Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.

Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically.

Implementation of a Neonatal Audit Tool to Drive Quality Initiatives.

Audit tools optimize the delivery of healthcare to patients. A network of 11 neonatal intensive care units (NICUs) affiliated with a large urban pediatric care institution implemented an audit tool for use on daily patient rounds. The article reports findings collected from 2011 to 2016. METHODS: Primary drivers for implementation were (1) engagement from local providers; (2) identification of local improvement needs and improvement progress; (3) ability to customize audit questions based on local needs; (4) encouragement of information sharing between NICUs; and (5) improving measurable outcomes in neonatal care delivery. The Level IV NICU managed and refined a centralized process for managing site-specific tools, data analysis, and reporting. Each NICU customized the number and wording of action questions based on their needs. Answer choices were limited to "yes" or "no," which corresponded to favorable or unfavorable actions toward the patient. Users also answered, "Was action taken as a result of an unfavorable response?" RESULTS: Plan-Do-Study-Action cycles were completed to refine the tool and its implementation process. Adherence was variable among and within each network site. Across the network, 11.4% of actions tracked by the audit indicated improvement over time. CONCLUSION: Generalized use of the Audit Tool resulted in limited optimization of care actions addressed in the NICUs. Success depended on multi-disciplinary, multi-professional teamwork, respect for local autonomy, and leadership support. Increasing the use of the Audit Tool likely depends on the team's ability to evolve the tool's intrinsic value from a reminder to a monitoring system.

Increasing Immunization Rates in Infants with Severe Chronic Lung Disease: A Quality Improvement Initiative.

OBJECTIVES: Immunizations provide important protection from serious childhood illnesses. Infant chronic lung disease (CLD) is a serious complication of prematurity and predisposes premature infants to respiratory morbidity, rehospitalization, and mortality. This high-risk group is especially vulnerable to infections, such as invasive pneumococcal disease, influenza, and bronchiolitis. Our purpose for this project was to increase 2-, 4-, and 6-month immunization rates in eligible infants with CLD in the NICU by 30% through December 2016. METHODS: A multidisciplinary team developed weekly targeted rounds to identify eligible patients with outstanding immunizations. Exclusion criteria included the following: (1) a fraction of inspired oxygen requirement of >80%, (2) pulmonary hypertensive crisis, (3) positive blood culture results or if within 48 hours of a sepsis evaluation, (4) if within 5 days of a surgical or interventional procedure, (5) receiving steroid treatment (not including a physiologic hydrocortisone dose for adrenal insufficiency), (6) a CLD team consensus of contraindication, and (7) parental refusal. RESULTS: The project managed 60 patients from March 2016 to December 2016. Immunization of eligible patients increased from 44% to 75% and was sustained for the next 6 months. The average number of days from admission to immunization record review decreased from 71 days at baseline to 27 days. CONCLUSIONS: The implementation of (1) an in-hospital immunization record review, (2) an e-mail reminder, (3) a weekly multidisciplinary eligibility discussion, and (4) an updated rounding tool was successful in increasing and sustaining immunization rates in this population of infants with CLD. The multidisciplinary CLD meeting was a novel opportunity to discuss immunization eligibility and safety monitoring.

Issues related to providing quality pediatric palliative care in the community.

The medical practitioner in the community is in a unique position to assist children and their families from the time of diagnosis with a life-threatening condition through to the end of life. The purpose of this article is to inform medical practitioners who care for children with complex, chronic, and life-limiting conditions about pediatric palliative care in the community. It is intended as a guide to improve understanding about (1) the misconceptions and barriers surrounding the provision of care in the community for children with chronic, complex, and life-limiting conditions; (2) the availability of services for care in the community; (3) challenges concerning out-of hospital do-not-attempt-resuscitation orders for children; and (4) reimbursement issues that impact the provision of care.

Psychosocial and spiritual needs of children living with a life-limiting illness.

Quality end-of-life care includes the management of distressing symptoms; provisions of care, including the assessment and management of psychosocial and spiritual needs; and respite from diagnosis through death and bereavement. Meeting the palliative care goal of improved quality of life depends on medical and nursing practitioners understatnding and effectively assessing psychosocial symptoms.

Partners in pediatric palliative care: a program to enhance collaboration between hospital and community palliative care services.

The provision of high-quality palliative care services to dying children and their families often requires extensive collaboration between hospital-based and community-based care teams. This article describes the origins and development of the Partners in Pediatric Palliative Care program, which has provided pediatric-specific educational offerings and fostered joint endeavors between a palliative care service located in a tertiary care children's hospital and a wide range of hospice and home care agencies in 5 states. The Partners in Pediatric Palliative Care program is evaluated in terms of the favorable ratings that attendees have given the educational components, the relatively modest direct costs of mounting the regional meetings, and the expanded capacity to provide home-based palliative services to children and families who desire them. The Partners in Pediatric Palliative Care program provides another feasible means for hospitals and community agencies to work together to improve pediatric palliative care.

Pediatric palliative, end-of-life, and bereavement care.

The pediatric hospitalist plays an integral role in providing palliative, end-of-life, and bereavement care for children and families. This article focuses on a multifaceted approach to this domain of care in which the physician is a key member of an interdisciplinary team. We believe that we can improve quality of life and relieve suffering only by paying attention to the medical, emotional, spiritual, and practical needs and goals of dying children and their loved ones.

Pediatric do-not-attempt-resuscitation orders and public schools: a national assessment of policies and laws.

Some children living with life-shortening medical conditions may wish to attend school without the threat of having resuscitation attempted in the event of cardiopulmonary arrest on the school premises. Despite recent attention to in-school do-not-attempt-resuscitation (DNAR) orders, no assessment of state laws or school policies has yet been made. We therefore sought to survey a national sample of prominent school districts and situate their policies in the context of relevant state laws. Most (80%) school districts sampled did not have policies, regulations, or protocols for dealing with student DNARs. A similar majority (76%) either would not honor student DNARs or were uncertain about whether they could. Frequent contradictions between school policies and state laws also exist. Consequently, children living with life-shortening conditions who have DNARs may not have these orders honored if cardiopulmonary arrest were to occur on school premises. Coordinated efforts are needed to harmonize school district, state, and federal approaches in order to support children and families' right to have important medical decisions honored.

TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage.

Tyrosyl DNA phosphodiesterase (TDP1) is a DNA 3'-end processing enzyme that preferentially hydrolyses the bond between the 3'-end of DNA and stalled DNA topoisomerase 1. the importance of TDP1 is highlighted by its association with the human genetic disease spinocerebellar ataxia with axonal neuropathy. TDP1 comprises of a highly conserved C-terminus phosphodiesterase domain and a less conserved N-terminus tail. the importance of the N-terminus domain was suggested by its interaction with Lig3alpha. Here we show that this interaction is promoted by serine 81 that is located within a putative S/TQ site in the N-terminus domain of TDP1. Although mutation of serine 81 to alanine had no impact on TDP1 activity in vitro and had little impact on the ability of TDP1 to mediate the rapid repair of CPT- or IR-induced DNA breaks in vivo, it led to marked reduction of protein stability. Moreover, it reduced the ability of TDP1 to promote cell survival following genotoxic stress. Together, our findings highlight a novel mechanism for regulating TDP1 function in mammalian cells that is not directly related to its enzymatic activity.