A Quality Improvement Initiative to Improve Pediatric Discharge Medication Safety and Efficiency.

Medication errors are a leading safety concern, especially for families with limited English proficiency and health literacy, and patients discharged on multiple medications with complex schedules. Integration of a multilanguage electronic discharge medication platform may help decrease medication errors. This quality improvement (QI) project's primary aim (process measure) was to increase utilization in the electronic health record (EHR) of the integrated MedActionPlanPro (MAP) for cardiovascular surgery and blood and marrow transplant patients at hospital discharge and for the first clinic follow-up visit to 80% by July 2021. Methods: This QI project occurred between August 2020 and July 2021 on 2 subspecialty pediatric acute care inpatient units and respective outpatient clinics. An interdisciplinary team developed and implemented interventions, including integration of MAP within EHR; the team tracked and analyzed outcomes for discharge medication matching, and efficacy and safety MAP integration occurred with a go-live date of February 1, 2021. Statistical process control charts tracked progress. Results: Following the implementation of the QI interventions, there was an increase from 0% to 73% in the utilization of the integrated MAP in the EHR across the acute care cardiology unit-cardiovascular surgery/blood and marrow transplant units. The average user hours per patient (outcome measure) decreased 70% from the centerline of 0.89 hours during the baseline period to 0.27 hours. In addition, the medication matching between Cerner inpatient and MAP inpatient increased significantly from baseline to postintervention by 25.6% (P < 0.001). Conclusion: MAP integration into the EHR was associated with improved inpatient discharge medication reconciliation safety and provider efficiency.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast-derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

Assessment of Metabolic Pathways and Parameters in Extracellular Matrix-Detached Cells.

Changes in metabolism can alter a variety of distinct cellular parameters in a number of physiological and pathological contexts. Relatedly, the loss of integrin-mediated attachment to extracellular matrix (ECM) is now appreciated to alter metabolism in a variety of distinct fashions. As such, assays to quantify and assess metabolism during ECM detachment are critical to better understanding the cellular and molecular changes that impact the behavior and survival of ECM-detached cells. Here, we discuss assays and approaches commonly used to study metabolism during ECM detachment.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

Current Postlaunch Implementation of State Mandates of Newborn Screening for Critical Congenital Heart Disease by Pulse Oximetry in U.S. States and Hospitals.

OBJECTIVE: Our objective was to gauge adherence to nationally endorsed protocols in implementation of pulse oximetry (POx) screening for critical congenital heart disease (CCHD) in infants after mandate by all states and to assess associated characteristics. STUDY DESIGN: Between March and October 2019, an online questionnaire was administered to nurse supervisors who oversee personnel conducting POx screening. The questionnaire used eight questions regarding performance and interpretation of screening protocols to measure policy consistency, which is adherence to nationally endorsed protocols for POx screening developed by professional medical societies. Multilevel linear regression models evaluated associations between policy consistency and characteristics of hospitals and individuals, state of hospital location, early versus late mandate adopters, and state reporting requirements. RESULTS: Responses from 189 nurse supervisors spanning 38 states were analyzed. Only 17% received maximum points indicating full policy consistency, and 24% selected all four options for potential hypoxia that require a repeat screen. Notably, 33% did not recognize ≤90% SpO2 as an immediate failed screen and 31% responded that an infant with SpO2 of 89% in one extremity will be rescreened by nurses in an hour rather than receiving an immediate physician referral. Lower policy consistency was associated with lack of state reporting mandates (beta = -1.23 p = 0.01) and early adoption by states (beta = -1.01, p < 0.01). CONCLUSION: When presented with SpO2 screening values on a questionnaire, a low percentage of nurse supervisors selected responses that demonstrated adherence to nationally endorsed protocols for CCHD screening. Most notably, almost one-third of respondents did not recognize ≤90% SpO2 as a failed screen that requires immediate physician follow-up. In addition, states without reporting mandates and early adopter states were associated with low policy consistency. Implementing state reporting requirements might increase policy consistency, but some inconsistency may be the result of unique protocols in early adopter states that differ from nationally endorsed protocols. KEY POINTS: · Low adherence to nationally endorsed protocols.. · Inconsistent physician follow-up to hypoxia.. · Reporting improved consistency with national policy..

Rethinking Pulse Oximetry Screening in the Level-IV Neonatal Intensive Care Unit.

OBJECTIVE: This study aimed to evaluate the outcomes of newborn pulse oximetry screening in a level IV, tertiary care neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study of neonates who received newborn pulse oximetry screening after being admitted to a single-center, level-IV NICU between 2014 and 2021. Neonates with known critical congenital heart disease were excluded from the study. RESULTS: Of the 4,493 neonates who had pulse oximetry screening, there were three positive screens (fail rate of 0.067%, 0.67 per 1,000 screened). The average age of screening was 818 hours. There were no positive screens of newborns who were admitted during their initial birth hospitalization and were screened while off oxygen. There were no new diagnoses of critical congenital heart disease (true positives) and there were no known false negatives. CONCLUSION: The results bring into question whether pulse oximetry screening with the current AAP-endorsed algorithm should be re-evaluated for a level-IV NICU at a children's hospital. However, the results may not be generalizable to other NICU's where echocardiography and prenatal echocardiograms are not as readily available. KEY POINTS: · Pulse oximetry has been shown to be effective in decreasing delayed diagnosis of critical congenital heart disease (CCHD); however, there are limited prior studies on newborn pulse oximetry in the NICU.. · In our study of over 4,000 neonates admitted to a level IV tertiary care NICU, there were no true positives (no new diagnoses of CCHD).. · Special considerations may be needed for pulse oximetry screening in the NICU setting..

Shifting the Paradigm: A Quality Improvement Approach to Proactive Cardiac Arrest Reduction in the Pediatric Cardiac Intensive Care Unit.

INTRODUCTION: Children with cardiac conditions are at higher risk of in-hospital pediatric cardiopulmonary arrest (CA), resulting in significant morbidity and mortality. Despite the elevated risk, proactive cardiac arrest prevention programs in the cardiac intensive care unit (CICU) remain underdeveloped. Our team developed a multidisciplinary program centered on developing a quality improvement (QI) bundle for patients at high risk of CA. METHODS: This project occurred in a 26-bed pediatric CICU of a tertiary care children's hospital. Statistical process control methodology tracked changes in CA rates over time. The global aim was to reduce CICU mortality; the smart aim was to reduce the CA rate by 50% over 12 months. Interprofessional development and implementation of a QI bundle included visual cues to identify high-risk patients, risk mitigation strategies, a new rounding paradigm, and defined escalation algorithms. Additionally, weekly event and long-term data reviews, arrest debriefs, and weekly unit-wide dissemination of key findings supported a culture change. RESULTS: After bundle implementation, CA rates decreased by 68% compared to baseline and 45% from the historical baseline. Major complications decreased from 17.1% to 12.6% (P < 0.001) and mortality decreased from 5.7% to 5.0% (P = 0.048). These results were sustained for 30 months. CONCLUSIONS: Cardiac arrest is a modifiable, rather than inevitable, metric in the CICU. Reduction is achievable through the interprofessional implementation of bundled interventions targeting proactive CA prevention. Once incorporated into widespread efforts to engage multidisciplinary CICU stakeholders, these patient-focused interventions resulted in sustained improvement.

Lessons Learned from Infants with Late Detection of Critical Congenital Heart Disease.

Late detection of critical congenital heart disease (CCHD) is multifactorial and ill defined. We investigated the results of pulse oximetry screening (POS) and points in the care chain that contribute to delayed detection of CCHD. The medical records of 13 infants with delayed detection at a single pediatric cardiac center between 2013 and 2016 were identified and reviewed. Left heart obstructive lesions were the most common diagnosis (n = 8; 62%) and included coarctation of the aorta (n = 6), interrupted aortic arch with ventricular septal defect (n = 1), and critical aortic stenosis (n = 1). Tetralogy of Fallot (TOF) (n = 2), truncus arteriosus (n = 1), pulmonary atresia with ventricular septal defect (n = 1), and total anomalous pulmonary venous drainage (n = 1) made up the remainder of the conditions. Routine prenatal care was reported in most infants (10/13). Infants with late detection had either a true negative POS (10/13 infants) or no POS performed (3/13 infants). At the time of detection, 5/6 (83%) infants with coarctation had normal pulse oximetry values, whereas 6/7 (86%) infants with other CCHD developed abnormal pulse oximetry values. At diagnosis, 11/13 (85%) infants had significant signs or symptoms of clinical deterioration; only 2 infants were completely asymptomatic. Late detection of CCHD is uncommon and multifactorial. Eliminating late detection is dependent upon improving detection on screening obstetrical ultrasounds, enforcement of universal POS, and attention to the neonatal physical exam.

Newborn Pulse Oximetry Screening at a Community Hospital: An 8-Year Experience.

OBJECTIVES: To evaluate newborn pulse oximetry screening (POS) outcomes at a large community hospital and the impact of the recommended revised POS algorithm. METHODS: A retrospective cohort study was performed to evaluate the results of POS in the well-infant nursery between 2012 and 2020. The POS results were obtained from an electronic platform. Chart review was completed for newborns with failed screens. The recommended revision to POS, no second rescreen, was applied to the data to evaluate screening outcomes. RESULTS: Of the total 65 414 infants admitted to the well-infant nursery during this 8-year period, >99% (n = 64 780) received POS. Thirty-one infants failed POS (4.6 per 10 000 screened). All infants who failed POS were found to have a disorder, with 12 (39%) having critical congenital heart disease (CCHD), 9 (29%) having non-CCHD requiring further follow-up, and 10 (32%) having noncardiac conditions. One false-negative screen result was identified through the Maryland Department of Health Newborn Screening Follow-up Program. The positive predictive value of POS for those screened was 39% for CCHD, with a specificity of 99.97%. Eliminating the second rescreen in the POS algorithm would have resulted in an additional 5 newborns without CCHD failing POS, increasing the false-positive rate from 0.03% to 0.04%. CONCLUSIONS: POS is an effective tool for identifying CCHD and secondary conditions. POS was successfully implemented with few missed screens and was highly specific. Elimination of the second rescreen in the pulse oximetry algorithm would have resulted in a minimal increase in false-positive results and faster evaluation of newborns with CCHD.

Development of an international standard set of clinical and patient-reported outcomes for children and adults with congenital heart disease: a report from the International Consortium for Health Outcomes Measurement Congenital Heart Disease Working Group.

AIMS: Congenital heart disease (CHD) is the most common congenital malformation. Despite the worldwide burden to patient wellbeing and health system resource utilization, tracking of long-term outcomes is lacking, limiting the delivery and measurement of high-value care. To begin transitioning to value-based healthcare in CHD, the International Consortium for Health Outcomes Measurement aligned an international collaborative of CHD experts, patient representatives, and other stakeholders to construct a standard set of outcomes and risk-adjustment variables that are meaningful to patients. METHODS AND RESULTS: The primary aim was to identify a minimum standard set of outcomes to be used by health systems worldwide. The methodological process included four key steps: (i) develop a working group representative of all CHD stakeholders; (ii) conduct extensive literature reviews to identify scope, outcomes of interest, tools used to measure outcomes, and case-mix adjustment variables; (iii) create the outcome set using a series of multi-round Delphi processes; and (iv) disseminate set worldwide. The Working Group established a 15-item outcome set, incorporating physical, mental, social, and overall health outcomes accompanied by tools for measurement and case-mix adjustment variables. Patients with any CHD diagnoses of all ages are included. Following an open review process, over 80% of patients and providers surveyed agreed with the set in its final form. CONCLUSION: This is the first international development of a stakeholder-informed standard set of outcomes for CHD. It can serve as a first step for a lifespan outcomes measurement approach to guide benchmarking and improvement among health systems.

Pulse Oximetry and Congenital Heart Disease Screening: Results of the First Pilot Study in Morocco.

Congenital heart disease (CHD) is the most common congenital malformation. Diagnosis of critical congenital heart disease (CCHD), the most severe type of congenital heart disease, in a newborn may be difficult. The addition of CCHD screening, using pulse oximetry, to clinical assessment significantly improves the rate of detection. We conducted a pilot study in Morocco on screening neonates for critical congenital heart disease. This study was conducted in the maternity ward of Mohammed VI University Hospital of Marrakesh, Morocco, and included asymptomatic newborns delivered between March 2019 and January 2020. The screening of CCHD was performed by pulse oximetry measuring the pre- and post-ductal saturation. Screening was performed on 8013/10,451 (76.7%) asymptomatic newborns. According to the algorithm, 7998 cases passed the screening test (99.82%), including one inconclusive test that was repeated an hour later and was normal. Fifteen newborns failed the screening test (0.18%): five CCHD, five false positives, and five CHD but non-critical. One false negative case was diagnosed at 2 months of age. Our results encourage us to strengthen screening for CCHD by adding pulse oximetry to the routine newborn screening panel.

Newborn Critical Congenital Heart Disease Screening Using Pulse Oximetry: Value and Unique Challenges in Developing Regions.

Newborn screening for critical congenital heart disease (CCHD) is recommended for implementation in many developed countries as the standard of care. Efforts to implement this point of care screen in developing regions face unique barriers, and present important opportunities. The First Pan-African Newborn Screening Conference, held in Rabat in June 2019, incorporated a workshop dedicated specifically to identifying and discussing CCHD screening issues in the Middle East Northern Africa (MENA) region. The issues explored may be beneficial as part of the greater discussion of CCHD screening's growing importance in developing regions around the world. Screening experts presented education and lessons learned from previous CCHD implementations, including a hands-on technical demonstration of CCHD screening. Children's HeartLink, The Newborn Foundation, and Children's National Hospital each presented on their experiences working with teams and pilot projects from around the world. Experience in implementation from Children's Hospital Marrakesh was presented and highlighted some of the unique findings, challenges, and experiences of screening in Morocco. As developing regions investigate the implementation of CCHD screening using pulse oximetry either as part of research studies, pilots, regional studies, or as part of a nationally supported program, data to inform policymakers on the benefits of screening and specific needs for infrastructure development and resources are essential. This special issue contains initial lessons learned on newborn CCHD screening from a select number of developing countries, including Saudi Arabia and Morocco and regions such as Latin America.

Updated Strategies for Pulse Oximetry Screening for Critical Congenital Heart Disease.

Seven years after its addition to the US Recommended Uniform Screening Panel, newborn screening for critical congenital heart disease (CCHD) using pulse oximetry became mandatory in the United States. Although CCHD newborn screening reduces morbidity and mortality, there remain important opportunities to improve. An expert panel convened for a 1-day meeting in September 2018, including subject matter experts and representatives from stakeholder organizations. Presentations on CCHD outcomes, variations in approach to screening, and data and quality improvement helped identify improvement opportunities. The expert panel concluded that sufficient evidence exists to recommend modifying the current American Academy of Pediatrics algorithm by (1) requiring an oxygen saturation of at least 95% in both (formerly either) the upper and lower extremities to pass and (2) requiring only 1 repeat screen instead of 2 for cases that neither pass nor fail initially. The panel underscored the importance of improving public health reporting by further specifying the targets of screening and criteria for reporting outcomes (false-negative and false-positive cases). The panel also highlighted the need to ensure sufficient public health funding for CCHD newborn screening and opportunities for education and global implementation. Newborn screening for CCHD using pulse oximetry has led to significant improvements in child health outcomes. However, further important work is required to understand and improve the effectiveness and efficiency of screening.

Quality Improvement Interventions to Improve Critical Congenital Heart Disease Screening.

Newborn screening for critical congenital heart disease (CCHD) using pulse oximetry improves detection and is associated with decreased related infant mortality. In 2015, the Healthy Hearts of Babies Act required hospitals to screen all newborns in the District of Columbia for CCHD using pulse oximetry and to provide documentation of individual screening results to the Department of Health. A regulatory report from the electronic health record revealed an opportunity to improve both documentation and protocol adherence within our hospital. We aimed to reduce documentation errors and protocol violations by 75% and sustain this improvement for 6 months. METHODS: In February of 2014, our center, a large free-standing children's hospital, implemented CCHD screening in the neonatal intensive care unit on all infants without known congenital heart disease or receiving supplemental oxygen. During the intervention period (January 2016 to December 2018), an interdisciplinary team engaged in regular review and analysis of reports, monthly closed-loop feedback, and iterative refinements to the electronic health record. Statistical process control charts were used to compare a baseline period to the intervention period and track monthly progress. RESULTS: Between February 2014 and December 2018, we screened 2,214 infants for CCHD. The average percentage of documentation errors decreased from 23.5% during the baseline period to 1.2% during the intervention period, a sustained reduction for over 2 years. Protocol violations occurred at an average of 2.1% in the baseline period, with a sustained decrease to 0.6% during the intervention period. CONCLUSIONS: This multimodal quality improvement project demonstrated a sustained reduction of CCHD screening documentation errors and protocol violations.

Updates in Congenital Heart Disease: Can Outcomes Improve?

Despite numerous advances in medical and surgical management, congenital heart disease (CHD) remains the number one cause of death in the first year of life from congenital malformations. The current strategies used to approach improving outcomes in CHD are varied. This article will discuss the recent impact of pulse oximetry screening for critical CHD, describe the contributions of advanced cardiac imaging in the neonate with CHD, and highlight the growing importance of quality improvement and safety programs in the cardiac intensive care unit.

Newborn Critical Congenital Heart Disease Screening Using Pulse Oximetry: Nursing Aspects.

Congenital heart disease (CCHD) is the most common birth defect. Screening for the most critical forms (CCHD) using pulse oximetry was added to the Recommended Uniform Screening Panel in the United States in 2011. Since then, CCHD screening has become nearly universal in the United States. Nurses are ideally situated to contribute to the development of best practices for implementation and provide education to families on CCHD screening. Much of the standardization, advocacy, and development of national recommendations occurred with key input from nurses. Nurses often have responsibility for educating parents, performing the screening, interpreting the screening algorithm, and the documentation of results. The nurse role often includes implementing follow-up quality improvement initiatives to ensure that systematic and accurate screening occurs. Smooth implementation can be achieved by identifying champions early, obtaining input from a multidisciplinary team including both physician and nursing leaders, and identifying ways to integrate screening into already existing workflow. By knowing the basics of why screening is important, how to screen, current recommendations on the follow-up for positive screens and the limitations of CCHD screening, nurses can advocate for their patients and positively impact outcomes for infants born with CCHD through early identification before discharge.

The Impact of a Designated Cardiology Team Involving Telemedicine Home Monitoring on the Care of Children with Single-Ventricle Physiology After Norwood Palliation.

We evaluated the effect of an interdisciplinary single-ventricle task force (SVTF) that utilizes a family-driven, telemedicine home monitoring program on clinical outcomes of stage II admissions and its acceptance by parents and cardiologists. Study population was divided into two cohorts, one with Norwood surgery dates before the SVTF (pre-SVTF) and one interventional (post-SVTF). Post-SVTF data also included surveys of parents and cardiologists on the efficacy of the SVTF. Comparative and multivariate statistical testing was performed. Compared to the pre-SVTF group, the post-SVTF group had lower complications after stage II (18.4 vs. 34.1 %, p = 0.02), higher weight-for-age z scores at stage II (-1.5 ± 0.97 vs. -1.58 ± 1.34, p = 0.02) and were less likely to have a stage II weight-for-age z score below -2 (26.5 vs. 31.7 %, p = 0.03). A multivariate regression analysis showed providing a written red-flag action plan to parents at discharge was independently associated with higher weight at stage II (ß = 0.42, p = 0.04) and higher weight-for-age z score (ß = 0.48, p = 0.02). Parents' satisfaction with SVTF (α = 0.97) was 4.34 ± 0.62; (95 % CI 4.01-4.67) and cardiologists' acceptance (α = 0.93) was 4.1 ± 0.7 (95 % CI 3.79-4.42). Development of SVTF was associated with a reduction in complications post-stage II and improved weight status at stage II. A written red-flag action plan provided to parents at the time of Norwood discharge was associated with higher weight status at stage II. Parents and cardiologists expressed satisfaction with the utility of SVTF and encouraged expansion to cover all children with congenital heart disease.

Legal and Ethical Considerations in Allowing Parental Exemptions From Newborn Critical Congenital Heart Disease (CCHD) Screening.

Critical congenital heart disease (CCHD) screening is rapidly becoming the standard of care in the United States after being added to the Recommended Uniform Screening Panel (RUSP) in 2011. Newborn screens typically do not require affirmative parental consent. In fact, most states allow parents to exempt their baby from receiving the required screen on the basis of religious or personally held beliefs. There are many ethical considerations implicated with allowing parents to exempt their child from newborn screening for CCHD. Considerations include the treatment of religious exemptions in our current legal system, as well as medical and ethical principles in relation to the rights of infants. Although there are significant benefits to screening newborns for CCHD, when a parent refuses for religious or personal beliefs, in the case of CCHD screening, the parental decision should stand.

U.S. international efforts on critical congenital heart disease screening: can we have a uniform recommendation for Europe?

An estimated 90% of births or more in the United States will be screened for critical congenital heart disease (CCHD) by the end of 2014. Europe has made less progress despite providing the population-based studies that were critical in driving support for efforts within the United States. Congenital Heart Disease (CHD) advocacy groups, investigators in screening for CCHD and international health organizations have been meeting with health care providers and government officials on a country by country basis. Countries that are implementing or have pilot projects have been identified to track global implementation. The Nordic countries, the United States, Switzerland and the United Arab Emirates are closest to universal screening for CCHD in newborns. Significant pilot projects tailored to unique care delivery systems screen through the use of midwives in the Netherlands, on maternity wards in the United Kingdom and while developing newborn care infrastructure in China. In Africa, South and Central America, individual countries are in the early stages of organization. Screening for CCHD is spreading across the globe. Early recognition has the ability to improve care in countries providing CHD treatment and prepare parents for adverse events in countries where care is not accessible. Impact of screening in regions with less access to intervention will be important to track.

Glis3 regulates neurogenin 3 expression in pancreatic ß-cells and interacts with its activator, Hnf6.

The Krüppel-like zinc finger transcription factor, Glis3, has been associated with neonatal diabetes in humans and mice, and implicated in the regulation of pancreatic ß-cell generation. However, its precise function in the development of pancreatic ß-cells has not yet been elucidated. In this study, we provide evidence that Glis3 regulates Neurogenin 3 (Ngn3) through its distal promoter region. Previous studies showed that the distal region and proximal region of Ngn3 promoter contains various transcription binding sites, including binding sites for pancreatic and duodenal homeobox 1 (Pdx1), Hnf1ß and Hnf6. Interestingly, putative Glis3 binding sites (Glis3BS) were found in the distal region of Ngn3 promoter close to the Hnf6 binding sites. This suggested that along with Hnf6, Glis3 may also be involved in the regulation of Ngn3 expression. This hypothesis is supported by data showing that Glis3 can bind to the Ngn3 promoter directly and activate Ngn3 transcriptional activity. Additionally, Glis3 can interact directly with Hnf6 in vitro and in vivo. The amino-terminus in Glis3 and the homeodomain of Hnf6 are critical for this interaction. These data suggest that crosstalk between Glis3 and Hnf6 may play an important role in the regulation of Ngn3 during pancreatic endocrine progenitor cell specification and development.