Sustained response off-treatment in eltrombopag-treated adult patients with ITP who are refractory or relapsed after first-line steroids: Primary, final, and ad-hoc analyses of the Phase II TAPER trial.

Immune thrombocytopenia (ITP) is characterized by reduced platelet count due to increased destruction and is categorized according to the time following diagnosis (newly diagnosed, persistent, chronic). First-line corticosteroid therapy is associated with transient response, high relapse rates, and considerable toxicity. TAPER (NCT03524612) is a Phase II, prospective, single-arm trial investigating whether eltrombopag can induce a sustained response off-treatment (SRoT) in adult patients with ITP after first-line corticosteroid failure. This study defines SRoT as an off-treatment period wherein platelet count remains above 30 × 109 /L in the absence of bleeding or rescue therapy. The primary endpoint was the proportion of patients who achieved SRoT until Month 12, which was 30.5% (n = 32/105; p < .0001 testing hypothesis H1: proportion >15%) following eltrombopag tapering and discontinuation, and median SRoT duration was ~8 months until Month 12. Median platelet count increased within 1 month of treatment and remained elevated until Month 12. Quality of life improved within 3 months and was maintained. Headache (21%) was the most common adverse event. None of the 4 deaths reported were considered treatment-related. In summary, ~one-third of patients achieved SRoT until Month 12 following eltrombopag tapering and discontinuation. An ad-hoc early-use analysis, stratified by ITP duration at baseline, assessed initial hematologic responses and safety. Results suggest that eltrombopag has similar efficacy in newly diagnosed and later stages of ITP. In follow-up until Month 24, a median SRoT duration of ~22 months was observed (n = 20). The safety profile was comparable across analyses and ITP duration groups and aligned with its well-established safety profile.

Assembly of the secretion pores GspD, Wza and CsgG into bacterial outer membranes does not require the Omp85 proteins BamA or TamA.

In Gram-negative bacteria, ß-barrel proteins are integrated into the outer membrane by the ß-barrel assembly machinery, with key components of the machinery being the Omp85 family members BamA and TamA. Recent crystal structures and cryo-electron microscopy show a diverse set of secretion pores in Gram-negative bacteria, with α-helix (Wza and GspD) or ß-strand (CsgG) transmembrane segments in the outer membrane. We developed assays to measure the assembly of three distinct secretion pores that mediate protein (GspD), curli fibre (CsgG) and capsular polysaccharide (Wza) secretion by bacteria and show that depletion of BamA and TamA does not diminish the assembly of Wza, GspD or CsgG. Like the well characterised pilotins for GspD and other secretins, small periplasmic proteins enhance the assembly of the CsgG ß-barrel. We discuss a model for integral protein assembly into the bacterial outer membrane, focusing on the commonalities and differences in the assembly of Wza, GspD and CsgG.

Nonplasmacytoid, high IFN-α-producing, bone marrow dendritic cells.

Plasmacytoid dendritic cells (pDC) are the producers of type I IFNs in response to TLR9 ligands. However, we have found that when bone marrow is depleted of pDC, the IFN-α produced in response to TLR9 ligands is not fully removed. We assign the source of this non-pDC IFN-α as a newly described DC type. It displays the high IFN-α producing activity of pDC but to a more limited range of viruses. Unlike pDC, the novel DC display high T cell stimulation capacity. Moreover, unlike mouse pDC, they are matured with GM-CSF and are less prone to apoptosis upon activation stimuli, including viruses. We propose that these DC constitute a novel bone marrow inflammatory DC type, ideally geared to linking innate and adaptive immune responses in bone marrow via their potent IFN-α production and high T cell stimulatory capacity.

Fine structure of neurally differentiated iPS cells generated from a multiple sclerosis (MS) patient: a case study.

We compared the characteristics of neural cells derived from induced pluripotent stem (iPS) cells from a patient with multiple sclerosis versus neurally differentiated control iPS cells of a healthy individual. The iPS cells were differentiated toward the oligodendrocyte lineage using a four-step protocol established for the differentiation of embryonic stem cells. The resulting cell population was immunostained on day 112 of differentiation for the presence of oligodendrocytes and analyzed by transmission electron microscopy (TEM). Both patient and control samples resembled a mixed population of neural cells rather than oligodendroglia of high purity, including neural stem cell-like cells and possibly oligodendrocytes demonstrable by TEM.

Nursing and the science of prevention for population health.

The topic of patient-centered care is at the very epicenter of the contemporary emphasis on a value-based approach to health care. Multiple studies confirm that positive outcomes are consistently achieved when clinicians and administrators put appropriate emphasis on patient-centered care. Although we would agree that the patient-centered approach is necessary for achieving positive clinical outcomes for individual patients, we suggest that this approach alone is insufficient to sustain these outcomes across large populations over an extended-period of time. We believe that a science-based approach to population health coupled with patient-centered care pathways will achieve the most effective, long-term impact for large groups of individuals. Furthermore, we believe that nurses play a central role in a science-based approach to patient-centered medical care. In this article, we discuss the intersection of preventative science, patient-centered care, and the role of nurses. We present our experience at Texas Health Resources with the use of clinical nurse leaders in a science-based population health approach to achieve more consistent, positive outcomes during transition of care. Finally, we suggest that care providers integrate the science of prevention with the principles of patient-centered care to more consistently deliver on the promise of population health.

Activity and safety of eltrombopag in combination with cyclosporin A as first­line treatment of adults with severe aplastic anaemia (SOAR): a phase 2, single-arm study.

BACKGROUND: Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG. METHODS: SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 µg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed. FINDINGS: 54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment. INTERPRETATION: Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated. FUNDING: Novartis Pharmaceuticals.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up.

Patients with ß-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with ß-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Fine structure of progenitor cells in early ectopic human embryos.

This study has documented the major types of lineage progenitor cells at the second level of cell differentiation after the establishment of the primary germ layers in ectopic human embryos in vivo. These correspond to stages 8 and 9 of embryogenesis (weeks 3-4) in the Carnegie collection. The aim of this study was to provide images of fine structure of tissue progenitor cells to compare them with current imaging of their equivalent stem cells identified using fluorescent stem cell markers. These include neural, mesenchymal, endodermal, ectodermal (epidermal) and haematopoietic progenitor cells, including those for amniotic, yolk sac and chorionic tissues that are used in current stem cell research. Neural induction by the notochord has been imaged. This study should give valuable clues to understand the pattern of cell differentiation of embryonic stem cells (ESC) in vitro, which are more or less mimicked in ESC colonies, embryoid bodies and neurospheres as documented in the literature. The fine structure of week-3 and week-4 human ectopic embryos is presented to demonstrate progenitor tissue cells that will eventually form the brain, spinal cord, skin, gut, heart, blood, muscle, bone and other tissues of the human body later on in development. These images should help stem cell researchers using fluorescent markers and other techniques to identify embryonic and adult stem cells in culture.

The system chief nurse executive role: sign of the changing times?

As the health care system landscape continues to evolve toward more integrated care, a trend toward consolidation of hospitals into larger systems continues. The systems are more than the traditional hospital-centric structures, as acute care becomes just one component to a larger system that includes ambulatory care, acute and post-acute care, chronic disease and end-of-life management, and all structures in between. To provide leadership in these new models, there have been an increasing number of system chief nurse executives hired both to facilitate the integration of care and to align and standardize nursing practice across the continuum. By definition, the role of the system chief nurse executive differs from that of the entity chief nursing officer. A crosswalk is presented that describes the differences between the roles and reflects on the implication for system chief nurse executives during our changing times.

The fine structure of human germ layers in vivo: clues to the early differentiation of embryonic stem cells in vitro.

The fine structure of the three germ layers in human ectopic embryos (stage 7) have been documented by digital light and electron microscopy. The formation of ectoderm, endoderm and mesoderm and notochordal cells, and also the extraembryonic membranes, amnion and yolk sac, are imaged. The germ layers give rise to all the cells and tissues of the human body. Possible clues to the early differentiation of embryonic stem cells (ESC) in vitro were obtained, since these events are more or less mimicked in cultures of ESC derived from the inner cell mass of human blastocysts. The findings are discussed with reference to previous studies on the fine structure of ESC using the same technique.

Jacqueline Herd DNP, RN, NEA-BC.

Jacqueline Herd, DNP, MSN, RN, NEA-BC is the Executive Vice President and Chief Nursing Officer (CNO) at Grady Health System in Atlanta, Georgia. She is a California native and moved to Georgia in 2009 as the chief nursing officer at Grady Health Care in Atlanta (Tenet Health Care). With over 20 years' experience as a nurse executive, her passion is inspiring and empowering nurses to lead. Before moving to Georgia, she was a member of the Association of California Nurse Leaders (ACNL), and since moving to Georgia, she is a member of the Georgia Nurses Association, American Nurses Association, and an active member of Georgia Organization of Nurse Leaders (GONL). She has served as a member at large, president elect, president and immediate past president on the GONL State Board. She is an active member of American Organization of Nurse Leaders (AONL), has volunteered on the by-laws committee and the publication committee for the "Voice of Nursing Leadership," and is current AONL board member elected to represent Region 4. She is a strong advocate for the March of Dimes (MOD) and has served on the MOD Atlanta Planning Committee and the Nurse of the Year nominating committee. She has also served on the Georgia State Community Advisory Board and is currently on the Emory University Nell Hodgson Woodruff School of Nursing DNP Community Advisory Board. She is married with 3 children and 7 grandchildren.

Efficacy and safety of deferasirox doses of >30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload.

The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including beta-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 microg/l (P < 0.0001) from pre-dose-escalation to the time-of-analysis; significant decreases were also observed in adult and paediatric patients, as well as beta-thalassaemia patients. The adverse event profile in patients who received deferasirox doses of >30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden.

The functional development of Leydig cells in a marsupial.

Leydig cells are the major source of androgen in the male mammal. We describe here for the first time the development of the Leydig cell in a macropodid marsupial, the tammar wallaby, Macropus eugenii. Leydig cells are first recognized morphologically 2 days after birth with the appearance of lipid droplets in the cytoplasm of certain interstitial cells. Lipid content closely matches the steroid content of the developing testis and marks the maturation of the steroid synthesis pathway in the tammar testis. Morphologically mature Leydig cells, marked by distinct mitochondria with tubular cristae and an extensive anastomosing network of smooth endoplasmic reticulum, are developed by day 10 after birth - the time of peak testosterone content in perinatal tammar testes. The volume percentage of each cell type in the testis does not change over time so the growth of each cellular component keeps pace with growth of the whole testis. There was no morphological or quantitative evidence of a change from one population of Leydig cells to another in the tammar testis as has been reported in several other species including the rat, mouse and human. Maturation of the testis is also marked by the development of tight junctions between the cell membranes of adjacent Sertoli cells. These appear around day 30 after birth and coincide with the onset of mitotic arrest in male germ cells. Overall, the development of the Leydig cell in the tammar wallaby follows a similar pattern to that seen in other mammals, although the start of Leydig cell differentiation is, like many other organ systems in marsupials, post natal, not fetal and there appears to be only a single population of Leydig cells.

CXCR3 ligands contribute to Th1-induced inflammation but not to homing of Th1 cells into the lung.

Th1 cells are implicated in numerous pulmonary inflammatory disorders, and adoptive transfer of alloreactive Th1 cells mediates lung injury and inflammation in mice. In response to Th1-mediated immune injury, CXCR3 ligands IP10 and MIG are markedly induced. Because Th1 cells express high levels of CXCR3, their recruitment and activity may be influenced by CXCR3 ligands. To examine the role of CXCR3 ligands, the authors inhibited CXCR3-ligand interaction by 2 approaches: (1) antibody ablation of CXCR3 ligands IP10 (CXCL10/interferon-gamma -inducible 10-kDa protein) and MIG (CXCL9/monokine-induced by interferon-gamma), and (2) use of cxcr3(-/-) mice. Antibody neutralization of IP10 and MIG reduced Th1-cell mediated lung inflammation but did not alter Th1-cell influx in the lung. In contrast, a lack of CXCR3 on host cells had no effect on Th1 cells influx or acute inflammation. In vitro, ablation of endogenous IP10 and MIG inhibited antigen-mediated Th1-cell proliferation. These results suggest that the influx of alloreactive Th1 cells into the lung does not require CXCR3 ligands, but that these chemokines do affect Th1-cell proliferation and activity within the affected tissue. Other CXCR3(+) leukocytes do not contribute to acute alloimmune injury.

Plasticity of airway epithelial cell transcriptome in response to flagellin.

Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium.

Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation.

Lipopolysaccharide binding protein (LBP) function is dependent on circulating LBP levels. Disturbance of LBP transcription regulation may influence the risk for clinical events. In a nested case-control study using a single nucleotide polymorphism haplotype tagging (tagSNP) approach, we assessed whether genetic variation in the LBP gene influences the risk for Gram-negative (GN) bacteremia after allogeneic hematopoietic cell transplantation (HCT), then validated the association in a prospective cohort by correlating genetic variation with basal serum LBP levels and mortality. Presence of the tagSNP 6878 C allele among patients was associated with a 2-fold higher risk for GN bacteremia (odds ratio = 2.15; 95% confidence interval [CI], 1.31-3.52, P = .002). TagSNP 6878 was in strong linkage disequilibrium with 3 SNPs in the LBP promoter, one of which was SNP 1683 (r(2) = 0.8), located in a CAAT box that regulates LBP promoter efficiency. SNP 1683 was associated with higher median basal serum LBP levels (TT 8.07 microg/mL; TC 10.40 microg/mL; CC 17.39 microg/mL; P = .002), and a 5-fold increase in GN bacteremia related mortality after HCT (hazard ratio = 4.83; 95% CI, 1.38-16.75, P = .013). These data suggest that transcriptional regulation of the LBP gene contributes to the risk for developing GN bacteremia and death after HCT.

Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation.

Innate immunity is involved in the biology of graft versus host disease and common airway diseases. We screened 15 genes in this pathway using a linkage disequilibrium-based approach to identify potential candidate genes that may be involved in the development of airflow obstruction after hematopoietic cell transplantation. Sixty-nine single-nucleotide polymorphisms were selected for assessment in a discovery cohort (n = 363). Significant associations were validated in a validation cohort (n = 209). Expression of the candidate gene was demonstrated by detecting gene transcript and protein in malignant and normal small airway epithelial cells. In the discovery cohort, 133 patients developed significant airflow decline. Four patient and donor bactericidal/permeability-increasing (BPI) haplotypes were associated with a 2-fold to 3-fold increased risk of developing significant airflow decline (P values, .004-.038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P values, .013-.043). BPI gene transcript and protein were detected in airway epithelial cells. These results suggest mutations in the BPI gene significantly influence the risk of developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airway disease.

Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation.

RATIONALE: The role of pulmonary function before stem cell transplant as a potential risk factor for the development of early post-transplant respiratory failure and mortality is controversial. METHODS: We conducted a retrospective analysis of the pretransplant pulmonary function of 2,852 patients who received their transplant between 1990 and 2001. MEASUREMENTS: Pretransplant FEV(1), FVC, total lung capacity (TLC), diffusing capacity of carbon monoxide (DL(CO)), and the alveolar-arterial oxygen tension difference P(A-a)O(2) were measured and assessed for association with development of early respiratory failure and mortality in Cox proportional hazard logistic models. MAIN RESULTS: In multivariate analyses, progressive decrease of all lung function parameters was associated with a stepwise increase in risk of developing early respiratory failure and mortality when assessed in independent models. On the basis of a significant correlation between FEV(1) and FVC (r = 0.81), FEV(1) and TLC (r = 0.61), and FVC and TLC (r = 0.80), and a lack of correlation between FEV(1) and DL(CO), we developed a pretransplant lung function score based on pretransplant FEV(1) and DL(CO) to determine the extent of pulmonary compromise before transplant. Multivariate analysis indicated that higher pretransplant lung function scores are associated with a significant increased risk for developing early respiratory failure (category II hazard ratio [HR], 1.4; category III HR, 2.2; category IV HR, 3.1; p < 0.001) and death (category II HR, 1.2; category III HR, 2.2; category IV HR, 2.7; p < 0.005). CONCLUSIONS: These results suggest that not only does compromised pretransplant lung function contribute to the risk for development of early respiratory failure and mortality but this risk may be estimated before transplant by grading the extent of FEV(1) and DL(CO) compromise.

Comparison of lung function after myeloablative and 2 Gy of total body irradiation-based regimens for hematopoietic stem cell transplantation.

Lung function decline is a well-recognized occurrence after myeloablative hematopoietic stem cell transplantation (HCT) that has not been studied after nonmyeloablative conditioning regimens. We examined the lung function of patients before and after 2-Gy total body irradiation-based nonmyeloablative and myeloablative preparative regimens. Before HCT, at day 100, and 1 year after HCT, nonmyeloablative patients had lower 1-second forced expiratory volume (FEV1), forced vital capacity, total lung capacity, residual volume, and carbon monoxide diffusion capacity. However, after transplantation, the risk for experiencing a >20% per year decrease of FEV 1 was significantly lower for nonmyeloablative than myeloablative patients >50 years of age (odds ratio, 0.3; 95% confidence interval, 0.1-0.8; P = .01). Lower pretransplantation FEV 1 was associated with a higher mortality rate for both groups, with the highest mortality risk among patients with a pretransplantation FEV 1 <60% (nonmyeloablative: hazard ratio, 3.9; 95% confidence interval, 1.9-8.0; myeloablative: hazard ratio, 7.2; 95% confidence interval, 2.5-21.2). These results suggest that despite having worse lung function, patients who receive the 2-Gy total body irradiation-based nonmyeloablative regimen will likely experience less pulmonary toxicity than patients who receive a myeloablative regimen, and this may have important clinical implications when deciding on a conditioning regimen for patients >50 years of age with compromised pretransplantation lung function.