but also on the host environment. Total body irradiation is a component in various host conditioning regimens for HSCT. It is known that ionizing radiation exerts “bystander effects” on nontargeted cells and that HSCs transplanted into irradiated recipients undergo proliferative exhaustion. However, whether irradiated recipients pose a proliferation-independent bystander effect on transplanted HSCs is unclear. In this study, we found that irradiated mouse recipients significantly impaired the long-term repopulating ability of transplanted mouse HSCs shortly (∼ 17 hours) after exposure to irradiated hosts and before the cells began to divide. There was an increase of acute cell death associated with accelerated proliferation of the bystander hematopoietic cells. This effect was marked by dramatic down-regulation of c-Kit, apparently because of elevated reactive oxygen species. Administration of an antioxidant chemical, N-acetylcysteine, or ectopically overexpressing a reactive oxygen species scavenging enzyme, catalase, improved the function of transplanted HSCs in irradiated hosts. Together, this study provides evidence for an acute negative, yet proliferation-independent, bystander effect of irradiated recipients on transplanted HSCs, thereby having implications for HSCT in both experimental and clinical scenarios in which total body irradiation is involved.
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Kong, Yuan, Yue Hu, Yang Song, Yu-Tong Wang, Zheng-Fan Jiang, Hong-Kui Deng, and Xiao Jun Huang. "Increased Levels of Reactive Oxygen Species and Exhaustion of the Quiescent CD34+ Cells May Operate in Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 4337. http://dx.doi.org/10.1182/blood.v126.23.4337.4337.
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Abstract Background: Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms underlying PGF remain to be elucidated, which increases the difficulty of managing PGF. In murine study, effective cross-talk between hematopoietic stem cells (HSCs) and bone marrow (BM) micro-environment plays an important role in hematopoiesis. HSCs occupy a hypoxic BM micro-environment to protect them from oxidative stress, whereas excessive reactive oxygen species (ROS) could inhibit HSCs self-renewal and induce HSCs exhaustion resulting in hematopoietic dysfunction. We recently reported that the impaired BM micro-environment may contribute to the occurrence of PGF post-HSCT using a prospective nested case-control study (Kong Y, et al. Biol Blood Marrow Transplant. 2013;19:1465-1473). Nevertheless, it is largely unknown whether the quantitatively and functionally impaired HSCs pre- and post-HSCT operate in the occurrence of PGF in allotransplants patients. Aims: To investigate whether the quantitative and functional abnormalities of the donor BM CD34+ cells pre- and post-HSCT are involved in the pathogenesis of PGF. Methods: The hematopoietic reconstitution activities of the CD34+ cells, sorted from the donors' BM of PGF and good graft function (GGF) patients, were evaluated in xenografted NOD-Prkdcscid IL2rgnull mice as an indicator of donors' HSCs function. To further investigate the effect of oxidative stress on normal hematopoiesis post-HSCT, the BM CD34+ cells of GGF allotransplant patients were treated of hydrogen peroxide (H2O2) with or without antioxidant N-acetyl-L-cysteine (NAC) in vitro. Subsequently, a prospective nested case-control study was performed enrolling 15 patients with PGF, 30 matched patients with GGF after allo-HSCT and their healthy donors. Quantification of the frequency, intracellular ROS levels, and cell cycle status of the BM CD34+ cells were analyzed by flow cytometry pre- and post-HSCT. Colony-forming capacity was investigated in CD34+ cells post-HSCT in vitro. The study was approved by the Ethics Committee of Peking University People's Hospital and written informed consent was obtained from all subjects. Results: The hematopoietic reconstitution activity of the BM CD34+ cells in NOD-Prkdcscid IL2rgnull mice demonstrated no significant differences between the donors of PGF and GGF patients. In the subsequent in vitro study, increased ROS were found to play an important role in the exhaustion of the quiescent BM CD34+ cells of GGF patients, whereas treatment of ROS-abrogated CD34+ cells with the antioxidant NAC could partially, but significantly restore the exhaustion and colony-forming capacity of CD34+ cells. In the prospective nested case-control study, all patient- and therapy-related variables were similar between patients with PGF and GGF. Polymerase chain reaction DNA fingerprinting of the STRs confirmed 100% donor chimerism in these patients. The frequency, intracellular ROS levels and cell cycle status of the transplanted donor BM CD34+ cells showed no remarkable differences pre-HSCT. Nevertheless, the percentage of CD34+ cells post-HSCT and their colony-forming capacity, especially the quiescent CD34+ CD38low fraction, decreased remarkably in PGF patients when compared to that in GGF patients. Notably, significantly increased ROS levels were observed in CD34+ and CD34+ CD38low fractions of PGF patients post-HSCT. Summary/Conclusion: Although the frequency and function of the transplanted donor BM CD34+ cells of PGF were demonstrated normal pre-HSCT, the increased levels of ROS and exhaustion of the quiescent CD34+ cells may operate in PGF post-HSCT. Our preliminary data indicate that an impaired BM micro-environment which may hamper the hematopoietic reconstitution of the donor HSCs in the recipients, rather than the defective donor HSCs, was involved in the occurrence of PGF. Therefore, novel therapeutic approaches, such as antioxidative therapy to maintain hypoxia BM micro-environment, promise to facilitate hematopoietic recovery in PGF. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), and the Beijing Municipal Science and Technology Program (grant nos. Z141100000214011& Z151100004015164& Z151100001615020). Disclosures No relevant conflicts of interest to declare.
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Shchekina, A. E., G. M. Galstyan, M. Y. Drokov, L. A. Kuzmina, E. N. Denisova, N. M. Arapova, V. V. Troitskaya, and E. N. Parovichnikova. "Intensive care of life-threatening complications in allogeneic hematopoietic stem cell recipients." Russian journal of hematology and transfusiology 67, no. 3 (October 21, 2022): 308–27. http://dx.doi.org/10.35754/0234-5730-2022-67-3-308-327.
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Introduction. Life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can have a significant influence on the short-term and long-term prognosis in recipients of hematopoietic stem cells (allo-HSCs).Aim — to determine the life-threatening complications and the risk factors of their occurrence and to evaluate the short-term and long-term prognosis in critically ill allo-HSCs recipients.Materials and methods. All patients over the age of 18 who underwent allo-HSCT from 01.01.2012 to 01.01.2022 were included in the retrospective study. Patients were divided into two groups: those who required intensive care unit (ICU) admission and those who did not require ICU admission. In the group of ICU admitted allo-HSCs recipients the reasons of ICU admission, timing of their occurrence and the results of life support were recorded. The risk factors of life-threatening complications occurrence and prognostic factors were analyzed.Results. In total, 174 (26.7 %) of 652 allo-HSCs recipients required ICU admission. The risk factors of life-threatening complications were: allo-HSCT in patients with acute leukemia who did not achieve complete remission (hazard ratio (HR) = 2.10; 95 % confidence interval (95% CI): 1.28–3.44; p = 0.003), allo-HSCT without conditioning in patients with hematopoietic aplasia after chemotherapy (HR = 30.63; 95% CI: 8.787–107.04; p < 0.001), graft failure (HR = 2.51; 95% CI: 1.58–3.97; p < 0.001) and poor graft function (HR = 2.85; 95% CI: 1.6–5.05; p < 0.001), acute graft versus host disease (GVHD) (HR = 2.04; 95% CI: 1.459–2.85; p < 0.001). The main reasons of ICU admission were sepsis and/or septic shock (SS) (27.9 %), acute respiratory failure (23.9 %), neurological disorders (17.7 %). The type and periods of allo-HSCT influenced the timing and structure of critical illnesses. The ICU mortality rate after all ICU admissions and readmissions was 59.8 % with a maximum follow-up of 9 years. The risk factors of ICU mortality were the occurrence of critical conditions after +30 days of allo-HSCT, the need for mechanical ventilation and vasopressors. The overall survival (OS) rate of ICU admitted allo-HSCs recipients was 13.8 %. Sepsis and/or SS that occurred in the early phase after allo-HSCT were characterized by the most favorable long-term outcome (OS — 43.8 %) among all complications of the peritransplantation period. The OS of patients discharged from the ICU was worse than OS of patients who did not require ICU admission (34.6 % vs. 58.3 %; p = 0.0013). Conclusion. Transplant centers should have a specialized ICU because more than a quarter of allo-HSCT recipients experience life-threatening complications at different allo-HSCT periods. Sepsis and SS occurring in the early pre-engraftment phase had a more favorable prognosis than other life-threatening complications. The long-term outcomes in allo-HSCs recipients who survived critical illness are worse than in recipients who did not require ICU admission.
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Marcos, Ricardo, Eduardo Rocha, Rui M. F. Henrique, and Rogério A. F. Monteiro. "A New Approach to an Unbiased Estimate of the Hepatic Stellate Cell Index in the Rat Liver: An Example in Healthy Conditions1." Journal of Histochemistry & Cytochemistry 51, no. 8 (August 2003): 1101–4. http://dx.doi.org/10.1177/002215540305100814.
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Evaluation of activation and proliferation of hepatic stellate cells (HSCs) must be grounded on solid quantitative data under normal conditions. The HSC index (HSCI), number of HSCs per 1000 hepatocytes (HEP), is often used in hepatology but has been never determined using stereology. Systematically sampled sections were immunostained against glial fibrillary acidic protein and carcinoembryonic antigen, allowing unequivocal distinction of HSC and mononuclear/binuclear HEP. With the optical disector the HSCI was estimated as 109 (coefficient of error = 0.04). This work provides a sound technical basis for experiments in which the estimation of HSCI and/or simultaneous quantification of HSC and HEP are relevant.
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Corcoran, Cian, Manuel Ruiz-Adame, and Dominic Trépel. "Early assessment and intervention by a dedicated health and social care professional team in the emergency department in older adults compared to treatment-as-usual: Health Economic Analysis Plan for within-trial cost effectiveness analysis." HRB Open Research 6 (March 31, 2023): 22. http://dx.doi.org/10.12688/hrbopenres.13693.1.
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Background: Older adults (aged over 65 years) experience high rates of adverse outcomes after presenting to emergency departments (EDs). The OPTI-MEND trial aimed to examine what impact intervention and early assessment by a dedicated health and social care professional (HSCP) team can have on quality of care for older adults in EDs. This paper presents the finalized Health Economic Analysis Plan (HEAP) specifying how the within-trial cost effectiveness analysis (CEA) will be conducted. Methods: This HEAP was developed retrospectively in collaboration with the OPTI-MEND team and the trial health economist to provide a plan to conduct the CEA. The HEAP aimed to fulfil international recommendations from a consensus of the required items for inclusion in HEAPs. In line with best practice guidelines, and to ensure full visibility in the scientific process, this paper makes the HEAP available in the public domain. Results: This HEAP illustrates the plan we followed when conducting our CEA. As this paper is a protocol it has no concrete results. A detailed list of all items in the HEAP are provided as Extended data on Open Science Framework at https://doi.org/10.17605/OSF.IO/YVG2P. Conclusions: Cost effectiveness analysis is an opportunity to extend beyond the primary clinical analysis of a trial. Congruent to a trial’s statistical analysis plan (SAP), a HEAP outlines the plan for estimating cost effectiveness and avoiding potentially spurious post-hoc analysis and questionable policy recommendations.
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Adza, Wisdom K., Andrew S. Hursthouse, Jan Miller, and Daniel Boakye. "Exploring the Joint Association of Road Traffic Noise and Air Quality with Hypertension Using QGIS." International Journal of Environmental Research and Public Health 20, no. 3 (January 27, 2023): 2238. http://dx.doi.org/10.3390/ijerph20032238.
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There is growing evidence linking exposure to air pollution and traffic noise with hypertension. The aim of this study was to examine the associations of registered hypertension cases and hypertension rate with exposure to air pollution and road noise. In this cross-sectional study, we linked the information from the NHS Scotland database of 776,579 hypertension patients’ registrations and rates per 13.80 people at the Scottish NHS Board, HSCP, Cluster, and GP practice levels. Based on the geospatial attributes, the data on residential areas were added by modelling annual average air pollutant concentrations, including particulate matter (PM10 and PM2.5), nitrogen dioxide (NO2), and road-traffic noise at different frequency components (Lden). The relationships between exposure to road noise, air pollution, and hypertension were examined using multiple regression and multivariate analysis. Traffic noise and air pollution at various frequency components positively and negatively predicted registered hypertension cases and hypertension rate. Based on the canonical loading technique, the variance explained by the canonical independent variable at a canonical correlation of 0.342 is 89%. There is a significant correlation between joint air pollution and noise at different frequency components and combined registered hypertension cases and hypertension rate. Exploring the combined effects of the two environmental exposures and the joint modelling of noise and air pollutants with hypertension in geospatial views provides an opportunity to integrate environmental and health data to support spatial assessment strategies in public and environmental health.
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Kong, Yuan, Yue Hu, Yuan-yuan Zhang, Yu-Hong Chen, Wei Han, Xiao-Hui Zhang, Lan-Ping Xu, and Xiao-Jun Huang. "CD34+ Cells in Bone Marrow Are Quantitatively and Functionally Impaired in Patients with Poor Graft Function Following Allogeneic Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 3883. http://dx.doi.org/10.1182/blood.v124.21.3883.3883.
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Abstract Background: Poor graft function (PGF), defined as the presence of 2 or 3 cytopenic counts (ANC ≤0.5×109/L and PLT ≤20×109/L or Hb ≤70 g/L) for at least 3 consecutive days beyond day +28 post-transplantation with transfusion requirement, in the presence of complete donor chimerism, and in the absence of severe graft-versus-host disease (GVHD) or hematological relapse, remains a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Emerging evidence from mouse studies suggested that effective hematopoiesis depends on a particular bone marrow (BM) microenvironment in which hematopoietic stem cells (HSCs) reside. We recently found that the impaired BM microenvironment may contribute to the occurrence of PGF post-HSCT using a prospective nested case-control study (Kong Y, et al. Biol Blood Marrow Transplant.2013;19:1465-1473). However, it remains unclear whether the quantitative and functional abnormalities of HSCs are involved in the pathogenesis of PGF. Aims: To evaluate whether the quantitative and functional abnormalities of CD34+cells in BM are involved in the pathogenesis of PGF after allo-HSCT. Methods: The normal multilineage differentiation capacity of the CD34+ cells sorted from the donors BM of PGF and good graft function (GGF) patients underwent allo-HSCT were investigated in vivo using sublethally irradiated NOD-PrkdcscidIL2rgnull mice by intra-BM injection. Subsequently, a prospective nested case-control study was performed enrolling 15 patients with PGF, 30 matched patients with GGF after allo-HSCT and their healthy donors (HDs). To minimize the potential influence of the length of time after allo-HSCT, the PGF and GGF patients had their HSCs tested at a matched median time point after allo-HSCT. Quantification of CD34+ cells was performed by flow cytometry. Owning to the limited numbers of CD34+cells in PGF patients, colony-forming cell (CFC) assay, instead of xenograft assay, was performed to investigate the multi-pluripotency of post-HSCT HSCs in vitro. Additionally, the quiescent cell cycle status and reactive oxygen species (ROS) production of HSCs in the post-HSCT BM were further analyzed by flow cytometry in the aforementioned three groups of subjects. The study was approved by the Ethics Committee of Peking University People’s Hospital and written informed consent was obtained from all subjects. Results: CD34+ BM cells from donors of PGF and GGF patients demonstrated no significant differences of normal multilineage differentiation capacity in NOD-PrkdcscidIL2rgnull mice. In the prospective nested case-control study, the demographic and clinical characteristics showed no significant difference between allo-HSCT patients with PGF and those with GGF. The percentage of CD34+ cells significantly decreased in the BM of PGF patients post-HSCT, although similar amounts of CD34+ cells were transplanted. We observed a remarkable decrease in stem cell/progenitor frequency in post-HSCT CD34+ BM cells of PGF patients as determined by CFC assay. Additionally, post-HSCT BM of PGF patients contained a significantly lower number of quiescent cells in the CD34+CD38low fraction compared to the BM of GGF patients and HDs. Moreover, significantly higher levels of ROS were observed in BM CD34+, CD34+CD38low, CD34+CD38high fractions of PGF patients following allo-HSCT compared to that in GGF patients and HDs. Summary/Conclusion: Although the frequency and function of CD34+ BM cells were revealed normal pre-HSCT, CD34+ BM cells were quantitatively and functionally impaired in patients with PGF following allo-HSCT. Our data indicate that the diminished regenerative capacity of BM of PGF patients following allo-HSCT is possibly related to a loss of quiescence and a reduced tolerability of CD34+ cells to oxidative stress. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.
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Ma, Si-Wei, Li Lu, Ting-Ting Zhang, Dan-Tong Zhao, Bin-Ting Yang, Yan-Yan Yang, and Jian-Min Gao. "Receptive and Expressive Vocabulary Skills and Their Correlates in Mandarin-Speaking Infants with Unrepaired Cleft Lip and/or Palate." International Journal of Environmental Research and Public Health 17, no. 9 (April 26, 2020): 3015. http://dx.doi.org/10.3390/ijerph17093015.
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Background: Vocabulary skills in infants with cleft lip and/or palate (CL/P) are related to various factors. They remain underexplored among Mandarin-speaking infants with CL/P. This study identified receptive and expressive vocabulary skills among Mandarin-speaking infants with unrepaired CL/P prior to cleft palate surgery and their associated factors. Methods: This is a cross-sectional study involving patients at the Cleft Lip and Palate Center of the Stomatological Hospital of Xi’an Jiaotong University between July 2017 and December 2018. The Putonghua Communicative Development Inventories-Short Form (PCDI-SF) was used to assess early vocabulary skills. Results: A total of 134 children aged 9–16 months prior to cleft palate surgery were included in the study. The prevalences of delays in receptive and expressive vocabulary skills were 72.39% (95% CI: 64.00–79.76%) and 85.07% (95% CI: 77.89–90.64%), respectively. Multiple logistic regression identified that children aged 11–13 months (OR = 6.46, 95% CI: 1.76–23.76) and 14–16 months (OR = 24.32, 95% CI: 3.86–153.05), and those with hard/soft cleft palate and soft cleft palate (HSCP/SCP) (OR = 5.63, 95% CI: 1.02–31.01) were more likely to be delayed in receptive vocabulary skills. Conclusions: Delays in vocabulary skills were common among Mandarin-speaking CL/P infants, and age was positively associated with impaired and lagging vocabulary skills. The findings suggest the necessity and importance of early and effective identification of CL/P, and early intervention programs and effective treatment are recommended for Chinese CL/P infants.
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Colette Maïde, William Tchabo, Markusse Deli, Elie Baudelaire Djantou, Aboubakar, and Nicolas Njintang Yanou. "Hypolipidemic effects of microencapsulated powder fraction from Hibiscus sabdariffa. L calyx in hyperlipidic rats." GSC Biological and Pharmaceutical Sciences 23, no. 3 (June 30, 2023): 173–83. http://dx.doi.org/10.30574/gscbps.2023.23.3.0204.
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The lipid-lowering activity of microencapsulated and nonmicroencapsulated Hibiscus sabdariffa L. powder fractions in rats rendered hyperlipidemic by a hyperlipid diet (HLD) was determined. Dried calyces of H. sabdariffa were finely ground and fractionated on a sieve column to retain particle sizes ϕ < 315 µm, and were microencapsulated with maltodextrin (MD). Rats were randomly divided into four groups: normal control group, hyperlipid diet group (negative control groups), hyperlipid diet group supplemented with atorvastatin, non-microencapsulated (NMEPHS) and microencapsulated (MEPHS) powders from H. sabdariffa calyces groups. Rats received atorvastatin, NMEPHS and MEPHS for three weeks. Atorvastatin (10 mg/kg) and individual powders were dissolved in water and administered to rats at a dose of 250 mg/kg body weight for three weeks. Body weight, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate transferase (AST), alanine transferase (ALT), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were measured. Very low-density lipoprotein cholesterol (VLDL-C), hepatosomatic index (HSI), and adiposomatic index (ASI) were calculated. Lipid profil, and MDA were increased in the negative control rat groups compared with the negative control rat group. NMEPHS and MEPHS significantly reduced body weight gain, ASI, HSI, TC, TG, LDL-C, ALT, AST, and MDA and increased HDL-C level significantly. Moreover, SOD and CAT activities were reduced with HLD and significantly increased with HSCP intake. however, the most significant activities were revealed by MEPHS. These results suggest that MEPHS exerts potent lipid-lowering effects, promotes hepatic fat breakdown, and regulates antioxidant enzymes in a more efficient manner.
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Fañanas-Baquero, Sara, Israel Orman, Federico Becerra Aparicio, Silvia Bermudez de Miguel, Jordi Garcia Merino, Rosa M. Yañez, Yolanda Fernandez, et al. "Estrogens Enhance Human Hematopoietic Stem Cell Engraftment in a Xenogenic Transplantation Model." Blood 132, Supplement 1 (November 29, 2018): 2042. http://dx.doi.org/10.1182/blood-2018-99-112104.
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Abstract Hematopoietic Stem Cells (HSCs) is a rare cell population that sits atop a hierarchy of progenitors that become progressively restricted to several or a single blood lineage. HSCs are capable of self-renewal and multipotent differentiation to all blood cell lineages. HSCs are crucial in the maintenance of lifelong production of all blood cells. HSCs are highly regulated to maintain homeostasis through a delicate balance between quiescence, self-renewal and differentiation. However, this balance is altered during the hematopoietic recovery after Hematopoietic Stem Cell Transplantation (HSCT). HSCT is routinely used to reconstitute hematopoiesis after myeloablation, being the most commonly-used cell therapy. HSCT efficacy and multilineage reconstitution can be limited by inadequate HSC number, poor homing, engraftment, or limited self-renewal. Recent evidence indicates that estrogens are involved in regulating the hematopoietic system homeostasis. Estrogens are the primary female sex hormones and are responsible for controlling many cellular processes including growth, differentiation and function of the reproductive system. However, estrogens have also been proposed to regulate HSCs. b-Estradiol (E2) was shown to promote the cell cycle of HSCs and multipotent progenitors (MPPs) and increase erythroid differentiation in females (1). On the other hand, tamoxifen reduces the number of MPPs and short-term HSCs but activates proliferation of long-term HSCs (2). The potential clinical application of estrogens in HSCT mainly derives from the possibility that these drugs may enhance the engraftment of transplanted HSCs, thus reducing side effects associated to myeloablative conditioning. Here, we show that a short-term treatment of immunodeficient mice transplanted with hCD34+ cells with estrogens such as E2 and estetrol (E4) improves human hematopoietic engraftment. Fifty-thousand cord blood CD34+ cells (CB-CD34+) were transplanted into sublethally irradiated immunodeficient NSG mice. Three days after transplantation, mice were treated for four days with daily subcutaneous doses of E2, E4 or vehicle. Human hematopoietic engraftment was evaluated in the BM of transplanted mice at four months later. E2 and E4 estrogens increased the proportion of hCD45+ cells 1.8-fold and 2.4-fold as compared to values determined in control mice, without modifying the proportion of myeloid and lymphoid lineages. Significantly, animals treated with either estrogen had significantly higher levels of human hematopoietic progenitors (hCD45+CD34+). To study the engraftment of long-term engraftment HSCs in transplanted mice, human CD45+ cells from primary recipients were sorted and transplanted in secondary NSG recipients. Three months after transplants, the proportion of human hematopoietic cells in secondary recipients was also higher when primary recipients were treated with E2 or E4 than in vehicle-treated animals. Improved engraftments associated to the administration of E2 or E4 estrogens were confirmed when very low doses of CB-CD34+ cells were transplanted (5x103 hCD34+/mouse) in recipients of either sex. Collectively, our data support a new application of estrogens to improve the hematopoietic recovery after HSCT. This application may have particular relevance to enhance the hematopoietic recovery after myeloablative conditioning and when limiting numbers of HSCs are available. Disclosures Bueren: Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Segovia:Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.
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Persaud, Steve P., Matthew L. Cooper, Michael P. Rettig, and John F. DiPersio. "Conditioning for Hematopoietic Stem Cell Transplantation Using Antibody-Drug Conjugate Targeting CD45 Permits Engraftment across Immunologic Barriers." Blood 132, Supplement 1 (November 29, 2018): 2035. http://dx.doi.org/10.1182/blood-2018-99-116894.
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Abstract INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for benign and malignant hematologic diseases. It also holds great promise as treatment for infectious and autoimmune disease and for autologous gene therapy. However, due to the toxicity of conditioning regimens for HSCT, it is generally reserved for the most life-threatening diagnoses, such as acute leukemia. Targeted approaches to conditioning may improve the safety of HSCT and extend its applicability to other diseases. Recently, conditioning regimens were described consisting of treatment with anti-CD45.2 or anti-cKit antibodies conjugated to the ribosome-inhibiting protein saporin (CD45-SAP and cKit-SAP, respectively) (Palchaudhuri et al (2016), Nat Biotechnol, Czechowicz et al (2016), ASH Abstract). These were reported to deplete murine hematopoietic stem cells (HSCs) and permit engraftment of syngeneic HSCs with minimal toxicity. However, the ability of CD45-SAP and cKit-SAP to permit HSCT across immunologic barriers without chemotherapy or radiation, or to target malignant cells expressing these receptors, are potential applications that were not explored. METHODS: We compared CD45-SAP and cKit-SAP conditioning in syngeneic (B6 to B6) and allogeneic (CB6F1 to B6) murine transplantation models. Donor chimerism in peripheral blood (PB) and complete blood counts (CBCs) were assessed monthly during these experiments. Successful HSC engraftment was confirmed by serial transplantation experiments. Human CD45-SAP and cKit-SAP conjugates were also tested for their ability to target MOLM13 AML cells using XTT viability assays, and in targeting cord-blood derived HSCs using colony forming cell assays. RESULTS: We confirmed that CD45-SAP dosed at 75 µg per mouse could effectively deplete B6 mice of HSCs and condition them for syngeneic HSCT as reported (Palchaudhuri et al (2016), Nat Biotechnol), with normal-range CBCs and stable donor PB chimerism of approximately 80% at 6 months post-transplant. Donor-derived HSC in CD45-SAP treated mice successfully engrafted upon transplantation to secondary B6 recipients. cKit-SAP dosed at 10 µg per mouse was sufficient for HSC depletion, but robust syngeneic engraftment required dosing at 50 µg per mouse. Notably, CD45-SAP treatment combined with CD4+and CD8+ T cell depletion permitted haploidentical transplantation from CB6F1 donors to B6 recipients, with normal-range CBCs and stable donor PB chimerism of approximately 70% at 3 months post-transplant. Finally, human CD45-SAP conjugates could successfully target MOLM13 leukemia cells and cord-blood derived HSCs in vitro. CONCLUSIONS: Transplantation in mice across immunological barriers is achievable using CD45-SAP conditioning, with high-level donor chimerism without chemotherapy or radiation. Furthermore, human CD45-SAP conjugates can successfully target human leukemia cell lines and primary HSCs in vitro. Further studies are underway in three areas. First, by combining T and NK cell depletion with CD45-SAP conditioning, we are attempting full-mismatch HSCT in mice. Second, using humanized mouse models, we will assess the ability of CD45-SAP to target human leukemia cells and HSCs in vivo. Finally, we are exploring using HSCT with CD45-SAP conditioning as a treatment in mouse models of autoimmune disease. Disclosures Rettig: Amphivena Therapeutics: Research Funding; Novimmune: Research Funding.
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Takagi, Shinsuke, Yoriko Saito, Atsushi Hijikata, Satoshi Tanaka, Takashi Watanabe, Haruhiko Koseki, Osamu Ohara, et al. "Membrane-Bound Human Stem Cell Factor Promotes Differentiation of Human Granulocytes and Mast Cells In Vivo,." Blood 118, no. 21 (November 18, 2011): 3419. http://dx.doi.org/10.1182/blood.v118.21.3419.3419.
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Abstract Abstract 3419 Recently, advances in xenograft models for human hemamtopoietic stem cells (HSCs), or the humanized mice, have begun to allow investigators to examine the differentiation of human hematopoietic and immune cells in vivo. However, lymphoid-skewed human hematopoietic development in the mouse bone marrow is one of the remaining limitations in the humanized mouse models. The inefficient human myeloid development could at least partly be attributed to the mouse microenvironment not fully supporting differentiation and maturation of human myeloid lineage. To overcome this problem, we focused on the role of membrane-bound human stem cell factor in supporting the maintenance of human HSCs and inducing the development of human myeloid cells and created human stem cell factor transgenic NOD/SCID/IL2rgKO (hSCF Tg NSG) mice. Transplantation of 5000–50000 cord blood-derived Lin-CD34+CD38- cells resulted in significantly higher engraftment of human CD45+ leukocytes at 3–6 months post-transplantation in the bone marrow, spleen, and peripheral blood of hSCF Tg NSG recipients compared with those of non-transgenic NSG recipients. The enhanced human CD45+ engraftment was most prominent in the bone marrow (hSCF Tg recipients: 98.0 +/− 1.3%, n= 15, non-Tg NSG controls: 75.3 +/− 7.3%, n=7). In the bone marrow, the frequency of human CD33+ myeloid cells within the total human CD45+ population was significantly higher in the hSCF Tg NSG recipients than in the non-Tg NSG recipients and constituted the majority of human hematopoietic cells (hSCF Tg recipients: 54.6 +/− 4.5%, n=15 and non-Tg NSG controls: 29.3 +/− 4.0%, n=7). Flow cytometric analysis demonstrated that the majority of engrafted human myeloid cells in the hSCF Tg recipient bone marrow were side-scatter high, HLA-DR negative granulocytes. Reflecting the effect of human SCF on the development of human mast cells, human c-Kit+CD203c+ mast cells were identified in the bone marrow, spleen, and gastrointestinal tracts of the hSCF Tg NSG recipients. Altogether, the in vivo humanized mouse model demonstrates the essential role of membrane-bound SCF in human myeloid development. The hSCF Tg NSG humanized mice may facilitate the in vivo investigation of human HSCs, myeloid progenitors and mature myeloid lineage. Disclosures: No relevant conflicts of interest to declare.