An Aerodigestive Approach to Laryngeal Clefts and Dysphagia Using Injection Laryngoplasty in Young Children.

PURPOSE OF REVIEW: Our objective is to summarize the presentation, diagnosis, and management of mild laryngeal clefts in children. We focus on deep interarytenoid notches (DIN), a subclassification of type 1 laryngeal clefts (LC1), and review the literature and our multidisciplinary experience utilizing injection laryngoplasty (IL). RECENT FINDINGS: DIN is a mild form of LC1 and is considered a normal anatomical variant. Recent cohort studies demonstrate IL to be a safe, low-risk, and efficacious treatment of LC1, but few studies focus on DIN. We present results from two aerodigestive clinic (ADC) pilot studies at our institution, in patients 1-3 years old, with DIN-related dysphagia and aspiration (DA). Feeding, respiratory-related symptom scores, and aspiration/penetration assessed on modified barium swallow (MBS) significantly improved following combined IL and feeding therapy using a thickener weaning protocol (TWP). Subgroup analysis reveals combined IL and TWP to be particularly effective in patients with severe baseline DA. Multidisciplinary aerodigestive evaluation and management with IL and feeding therapy focused on weaning levels of thickener is emerging as a novel and effective approach for treatment of DIN-related DA in young children. Further comparative, prospective trials investigating effects of IL and feeding therapy are required to validate results.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the ß chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

Sex steroid-induced DNA methylation changes and inflammation response in prostate cancer.

BACKGROUND: Sex steroid hormones have been reported to induce inflammation causing dysregulation of cytokines in prostate cancer cells. However, the underlying epigenetic mechanism has not well been studied. The objective of this study was to evaluate the effect of sex steroid hormones on epigenetic DNA methylation changes in prostate cancer cells using a signature PCR methylation array panel that correspond to 96 genes with biological function in the human inflammatory and autoimmune signals in prostate cancer. Of the 96-gene panel, 32 genes showed at least 10% differentially methylation level in response to hormonal treatment when compared to untreated cells. Genes that were hypomethylated included CXCL12, CXCL5, CCL25, IL1F8, IL13RAI, STAT5A, CXCR4 and TLR5; and genes that were hypermethylated included ELA2, TOLLIP, LAG3, CD276 and MALT1. Quantitative RT-PCR analysis of select genes represented in a cytokine expression array panel showed inverse association between DNA methylation and gene expression for TOLLIP, CXCL5, CCL18 and IL5 genes and treatment of prostate cancer cells with 5'-aza-2'-deoxycytidine with or without trichostatin A induced up-regulation of TOLLIP expression. Further analysis of relative gene expression of matched prostate cancer tissues when compared to benign tissues from individual patients with prostate cancer showed increased and significant expression for CCL18 (2.6-fold; p<0.001), a modest yet significant increase in IL5 expression (1.17-fold; p=0.015), and a modest increase in CXCL5 expression (1.4-fold; p=0.25). In conclusion, our studies demonstrate that sex steroid hormones can induce aberrant gene expression via differential methylation changes in prostate carcinogenesis.

Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻7). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

Knockdown of estrogen receptor-α induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death.

Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-α. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of antiestrogen resistance limits clinical use. We used antiestrogen-sensitive and -resistant cells to determine the effect of antiestrogens/ERα on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ERα significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to antiestrogen drugs. Interestingly, ERα knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by antiestrogens was prosurvival but did not prevent ERα knockdown-mediated death. We built a novel mathematical model to elucidate the interactions among UPR, autophagy, ER signaling, and ROS regulation of breast cancer cell survival. The experimentally validated mathematical model explains the counterintuitive result that knocking down the main target of ICI (ERα) increased the effectiveness of ICI. Specifically, the model indicated that ERα is no longer present in excess and that the effect on proliferation from further reductions in its level by ICI cannot be compensated for by increased autophagy. The stimulation of signaling that can confer resistance suggests that combining autophagy or UPR inhibitors with antiestrogens would reduce the development of resistance in some breast cancers.

Cultural Competence in Rural Nursing Education: Are We There Yet?

AIM: This multimethod study assessed the capacity of nursing education programs to promote culturally congruent practice in a single rural state. BACKGROUND: An important objective of our HRSA-funded Advanced Education in Nursing grant was to increase nurse educator proficiency in teaching cultural concepts. This study served as a statewide baseline assessment to inform future faculty development efforts. METHOD: Subjects included faculty, graduate students, and clinical educators representing all levels of nursing education programs. Self-report cultural proficiency data were collected via survey while focus groups and electronic surveys were utilized to assess curricula. RESULTS: No significant differences in proficiency were found by faculty age or education. Qualitative data indicated that concepts of culture are not easily identified across the curriculum. CONCLUSION: There is need for increased and explicit focus on concepts of culture in nursing education programs to prepare nurses for culturally congruent practice with potential to reduce health disparities.

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients.

AIMS/HYPOTHESIS: Type 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells. METHODS: We used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples. RESULTS: We identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p = 1.17 × 10(-3)). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p = 4.8 × 10(-3)). CONCLUSIONS/INTERPRETATION: The 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients.

Caregivers' Knowledge and Food Accessibility Contributes to Childhood Malnutrition: A Case Study of Dora Nginza Hospital, South Africa.

Amongst the problems facing South Africa today are malnutrition and food insecurity, and there is a need for interventions and innovative strategies to address these. The aim of the study was to determine the contribution of caregivers' knowledge of nutrition and household food security among children aged 0 to 60 months. A cross-sectional study design was applied using a quantitative approach. A convenience sample (n = 184) of caregiver-child pairs (for children 0 to 60 months) from the Dora Nginza Hospital Paediatric Outpatient Department was used. A structured questionnaire was applied to collect data on socio-economic factors, health status, household food security, and caregivers' knowledge. In addition, interviews were conducted, and anthropometric measurements of children were taken to determine their nutritional status. The results indicate that most caregivers were female, and more than half completed high school, yet almost 75% were unemployed. Most of the caregivers (58.2%) were either overweight or obese. The results also show that only 33.2% of households were food secure, 29.3% were at risk of hunger, and 37.5% experienced hunger. The prevalence of stunting, underweight, and wasting among children in the study was high. A significant, slightly positive correlation was found between the body mass index of the caregiver and height for age. Poor socio-economic status and food inaccessibility were identified as possible underlying contributing factors to malnutrition, contributing to food insecurity and therefore poor dietary intake.

Nursing Theory Informs Dressage.

Application of nursing theory in daily life by applying elements of Parse's paradigm allowed for a more expansive view of the dressage experience by focusing on the paradox of visible-invisible in the unique rhythmic-patterns of the horse-rider team. The study of classical nursing theory has diminished in a similar pattern as classical dressage. The importance of studying the classics in any field is emphasized along with concerns about the future of nursing and healthcare.

Nursing: Forever Changed by a Pandemic.

The paper consists of reflections on the corona pandemic and nursing knowledge as practice. Nurses have been so appreciated by the public during this time that they are referred to as heroes. The moral injustice of taking nurses who come so willing to serve and not provide protective gear for their practice is addressed.

NurseTRUST: A Leadership Model for Advancing Population Health.

An interview with one of the current leaders for NurseTRUST tells the story of a newly formed organization to advance nursing leadership to address population health. The vision has always been to prepare nurse leaders for advanced positions in senior leadership roles in healthcare. The RWJ-Nurse Executive Fellowship created national leaders to influence population health. The postprogram Fellows are leveraging this design for the next generation of leaders through the NurseTRUST organization. The network of trusted colleagues can address emerging issues with their national colleagues who are leaders in their field while mentoring the next generation of nurse leaders.

Typology of high users of health services among a rural medicaid population.

OBJECTIVES: To identify a typology for high system users among a rural Medicaid population that could assist policy makers and providers in better and more efficiently serving this population. DESIGN AND SAMPLE: Exploratory secondary data analysis of a large integrated Medicaid database in a western state. Five hundred and thirty-nine Medicaid recipients receiving 2 or more state services and receiving 10 or more unique medications. MEASURES: Data analysis examining health care use, medication use, and demographic characteristics using SAS to identify patterns of use of services in the population. Results were confirmed with a statewide sample of 2,287 Medicaid users. RESULTS: 3 characteristics-(1) use of 36 or more health care services in a year; (2) no gap in health care service use over the entire year; and (3) use of >12 health care services in 1 month-describe high-risk groups of Medicaid users. CONCLUSIONS: Public health nurses, particularly as case managers and program planners, can look at service use patterns through client histories and their own agency records, in order to identify high-risk groups who may benefit the most from programs that address their support, education, and coordination of health care needs.

From theory to practice: caring science according to Watson and Brewer.

Caring science is presented by Jean Watson and Barbara Brewer through an interview and dialogue format. Jean Watson presents caring science and its philosophy and evolution and the impact of her model on nursing and other disciplines. Barbara Brewer addresses the implementation of the model in a Magnet hospital setting and describes how her leadership facilitated implementation.

Imogene M. King's scholars reflect on her wisdom and influence on nursing science.

Reflections on the impact of the work of great leaders are vital for both scientists and practitioners to gain important perspectives on the progress of the evolution of the discipline. Recognizing the influence of a particular theorist's impact is particularly important at the time of death, which is the time where the development of a particular theory moves from the originator to the followers. This column serves as a tribute to Imogene M. King, and is dedicated to her wisdom in promoting the conceptual system she developed.

The impact of Dorothea E. Orem's life and work: an interview with Orem scholars.

This column serves as a tribute to Dorothea Orem's work and focuses on her leadership in the development of nursing science and nursing theory. Nurse scholars give a picture of Orem's contributions over her life and reflections about the future of nursing and healthcare.

Caring: some reflections on the impact of the culture care theory by McFarland & Andrews and a conversation with Leininger.

This column is the first of two with a special focus on the construct of caring. In this dialogue, two Leininger scholars together address the questions related to the global impact on practice and the contribution of the model to scientific development in nursing. Then, in a special conversation, nurse theorist Madeleine Leininger offers her view of the impact of her work as well as some of her early experiences.

Open or Conventional Access: Integrity in the Process.

A wave of new publishing options has opened for nursing. This dialogue examines factors, such as quality and cost, that may influence new authors. There are numerous options for young scientists with many new journal titles and promises of a quick review and guaranteed publication. Choices between Open Access and conventional journals can be difficult since higher cost to the author does not correlate with higher quality.

Paradoxes in Healthcare Leadership: Being-Nonbeing.

The paradox of being-nonbeing is explored from the perspective of the Vice President of Nursing and Clinical Services for a large rural integrated healthcare system in the United States. Being-nonbeing for the nurse leader is experienced daily. Being-nonbeing is experienced with self and others as she provides vision, leadership, and courageous support to the workplace and care environment.

Deep interarytenoid notch in young children managed with systematic thickener wean and injection laryngoplasty.

OBJECTIVES: Deep interarytenoid notch (DIN) is a congenital variation of the larynx often associated with dysphagia and aspiration (DA) in young children. Feeding therapy with thickeners and surgical management with injection larygoplasty (IL) are used with various efficacies. Thickeners address the functional domain and IL addresses the anatomical domain of treatment. Our objective was to evaluate DIN patients managed with both interventions. METHODS: We conducted a retrospective pilot descriptive study of DIN patients with DA aged 1-3 years receiving thickeners and IL. Patients received a systematic weekly reduction of thickeners, referred to as the Thickener Weaning Protocol (TWP), based on clinical signs and symptoms of DA. The outcomes were assessed by the rate of thickener level reduction and DA-related sign/symptom frequency achieved at 6 months post-treatment. RESULTS: Thirteen patients with DIN associated DA were analyzed. The TWP was initiated within 2 months in 77% of patients, and within 4 months in 100% of patients. Thickener scores improved from an average of 5.76 (3/4 honey) to 2.15 (thin) (p = 0.001). DA-related signs/symptoms frequency improved from an average of 3.3 to 0.84 (p = 0.05). CONCLUSIONS: These findings suggest that treatment of DIN associated DA with a combination of thickeners and IL results in significant clinical improvements in young children.

Validation of two postpartum depression screening scales with a sample of First Nations and Métis women.

The purposes of this study were to determine the prevalence of postpartum depression (PPD) and to examine the utility of the Postpartum Depression Screening Scale (PDSS) and the Edinburgh Postnatal Depression Scale (EPDS) in First Nations and Métis women in the Canadian province of Saskatchewan. A total of 103 women who had given birth in the preceding 1 to 12 months were recruited from the city of Regina and from First Nations health centres in Saskatchewan. Self-report screening instruments assessing PPD were administered along with a structured clinical interview for DSM-IV Axis I disorders (SCID) to confirm the diagnosis of PPD. Of the 103 women, 17% were diagnosed with PPD. The findings support the validity of the PDSS and the EPDS as measures of PPD in First Nations and Métis women. The author discusses the need for primary health care professionals, including nurses, to offer postnatal screening for women who may be at risk for PPD.