Evaluation of Follow-up Colposcopy Procedures After Abnormal Cervical Screening Result Across a Statewide Study in Mississippi.

Purpose: Cervical screening is used to detect and treat precancers to prevent invasive cancers. However, successful prevention also requires adequate follow-up and treatment of individuals with abnormal screening results. The aim was to investigate demographics, clinical characteristics, and follow-up status for individuals needing colposcopy after an abnormal screening result. Methods: The STRIDES (Studying Risk to Improve DisparitiES) cohort comprises individuals undergoing cervical cancer screening and management at a Mississippi Health Department or University of Mississippi clinic. Follow-up status, demographics, and clinical data were assessed from electronic health records and, if necessary, patient navigation on individuals identified as needing a colposcopy after an abnormal screening. Results: Of the 1,458 individuals requiring colposcopy, 43.0% had the procedure within 4 months, 16.4% had a delayed procedure, and 39.5% had no documented follow-up, with significant predictors of follow-up identified as age and cytology diagnosis. Based on age, individuals 30 + were more likely to follow up with a colposcopy compared to individuals < 30 years (49% and 38.7%, respectively; p < .001). Individuals with cytology diagnoses of LSIL (52.9%), ASC-H (51.4%), and HSIL (62.3%) had higher percentages of adherence to follow-up colposcopy guidelines (p < .001). Conclusion: Despite high cervical cancer screening rates among Mississippians, a substantial portion did not have adequate next-step intervention. However, it is encouraging that highest risk individuals were more likely to have a colposcopy. Regardless, continuing to understand the underlying causes for incomplete follow-up is crucial for timely secondary targeted interventions to reduce cervical cancer burden, promote awareness, and improve health outcomes.

Analyzing the concept of toxic positivity for nursing: A dimensional analysis approach.

AIM: To analyze toxic positivity and its relevance to nursing. DESIGN: Concept analysis using Schatzman's dimensional analysis approach. DATA SOURCES: Two searches were conducted using Google Scholar, JSTOR, ProQuest and CINAHL (1990-2023). Keywords included "toxic positivity" (Phase 1) and "emotional suppression," "unrealistic optimism"; "disingenuous happiness," "forced gratitude" and "logical fallacy" (Phase 2). Retained sources (1) were in English (Phases 1 and 2); (2) used 'toxic positivity' as a construct reflecting the purpose of analysis (Phase 1); and (3) demonstrated relevance towards analytical findings (Phase 2). Total analytic sources were 35. METHODS: The analytic phase, identification, elucidated conceptual dimensions and contexts. The analytic phase, logistics, examined relationships among dimensions and contexts through an iterative process resulting in a dimensional matrix/conceptual model. RESULTS: Salient dimension is Emotional Suppression with two sub-dimensions, Logical Fallacy and Forced Gratitude. Other dimensions include Unrealistic Optimism and Disingenuous Happiness. Contexts include intra- and post-paradigmatic societal shifts and intra- and post-traumatic experiences. Analysis reveals toxic positivity as an exchange between a giver and receiver with the receiver experiencing negative outcomes. CONCLUSION: The concept appears consistent in its application and use across contexts and is emerging in nursing literature. IMPLICATIONS FOR THE PROFESSION: Acknowledging toxic positivity in nursing may inform theoretical and future research related to improving nursing burnout, bolstering retention, and enhancing well-being. Nurses across work environments may encounter toxic positivity. Leaders should consider policy adoption and inclusion of trauma-informed practices. IMPACT: Nursing workforce issues require deeper examination of potential contributing factors. Findings suggest toxic positivity may be encountered in work environments impacting nursing at individual and system levels. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Metabolic syndrome risk among adolescents in the Deep South and the relationships with behavioral health, food insecurity, and physical activity.

PURPOSE: A combination of physical and psychosocial risk factors put adolescents at risk for poor cardiometabolic health and chronic disease burden, often recognized as metabolic syndrome. The purposes of this study were to (1) identify the prevalence of metabolic syndrome risk among adolescents, utilizing the metabolic syndrome severity index, and (2) determine the relationship between metabolic syndrome risk and behavioral health, food insecurity, and physical inactivity among adolescents. METHODS AND DESIGN: A cross-sectional, descriptive, correlational design was deployed in an inner-city high school in the Deep South. An 8-month recruitment and enrollment period yielded a sample of 55 adolescents. A battery of measures included assessment of demographic data, anthropometric, cardiovascular, and psychosocial data. Utilizing these data elements, a progressive methodological approach was used to identify metabolic severity risk as a continuous variable for use in the adolescent population. RESULTS: All participants identified as African American/Black. Among them, 71% (N = 39) were female and an average age of 16 (SD = 1.3) years old, with 67.3% (N = 37) of the sample at risk for metabolic syndrome. There was not a statistically significant relationship between metabolic syndrome severity score and behavioral health risk, food insecurity, and physical inactivity in this sample. PRACTICE IMPLICATIONS: Future use of the continuous metabolic syndrome severity score may guide practice by utilizing longitudinal data to assess the trends of metabolic syndrome severity scores in relation to disease outcomes in adolescents. This may promote the identification of psychosocial and physical interrelationships with metabolic syndrome, thus improving overall health through the development of age-appropriate interventions.

The associations among nurse work engagement, job satisfaction, quality of care, and intent to leave: A national survey in the United States.

Objectives: Employee work engagement, job satisfaction, quality of care, and intent to leave are critical indicators for healthcare organizational performance. This study aimed to analyze the current state of nurses' work engagement and its factors to examine the associations among nurses' work engagement, job satisfaction, quality of care, and intent to leave in the United States (US). Methods: This is a quantitative descriptive cross-section design. Data were collected online from the US registered nurses from March to September 2022. Measures comprised the Utrecht Work Engagement Scale, the demographics, and questions regarding job satisfaction, perceived quality of care, and intent to leave. Results: Nine hundred nurses participated in the online survey. Among the participants, 79.2% reported holding a specialty certification, 59.4% scored high/very high on job satisfaction, 82.2% expressed high/very high on the perceived quality of nursing care, and 28.4% conveyed likely/very likely to leave in the following year. Nurses' work engagement was positively associated with nurses' job satisfaction and their perceived quality of care but negatively associated with intent to leave. More certified nurses reported high or very high job satisfaction than non-certified nurses. As for demographics, the linear regression analysis showed that nurses who were older, identified as White, and held doctorate degrees reported higher levels of work engagement in comparison to their counterparts. Conclusions: This study shows that nurses' work engagement is associated with their job satisfaction, perceived quality of care, and intent to leave. Nurses' work engagement in this study is lower than in other studies, especially before the COVID-19 pandemic, which may indicate a possible association with the COVID-19 impact. Because nurses' work engagement is significantly associated with job satisfaction, nurse leaders need to find ways to promote nurses' job satisfaction and retention.

Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation.

Porcine kidney xenotransplantation is accelerating towards clinical translation. However, despite the demonstrated ability of porcine kidneys to remove metabolic waste products, questions remain about their ability to faithfully recapitulate renal endocrine functions after transplantation. Here we analyze xenograft growth and function of two kidney dependent endocrine pathways in seventeen cynomolgus macaques after kidney xenotransplantation from gene edited Yucatan minipigs. Xenograft growth, the renin-angiotensinogen aldosterone-system, and the calcium-vitamin D-parathyroid hormone axis are assessed using clinical chemistries data, renin activity and beta-C-terminal-telopeptide assays, kidney graft RNA-sequencing and serial ultrasonography. We demonstrate that xenografts transplanted from minipigs show only modest growth and do not substantially contribute to recipient RAAS pathway activity. However, parathyroid hormone-independent hypercalcemia and hypophosphatemia are observed, suggesting a need for close monitoring and timely intervention during human testing. Further study of these phenotypes is warranted in designing prospective clinical trials.

Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques.

Porcine cells devoid of three major carbohydrate xenoantigens, αGal, Neu5GC, and SDa (TKO) exhibit markedly reduced binding of human natural antibodies. Therefore, it is anticipated that TKO pigs will be better donors for human xenotransplantation. However, previous studies on TKO pigs using old world monkeys (OWMs) have been disappointing because of higher anti-TKO pig antibodies in OWMs than humans. Here, we show that long-term survival of renal xenografts from TKO pigs that express additional human transgenes (hTGs) can be achieved in cynomolgus monkeys. Kidney xenografts from TKO-hTG pigs were transplanted into eight cynomolgus recipients without pre-screening for low anti-pig antibody titers. Two recipients of TKO-hTG xenografts with low expression of human complement regulatory proteins (CRPs) (TKO-A) survived for 2 and 61 days, whereas six recipients of TKO-hTG xenografts with high CRP expression (TKO-B) survived for 15, 20, 71, 135, 265, and 316 days. Prolonged CD4+ T cell depletion and low anti-pig antibody titers, which were previously reported important for long-term survival of αGal knock-out (GTKO) xenografts, were not always required for long-term survival of TKO-hTG renal xenografts. This study indicates that OWMs such as cynomolgus monkeys can be used as a relevant model for clinical application of xenotransplantation using TKO pigs.

Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso-occlusion and nephropathy in mouse models of sickle cell disease.

BACKGROUND AND PURPOSE: Reduced bioavailability of NO, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vaso-occlusion and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP-amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNFα-induced inflammation in wild-type C57BL/6 mice and in 'humanised' mouse models of SCD. EXPERIMENTAL APPROACH: Effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. KEY RESULTS: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte-endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic agent, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFα-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte-endothelial cell interactions, improved blood flow and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat- than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-h urine excretion, plasma levels of cystatin C and urinary excretion of N-acetyl-ß-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. CONCLUSION AND IMPLICATIONS: Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion and kidney injury in mouse models of SCD and systemic inflammation.

Physical activity and fitness: The feasibility and preliminary effectiveness of wearable activity tracker technology incorporating altruistic motivation in youth.

PURPOSE: The purpose of this study was to examine the feasibility and preliminary effectiveness of using wearable activity tracker technology, integrated with altruistic motivation in children to increase physical activity (PA), fitness, and prosocial behavior. DESIGN AND METHODS: A quasiexperimental design was employed in two 4th grade classrooms in a rural southern state. The intervention was a wearable PA tracker and a web-based curriculum with activities to earn power points redeemable to provide life-saving food to undernourished kids internationally. Seventeen children in the intervention group participated in the 10-week PA program and 18 children were in the wait listed control group. Three measures were assessed in both groups at baseline and postintervention: (a) PA measured with accelerometers, (b) fitness levels measured with shuttle run, and (c) prosocial behavior measured with Strengths and Difficulties questionnaire. RESULTS: Of the 35 children enrolled, the majority were nine years old (n = 28), black (n = 31) and female (n = 23). An overall enrollment rate of 88%, attrition rate of 9%, and an accelerometer noncompliance rate of 25% was determined to assess feasibility. There was no statistical significance between the control and intervention group outcome variables. The average minutes of PA in the control group decreased 8 min from baseline to postintervention (p = .05). In the intervention group, PA decreased by 10 min from baseline to postintervention (p = .12). In both the control and intervention groups, prosocial behavior scores decreased (p = .09 control; p = .62 intervention). The fitness scores, VO2 max, did not significantly change (intervention p = .21; control p = .35). PRACTICE IMPLICATIONS: Developing effective interventions that foster PA and dissuade sedentary behaviors are essential to enhancing PA and fitness levels. The recruitment, retention, and accelerometer wear adherence suggest this setting, with this population is feasible. The intervention is deliverable, however, the potential of wearable activity trackers and the effect of prosocial behavior that benefits others in increasing PA and improving cardiorespiratory fitness, should be further researched by building on the successful elements of this study.

sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH.

Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO-sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.

Zfp423 Regulates Skeletal Muscle Regeneration and Proliferation.

Satellite cells (SCs) are skeletal muscle stem cells that proliferate in response to injury and provide myogenic precursors for growth and repair. Zfp423 is a transcriptional cofactor expressed in multiple immature cell populations, such as neuronal precursors, mesenchymal stem cells, and preadipocytes, where it regulates lineage allocation, proliferation, and differentiation. Here, we show that Zfp423 regulates myogenic progression during muscle regeneration. Zfp423 is undetectable in quiescent SCs but becomes expressed during SC activation. After expansion, Zfp423 is gradually downregulated as committed SCs terminally differentiate. Mice with satellite-cell-specific Zfp423 deletion exhibit severely impaired muscle regeneration following injury, with aberrant SC expansion, defective cell cycle exit, and failure to transition efficiently from the proliferative stage toward commitment. Consistent with a cell-autonomous role of Zfp423, shRNA-mediated knockdown of Zfp423 in myoblasts inhibits differentiation. Surprisingly, forced expression of Zfp423 in myoblasts induces differentiation into adipocytes and arrests myogenesis. Affinity purification of Zfp423 in myoblasts identified Satb2 as a nuclear partner of Zfp423 that cooperatively enhances Zfp423 transcriptional activity, which in turn affects myoblast differentiation. In conclusion, by controlling SC expansion and proliferation, Zfp423 is essential for muscle regeneration. Tight regulation of Zfp423 expression is essential for normal progression of muscle progenitors from proliferation to differentiation.

Student and Preceptor Advancement in a Dedicated Education Site: Innovation in Clinical Education for Advanced Practice Nurses.

In the 1990s, dedicated education units transformed undergraduate preceptorships, but graduate preceptorships remain static. The dyadic nurse practitioner preceptorship model supports an environment where faculty, students, and preceptors may overlook nuances that affect the teaching-learning process. This article describes an innovative clinical education model, Student and Preceptor Advancement in a Dedicated Education Site, designed to improve preceptorships for advanced practice nurses. The focus is on adaptations made to facilitate use in advanced practice nursing programs.

Development and Implementation of APRN Competency Validation Tools in Four Nurse-Led Clinics in Rural East Tennessee.

BACKGROUND: Graduate nursing academic faculty rely heavily on clinical preceptors for mentorship and clinical practicum experiences for BSN-DNP degree-seeking family nurse practitioner (FNP) students. Thus, it is important that preceptors have documented clinical competencies to assure the delivery of quality, evidence-based practice that meets regulatory requirements prior to precepting students. OBJECTIVES: The objectives of this quality improvement project were to develop and implement APRN competency validation tools (CVTs) in nurse-led clinic settings. METHODS: Rapid Cycle Quality Improvement (RCQI) strategies were used to develop and implement APRN CVTs. RESULTS: Three APRN CVTs were successfully developed, tested, refined, and implemented in four nurse-led clinics in rural east Tennessee. With one exception, the APRN preceptors had documentation of clinical competency prior to approval as a SPADES preceptor. Graduate academic faculty, preceptors, and students reported satisfaction with the SPADES project. CONCLUSION: CVTs are feasible tools for documentation of validated clinical APRN preceptors' competency in nurse-led clinics. The CVTs and the medical record review checklist are available upon request from the primary author. IMPLICATIONS FOR NURSING: Use of APRN CVTs provides documentation that the preceptor uses evidence-based practice in the clinic setting prior to precepting students.

Lack of ADAM10 in endothelial cells affects osteoclasts at the chondro-osseus junction.

Mice lacking ADAM10 in endothelial cells (Adam10ΔEC mice) have shorter femurs, tibiae, and humeri than controls, raising questions about how endothelial cells could control long bone growth. We performed a histopathological evaluation of the femur and tibia growth plates at different postnatal stages, and assessed the distribution of TRAP-positive osteoclasts and endothelial cells at the growth plate. The growth plates in Adam10ΔEC mice appeared normal at P7 and P14, but a thickened zone of hypertrophic chondrocytes and increased trabecular bone density were apparent by P21 and later. The number of TRAP+ cells at the COJ was normal at P7 and P14, but was strongly reduced at P21 and later. Moreover, the density of endomucin-stained endothelial cells at the COJ was increased starting at P7. The defects in long bone growth in Adam10ΔEC mice could be caused by a lack of osteoclastogenesis at the COJ. Moreover, ADAM10 appears to regulate endothelial cell organization in the developing bone vasculature, perhaps in a similar manner as in the developing retinal vascular tree, where ADAM10 is thought to control Notch-dependent endothelial cell fate decisions. This study provides evidence for the regulation of osteoclast function by endothelial cells in vivo.

ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes.

Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.

Interleukin-1 stimulates ADAM17 through a mechanism independent of its cytoplasmic domain or phosphorylation at threonine 735.

ADAM17 (a disintegrin and metalloproteinase) is a membrane-anchored metalloproteinase that regulates the release of EGFR-ligands, TNFα and other membrane proteins from cells. ADAM17 can be rapidly activated by a variety of signaling pathways, yet little is known about the underlying mechanism. Several studies have demonstrated that the cytoplasmic domain of ADAM17 is not required for its rapid activation by a variety of stimuli, including phorbol esters, tyrosine kinases and some G-protein coupled receptors. However, phosphorylation of cytoplasmic residue T735 was recently reported as a crucial step for activation of ADAM17 by IL-1ß and by the p38 MAP-kinase pathway. One possible mechanism to reconcile these results would be that T735 has an inhibitory role and that it must be phosphorylated as a pre-requisite for the activation of ADAM17, which would then proceed via a mechanism that is independent of its cytoplasmic domain. To test this hypothesis, we performed rescue experiments of Adam17-/- cells with wild type and mutant forms of ADAM17. However, these experiments showed that an inactivating mutation (T735A) or an activating mutation (T735D) of cytoplasmic residue T735 or the removal of the cytoplasmic domain of ADAM17 did not significantly affect the stimulation of ADAM17 by IL-1ß or by activation of MAP-kinase with anisomycin. Moreover, we found that the MAP-kinase inhibitor SB203580 blocked activation of cytoplasmic tail-deficient ADAM17 and of the T735A mutant by IL-1ß or by anisomycin, providing further support for a model in which the activation mechanism of ADAM17 does not rely on its cytoplasmic domain or phosphorylation of T735.