Abnormal sickle red blood cell (sRBC) biomechanics, including pathological deformability and adhesion, correlate with clinical severity in sickle cell disease (SCD). Clinical intravenous fluids ...(IVFs) of various tonicities are often used during treatment of vaso-occlusive pain episodes (VOE), the major cause of morbidity in SCD. However, evidence-based guidelines are lacking, and there is no consensus regarding which IVFs to use during VOE. Further, it is unknown how altering extracellular fluid tonicity with IVFs affects sRBC biomechanics in the microcirculation, where vaso-occlusion takes place. Here, we report how altering extracellular fluid tonicity with admixtures of clinical IVFs affects sRBC biomechanical properties by leveraging novel in vitro microfluidic models of the microcirculation, including 1 capable of deoxygenating the sRBC environment to monitor changes in microchannel occlusion risk and an “endothelialized” microvascular model that measures alterations in sRBC/endothelium adhesion under postcapillary venular conditions. Admixtures with higher tonicities (sodium = 141 mEq/L) affected sRBC biomechanics by decreasing sRBC deformability, increasing sRBC occlusion under normoxic and hypoxic conditions, and increasing sRBC adhesion in our microfluidic human microvasculature models. Admixtures with excessive hypotonicity (sodium = 103 mEq/L), in contrast, decreased sRBC adhesion, but overswelling prolonged sRBC transit times in capillary-sized microchannels. Admixtures with intermediate tonicities (sodium = 111-122 mEq/L) resulted in optimal changes in sRBC biomechanics, thereby reducing the risk for vaso-occlusion in our models. These results have significant translational implications for patients with SCD and warrant a large-scale prospective clinical study addressing optimal IVF management during VOE in SCD.
•Intravenous fluids are used when treating VOE, but guidelines are lacking, and how IVF tonicity affects sickle red cell biomechanics is unknown.•Modifying extracellular fluid tonicity alters deformability, adhesivity, and occlusion risk for sRBCs in microfluidic vascular models.
Hematopoietic stem cell (HSC) quiescence is a tightly regulated process crucial for hematopoietic regeneration, which requires a healthy and supportive microenvironmental niche within the bone marrow ...(BM). Here, we show that deletion of Ptpn21, a protein tyrosine phosphatase highly expressed in HSCs, induces stem cell egress from the niche due to impaired retention within the BM. Ptpn21−/− HSCs exhibit enhanced mobility, decreased quiescence, increased apoptosis, and defective reconstitution capacity. Ptpn21 deletion also decreased HSC stiffness and increased physical deformability, in part by dephosphorylating Spetin1 (Tyr246), a poorly described component of the cytoskeleton. Elevated phosphorylation of Spetin1 in Ptpn21−/− cells impaired cytoskeletal remodeling, contributed to cortical instability, and decreased cell rigidity. Collectively, these findings show that Ptpn21 maintains cellular mechanics, which is correlated with its important functions in HSC niche retention and preservation of hematopoietic regeneration capacity.
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•Normal HSCs are stiffer and less deformable than mature blood cells•Ptpn21 loss decreases cell stiffness and increases mobility/deformability in HSCs•Deletion of Ptpn21 results in HSC egress due to impaired retention in the niche•Ptpn21 modulates cellular mechanics by dephosphorylation of Septin1 (Tyr246)
Ptpn21, a protein tyrosine phosphatase highly expressed in HSCs, plays an important role in maintaining cellular mechanics and HSC retention in the niche. Knockout of Ptpn21 results in decreased cellular stiffness, enhanced deformability and motility, stem and progenitor cell egress, and defective hematopoietic reconstitution capabilities. Mechanistically, Ptpn21 modulates cell mechanics by dephosphorylating Septin1 (Tyr246).
To assess the contribution of maternal and newborn characteristics to variation in neonatal intensive care use across regions and hospitals.
This was a retrospective population-based live birth ...cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 2 subcohorts: very low birth weight (VLBW) singletons and late preterm singletons. Crude and risk-adjusted neonatal intensive care unit (NICU) admission rates, intensive and intermediate special care days, and imaging procedures were calculated across Neonatal Intensive Care Regions (n = 21) and hospitals (n = 100). Total Medicaid payments were calculated.
Overall, 11.5% of live born, 91.7% of VLBW, and 37.6% of infants born late preterm were admitted to a NICU, receiving an average of 2 days, 58 days, and 5 days of special care with payments per newborn inpatient episode of $5231, $128 075, and $10 837, respectively. There was little variation across regions and hospitals in VLBW NICU admissions but marked variation for NICU admissions in late preterm newborn infants and for special care days and imaging rates in all cohorts. The variation decreased slightly after health risk adjustment. There was moderate substitution of intermediate for intensive care days across hospitals (Pearson r VLBW −0.63 P < .001; late preterm newborn −0.53 P < .001).
Across all risk groups, the variation in NICU use was poorly explained by differences in newborn illness levels and is likely to indicate varying practice styles. Although the “right” rates are uncertain, it is unlikely that all of these use patterns represent effective and efficient care.
Purpose
This paper seeks to demonstrate that assuming an increase in satisfaction will always lead to greater loyalty oversimplifies the complex association between these constructs. A more accurate ...view of the satisfaction‐loyalty relationship is gained by examining the moderating effect of involvement, switching costs, and relationship benefits.
Design/methodology/approach
This paper reports the results of a hierarchal‐moderated regression analysis on data gathered from a national mail survey of 509 customers across nine service types.
Findings
The findings of this study suggest that the satisfaction‐loyalty relationship is not as simple as it seems. Specifically, the negative effect that switching costs have on the association between satisfaction and loyalty declines as customer involvement with the service relationship grows, but increases as the customer perceives greater relationship benefit. These findings suggest that simply enhancing satisfaction will not always generate greater customer loyalty.
Research limitations/implications
Future research should consider the effects of other moderating variables, such as relationship investment and quality, on the satisfaction‐loyalty link.
Practical implications
This paper provides managers with insight as to how to best increase customer loyalty.
Originality/value
This paper is the first to simultaneously examine the moderating effect of customer involvement, switching costs, and social benefits on the satisfaction‐loyalty association.
The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include ...two-dimensional standard histological cell-counting approaches, which are rapidly performed error-prone and lack architectural context; or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine learning model (BiliQML) able to quantify biliary forms in the liver of anti-Keratin 19 antibody-stained whole slide images. Training utilized 5,019 researcher-labeled biliary forms, which following feature selection, and algorithm optimization, generated an F-score of 0.87. Application of BiliQML on seven separate cholangiopathy models; genetic (
-CRE;
,
CRE;
,
CRE;
), surgical (bile duct ligation), toxicological (3,5-diethoxycarbonyl-1,4-dihydrocollidine), and therapeutic (
with ileal bile acid transporter inhibition), allowed for a means to validate the capabilities, and utility of this platform. The results from BiliQML quantification revealed biological and pathological differences across these seven diverse models indicate a highly sensitive, robust, and scalable methodology for the quantification of distinct biliary forms. BiliQML is the first comprehensive machine-learning platform for biliary form analysis, adding much needed morphologic context to standard immunofluorescence - based histology, and provides clinical and basic-science researchers a novel tool for the characterization of cholangiopathies.
To test the hypothesis that newborn infants cared for in hospitals with greater utilization of neonatal intensive care experienced fewer postdischarge adverse events.
We developed 3 retrospective ...population-based cohorts of Texas Medicaid insured singletons born in 2010-2014 (very low birth weight VLBW n = 11 139, late preterm n = 57 509, and non-preterm n = 664 447) who received care in higher volume hospitals with level III/IV neonatal intensive care units (NICUs). Measures of NICU care were hospital-level risk adjusted NICU admission rates, special care days (days of nonroutine care) per infant, and the percent of intensive (highest billable care code) special care days. The units of analysis were hospitals (n = 80) and the primary outcome was an adverse event, (defined as admission, emergency department visit, or death) within 30 days postdischarge.
Higher use of NICU care at a hospital level was not associated with lower postdischarge 30-day adverse event. Infants cared for in hospitals with above vs below median special care day rates experienced slightly higher postdischarge adverse event per 100 infants (VLBW: 14.01 95% CI 12.74-15.27 vs 11.84 10.52-13.16, P < .05; late preterm: 7.33 6.68-7.97 vs 6.28 5.87-6.69, P < .01; non-preterm: 4.47 4.17-4.76 vs 3.97 3.75-4.18, P < .01). Weak positive associations (Pearson correlations of 0.31-0.37, P < .01) were observed for adverse event with special care days; in no instance was a negative association observed between NICU utilization and adverse event.
Higher utilization of NICU care was not associated with lower rates of short-term events suggesting that there may be opportunities to safely decrease admission rates and length of NICU stays.
Strategic management has long been the capstone course for business majors at most colleges and universities globally. As originally designed, the capstone course sought to teach students an array of ...skills and tools needed to actually perform strategic planning, primarily through integration and application of functional business concepts and techniques. Times have changed, however, and business schools have come under scrutiny regarding their ineffectiveness in developing graduates' skills commensurate with employers' requirements. Such criticism is justified as academics teaching the capstone business course have partitioned their instruction efforts to focus increasingly on theory rather than practical applications. After a pertinent evaluation of current academic research, we illuminate how and why increased focus on practice is needed in strategic-management pedagogy. We delineate how the once well-designed business capstone course has evolved into a course that too often fails to impart practical competencies to graduating students. To facilitate closing the gap between graduates' skills and employers' requirements, we present a strategic management pedagogical model designed to promote student learning and development of hard and soft skills related to actually doing strategic planning. The proposed model can help reduce the gap between graduates' skills and employers' requirements with the intended purpose to provide increased interest for teaching practical tools that were developed by practitioners. Such tools include the BCG matrix, developed by the Boston Consulting Group, and the Internal-External (IE) portfolio matrix derived from the General Electric (GE) Business Screen developed by Jack Welch, former CEO of GE. The proposed model also reveals the process of including both internal and external aspects into strategic decision making as evidenced by countless organizations performing Strength-Weakness-Opportunity-Threat (SWOT) analyses. The proposed model significantly enhances previous theory-based approaches for teaching the capstone strategic-management course.
The mechanism of action of the widely used in vivo ferric chloride (FeCl3) thrombosis model remains poorly understood; although endothelial cell denudation is historically cited, a recent study ...refutes this and implicates a role for erythrocytes. Given the complexity of the in vivo environment, an in vitro reductionist approach is required to systematically isolate and analyze the biochemical, mass transfer, and biological phenomena that govern the system. To this end, we designed an “endothelial-ized” microfluidic device to introduce controlled FeCl3 concentrations to the molecular and cellular components of blood and vasculature. FeCl3 induces aggregation of all plasma proteins and blood cells, independent of endothelial cells, by colloidal chemistry principles: initial aggregation is due to binding of negatively charged blood components to positively charged iron, independent of biological receptor/ligand interactions. Full occlusion of the microchannel proceeds by conventional pathways, and can be attenuated by antithrombotic agents and loss-of-function proteins (as in IL4-R/Iba mice). As elevated FeCl3 concentrations overcome protective effects, the overlap between charge-based aggregation and clotting is a function of mass transfer. Our physiologically relevant in vitro system allows us to discern the multifaceted mechanism of FeCl3-induced thrombosis, thereby reconciling literature findings and cautioning researchers in using the FeCl3 model.
•The multivariate mechanism of FeCl3-induced thrombosis is rooted in colloidal chemistry, mass transfer, and biological clotting.•FeCl3-induced thrombosis is mediated by charge-based binding of proteins (cell surface bound and soluble) to the Fe3+ ion.
Purpose - This paper seeks to examine the central role that commitment plays in driving customer loyalty and to identify the effect that confidence, social and special treatment benefits as well as ...relationship investment, communication and management have on the development of commitment, and ultimately customer loyalty.Design methodology approach - The paper reports the results of a national mail survey of 591 consumers across nine different service industries.Findings - The findings of the study suggest that relationship commitment drives customer loyalty and that confidence, social and special treatment benefits affect commitment to the service, as does relationship investment and management. Surprisingly, relationship communication was found to have a negative effect on commitment to the service.Practical implications - This paper provides managers with insight as to how they can better create and sustain loyal relationships through the creation of customer commitment.Originality value - The paper empirically demonstrates the importance of commitment in developing and sustaining loyal relationships while also providing a detailed assessment of the role of relationship benefits and maintenance in creating committed customers.
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