APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

Obesity-induced tissue alterations resist weight loss: A mechanistic review.

Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity-induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate ß-adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic-mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin-α4 deposition mitigates WAT accumulation, enhances browning, and protects against high-fat-diet-induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity-associated sarcopenia. Additionally, obesity suppresses sarcolipin-induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.

A parental communication assessment initiative in the paediatric cardiovascular ICU.

OBJECTIVE: Challenges to communication between families and care providers of paediatric patients in intensive care units (ICU) include variability of communication preferences, mismatched goals of care, and difficulties carrying forward family preferences from provider to provider. Our objectives were to develop and test an assessment tool that queries parents of children requiring cardiac intensive care about their communication preferences and to determine if this tool facilitates patient-centred care and improves families' ICU experience. DESIGN: In this quality improvement initiative, a novel tool was developed, the Parental Communication Assessment (PCA), which asked parents with children hospitalised in the cardiac ICU about their communication preferences. Participants were prospectively randomised to the intervention group, which received the PCA, or to standard care. All participants completed a follow-up survey evaluating satisfaction with communication. MAIN RESULTS: One hundred thirteen participants enrolled and 56 were randomised to the intervention group. Participants who received the PCA preferred detail-oriented communication over big picture. Most parents understood the daily discussions on rounds (64%) and felt comfortable expressing concerns (68%). Eighty-six percent reported the PCA was worthwhile. Parents were generally satisfied with communication. However, an important proportion felt unprepared for difficult decisions or setbacks, inadequately included or supported in decision-making, and that they lacked control over their child's care. There were no significant differences between the intervention and control groups in their communication satisfaction results. CONCLUSIONS: Parents with children hospitalised in the paediatric ICU demonstrated diverse communication preferences. Most participants felt overall satisfied with communication, but individualising communication with patients' families according to their preferences may improve their experience.

Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

The Association Between Central Line-Associated Bloodstream Infection and Central Line Access.

OBJECTIVES: Identifying modifiable risk factors associated with central line-associated bloodstream infections (CLABSIs) may lead to modifications to central line (CL) management. We hypothesize that the number of CL accesses per day is associated with an increased risk for CLABSI and that a significant fraction of CL access may be substituted with non-CL routes. DESIGN: We conducted a retrospective cohort study of patients with at least one CL device day from January 1, 2015, to December 31, 2019. A multivariate mixed-effects logistic regression model was used to estimate the association between the number of CL accesses in a given CL device day and prevalence of CLABSI within the following 3 days. SETTING: A 395-bed pediatric academic medical center. PATIENTS: Patients with at least one CL device day from January 1, 2015, to December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 138,411 eligible CL device days across 6,543 patients, with 639 device days within 3 days of a CLABSI (a total of 217 CLABSIs). The number of per-day CL accesses was independently associated with risk of CLABSI in the next 3 days (adjusted odds ratio, 1.007; 95% CI, 1.003-1.012; p = 0.002). Of medications administered through CLs, 88% were candidates for delivery through a peripheral line. On average, these accesses contributed a 6.3% increase in daily risk for CLABSI. CONCLUSIONS: The number of daily CL accesses is independently associated with risk of CLABSI in the next 3 days. In the pediatric population examined, most medications delivered through CLs could be safely administered peripherally. Efforts to reduce CL access may be an important strategy to include in contemporary CLABSI-prevention bundles.

Blocking FSH induces thermogenic adipose tissue and reduces body fat.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.

Surgical scheduling via optimization and machine learning with long-tailed data : Health care management science, in press.

Using data from cardiovascular surgery patients with long and highly variable post-surgical lengths of stay (LOS), we develop a modeling framework to reduce recovery unit congestion. We estimate the LOS and its probability distribution using machine learning models, schedule procedures on a rolling basis using a variety of optimization models, and estimate performance with simulation. The machine learning models achieved only modest LOS prediction accuracy, despite access to a very rich set of patient characteristics. Compared to the current paper-based system used in the hospital, most optimization models failed to reduce congestion without increasing wait times for surgery. A conservative stochastic optimization with sufficient sampling to capture the long tail of the LOS distribution outperformed the current manual process and other stochastic and robust optimization approaches. These results highlight the perils of using oversimplified distributional models of LOS for scheduling procedures and the importance of using optimization methods well-suited to dealing with long-tailed behavior.

Team Communication and Expectations Following Pediatric Cardiac Surgery: A Multi-Disciplinary Survey.

Patients and families desire an accurate understanding of the expected recovery following congenital cardiac surgery. Variation in knowledge and expectations within the care team may be under-recognized and impact communication and care delivery. Our objective was to assess knowledge of common postoperative milestones and perceived efficacy of communication with patients and families and within the care team. An 18-question survey measuring knowledge of expected milestones for recovery after four index operations and team communication in the postoperative period was distributed electronically to multidisciplinary care team members at 16 academic pediatric heart centers. Answers were compared to local median data for each respondent's heart center to assess accuracy and stratified by heart center role and years of experience. We obtained 874 responses with broad representation of disciplines. More than half of all respondent predictions (55.3%) did not match their local median data. Percent matching did not vary by care team role but improved with increasing experience (35.8% < 2 years vs. 46.4% > 10 years, p = 0.2133). Of all respondents, 62.7% expressed confidence discussing the anticipated postoperative course, 78.6% denoted confidence discussing postoperative complications, and 55.3% conveyed that not all members of their care team share a common expectation for typical postoperative recovery. Most respondents (94.6%) stated that increased knowledge of local data would positively impact communication. Confidence in communication exceeded accuracy in predicting the timing of postoperative milestones. Important variation in knowledge and expectations for postoperative recovery in pediatric cardiac surgery exists and may impact communication and clinical effectiveness.

E4orf1-induced reduction in endogenous insulin level is independent of pancreas endocrine function.

BACKGROUND: Obesity is often associated with hyperinsulinemia due to insulin resistance. In mice models of hyperinsulinemia, adenovirus-derived E4orf1 protein promotes glucose disposal via insulin-independent pathway, and reduces insulin response to glucose load, described as its "Insulin Sparing Action". This is likely because less insulin is needed for disposing glucose in presence of E4orf1, however, there are other potential possibilities. This study determined if E4orf1 reduces insulin response to glucose load because it a) suppresses the ability of pancreatic ß-cells to secret insulin, or b) upregulates glucagon production by the pancreas. METHODS: C57BL/6J wild type (control) and transgenic C57BL/6J (E4orf1) mice that express E4orf1 protein in adipose tissue upon doxycycline feeding, were used. Post-doxycycline feeding, insulin and glucagon secretion in response to glibenclamide or phenylephrine were compared between the two groups. The pancreases were examined for histological changes. RESULTS: In response to glibenclamide, E4orf1 mice secreted more insulin and exhibited lower blood glucose compared to control (47.4 ± 4.4 vs 27.4 ± 3.7 mg/dl, p < 0.003), but showed no difference in glucagon secretion. Post-phenylephrine injection, no differences were observed between the two groups for glucagon or insulin, except E4orf1 mice had a lower blood glucose rise after 10-min of injection compared to the control (39.7 ± 4.7 vs. 58.3 ± 7.5 mg/dl, p < 0.05). E4orf1 mice had significantly larger pancreatic islets and higher number of islets per mm2 tissue area. Neither the size nor the number of islets met the criteria of hypertrophy or hyperplasia. CONCLUSIONS/INTERPRETATION: E4orf1 retains and may enhance the ability of the pancreases to secret insulin in response to insulin secretagogue. Glucagon does not seem to play a role in the Insulin Sparing Action of E4orf1. Overall, the histology studies support better pancreatic islet health in presence of E4orf1, compared to that in control mice. The "insulin-independent" role of E4orf1 has potential therapeutic implications in addressing hyperinsulinemia in obesity.

Early Functional Status After Surgery for Congenital Heart Disease: A Single-Center Retrospective Study.

OBJECTIVES: The objective of this study is to investigate the change in functional status in infants, children, and adolescents undergoing congenital heart surgery using the Functional Status Scale. DESIGN: A single-center retrospective study. SETTING: A 26-bed cardiac ICU in a free-standing university-affiliated tertiary children's hospital. PATIENTS: All patients 0-18 years who underwent congenital heart surgery from January 1, 2014, to December 31, 2017. INTERVENTIONS: None. MEASUREMENTS AND MIN RESULTS: The primary outcome variable was change in Functional Status Scale scores from admission to discharge. Additionally, two binary outcomes were derived from the primary outcome: new morbidity (change in Functional Status Scale ≥ 3) and unfavorable functional outcome (change in Functional Status Scale ≥ 5); their association with risk factors was assessed using modified Poisson regression. Out of 1,398 eligible surgical encounters, 65 (4.6%) and 15 (1.0%) had evidence of new morbidity and unfavorable functional outcomes, respectively. Higher Surgeons Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass time were associated with new morbidity. Longer hospital length of stay was associated with both new morbidity and unfavorable outcome. CONCLUSIONS: This study demonstrates the novel application of the Functional Status Scale on patients undergoing congenital heart surgery. New morbidity was noted in 4.6%, whereas unfavorable outcome in 1%. There was a small change in the total Functional Status Scale score that was largely attributed to changes in the feeding domain. Higher Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass times were associated with new morbidity, whereas longer hospital length of stay was associated with both new morbidity and unfavorable outcome. Further studies with larger sample size will need to be done to confirm our findings and to better ascertain the utility of Functional Status Scale on this patient population.

Standardized Training for Physicians Practicing Pediatric Cardiac Critical Care.

OBJECTIVES: In the vast majority of Children's Hospitals, the critically ill patient can be found in one of three locations: the PICU, the neonatal ICU, and the cardiac ICU. Training, certification, and maintenance of certification for neonatology and critical care medicine are over seen by the Accreditation Council for Graduate Medical Education and American Board of Pediatrics. There is no standardization of training or oversight of certification and maintenance of certification for pediatric cardiac critical care. DATA SOURCES: The curricula from the twenty 4th year pediatric cardiac critical care training programs were collated, along with the learning objectives from the Pediatric Cardiac Intensive Care Society published "Curriculum for Pediatric Cardiac Critical Care Medicine." STUDY SELECTION: This initiative is endorsed by the Pediatric Cardiac Intensive Care Society as a first step toward Accreditation Council for Graduate Medical Education oversight of training and American Board of Pediatrics oversight of maintenance of certification. DATA EXTRACTION: A taskforce was established of cardiac intensivists, including the directors of all 4th year pediatric cardiac critical care training programs. DATA SYNTHESIS: Using modified Delphi methodology, learning objectives, rotational requirements, and institutional requirements for providing training were developed. CONCLUSIONS: In the current era of increasing specialized care in pediatric cardiac critical care, standardized training for pediatric cardiac critical care is paramount to optimizing outcomes.

Post-operative Morbidity and Mortality After Fontan Procedure in Patients with Heterotaxy and Other Situs Anomalies.

Heterotaxy is a complex, multisystem disorder associated with single ventricle heart disease and decreased survival. Ciliary dysfunction is common in heterotaxy and other situs abnormalities (H/SA) and may increase post-operative complications. We hypothesized that patients with H/SA have increased respiratory and renal morbidities and increased in-hospital mortality after Fontan procedure. We queried the Pediatric Health Information System database for hospitalizations with ICD-9/10 codes for Fontan procedure in patients aged 1 through 11 years from 2004 to 2019. H/SA was identified by codes for dextrocardia, situs inversus, asplenia/polysplenia, or atrial isomerism and compared to non-H/SA controls. Outcomes were in-hospital mortality or heart transplantation, ECMO, hemodialysis, length of stay (LOS), and mechanical ventilation or vasoactive medication use ≥ 4 days. We adjusted estimates with multivariable logistic regression. Of 7897 patients at 50 centers, 1366 (17%) met criteria for H/SA. H/SA had worse outcomes for all study measures: death/transplantation (1.9 vs 1.1%, OR 1.74 (95% CI 1.01-3.03); p = 0.047), ECMO (3.7 vs 2.3%, OR 1.74 (1.28-2.35); p < 0.001), hemodialysis (2.1 vs 1.2%, OR 1.66 (1.06-2.59); p = 0.026), prolonged mechanical ventilation (13.2% vs 7.6%, OR 1.85 (1.53-2.25); p < 0.001) and vasoactive medication use (29.4 vs 19.7%, OR 1.65 (1.43-1.90), and longer LOS (11 (8-17) vs 9 (7-14) days; p < 0.001). H/SA is associated with increased cardiovascular, renal, and respiratory morbidity, as well as in-hospital mortality after Fontan procedure. Attention to renal and respiratory needs may improve outcomes in this difficult population. The relationship between ciliary dysfunction and lung and renal morbidity should be explored further.

Assessment of physician training and prediction of workforce needs in paediatric cardiac intensive care in the United States.

OBJECTIVE: To assess the training and the future workforce needs of paediatric cardiac critical care faculty. DESIGN: REDCap surveys were sent May-August 2019 to medical directors and faculty at the 120 US centres participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Faculty and directors were asked about personal training pathway and planned employment changes. Directors were additionally asked for current faculty numbers, expected job openings, presence of training programmes, and numbers of trainees. Predictive modelling of the workforce was performed using respondents' data. Patient volume was projected from US Census data and compared to projected provider availability. MEASUREMENTS AND MAIN RESULTS: Sixty-six per cent (79/120) of directors and 62% (294/477) of contacted faculty responded. Most respondents had training that incorporated critical care medicine with the majority completing training beyond categorical fellowship. Younger respondents and those in dedicated cardiac ICUs were more significantly likely to have advanced training or dual fellowships in cardiology and critical care medicine. An estimated 49-63 faculty enter the workforce annually from various training pathways. Based on modelling, these faculty will likely fill current and projected open positions over the next 5 years. CONCLUSIONS: Paediatric cardiac critical care training has evolved, such that the majority of faculty now have dual fellowship or advanced training. The projected number of incoming faculty will likely fill open positions within the next 5 years. Institutions with existing or anticipated training programmes should be cognisant of these data and prepare graduates for an increasingly competitive market.

Metformin effectively restores the HPA axis function in diet-induced obese rats.

INTRODUCTION: The hypothalamo-pituitary-adrenal (HPA) axis is perturbed in obesity. We previously reported presence of leptin resistance in the brainstem and uncoupling between central noradrenergic tone and the HPA axis in obesity-prone (DIO) rats. Metformin is shown to lower body weight and adiposity, but the underlying mechanism is unclear. We hypothesized that this is associated with restored HPA axis function. METHODS: Adult male DIO rats were placed on either a regular chow or HF diet for 7 weeks. Starting week 4, the animals were given either a low dose (60 mg/kg) or high dose (300 mg/kg) of metformin in drinking water. In addition to body weight and feeding, we examined different arms of the HPA axis to test if metformin can reinstate its function and coupling. To understand potential mechanisms, leptin signaling in the brainstem and circulating free fatty acid levels were also assessed. RESULTS: Metformin treatment lowered weight gain, fat mass, caloric intake, and serum leptin levels. HPA axis activity as determined by corticotropin-releasing hormone in the median eminence and serum corticosterone was decreased by metformin in a dose-dependent manner, and so was norepinephrine (NE) in the paraventricular nucleus. Importantly, metformin completely normalized the NE-HPA axis uncoupling. While brainstem pSTAT-3 and SOCS-3, key markers of leptin signaling, were not different between groups, circulating saturated and unsaturated free fatty acids were reduced in HF-fed, metformin-treated animals. CONCLUSIONS: These findings suggest that oral metformin can successfully correct HPA axis dysfunction that is associated with lowered circulating free fatty acids in DIO rats, thereby uncovering a novel effect of metformin in the treatment of obesity.

Target-Based Care: An Intervention to Reduce Variation in Postoperative Length of Stay.

OBJECTIVES: To derive care targets and evaluate the impact of displaying them at the point of care on postoperative length of stay (LOS). STUDY DESIGN: A prospective cohort study using 2 years of historical controls within a freestanding, academic children's hospital. Patients undergoing benchmark cardiac surgery between May 4, 2014, and August 15, 2016 (preintervention) and September 6, 2016, to September 30, 2018 (postintervention) were included. The intervention consisted of displaying at the point of care targets for the timing of extubation, transfer from the intensive care unit (ICU), and hospital discharge. Family satisfaction, reintubation, and readmission rates were tracked. RESULTS: The postintervention cohort consisted of 219 consecutive patients. There was a reduction in variation for ICU (difference in SD -2.56, P < .01) and total LOS (difference in SD -2.84, P < .001). Patients stayed on average 0.97 fewer days (P < .001) in the ICU (median -1.01 [IQR -2.15, -0.39]), 0.7 fewer days (P < .001) on mechanical ventilation (median -0.54 [IQR -0.77, -0.50]), and 1.18 fewer days (P < .001) for the total LOS (median -2.25 [IQR -3.69, -0.15]). Log-transformed multivariable linear regression demonstrated the intervention to be associated with shorter ICU LOS (ß coefficient -0.19, SE 0.059, P < .001), total postoperative LOS (ß coefficient -0.12, SE 0.052, P = .02), and ventilator duration (ß coefficient -0.21, SE 0.048, P < .001). Balancing metrics did not differ after the intervention. CONCLUSIONS: Target-based care is a simple, novel intervention associated with reduced variation in LOS and absolute LOS across a diverse spectrum of complex cardiac surgeries.

Hyperoxia During Cardiopulmonary Bypass Is Associated With Mortality in Infants Undergoing Cardiac Surgery.

OBJECTIVES: Patients undergoing cardiac surgery using cardiopulmonary bypass have variable degrees of blood oxygen tension during surgery. Hyperoxia has been associated with adverse outcomes in critical illness. Data are not available regarding the association of hyperoxia and outcomes in infants undergoing cardiopulmonary bypass. We hypothesize that among infants undergoing cardiac surgery, hyperoxia during cardiopulmonary bypass is associated with greater odds of morbidity and mortality. DESIGN: Retrospective study. SETTING: Single center at an academic tertiary children's hospital. PATIENTS: All infants (< 1 yr) undergoing cardiopulmonary bypass between January 1, 2015, and December 31, 2017, excluding two patients who were initiated on extracorporeal membrane oxygenation in the operating room. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study included 469 infants with a median age of 97 days (interquartile range, 14-179 d), weight 4.9 kg (interquartile range, 3.4-6.4 kg), and cardiopulmonary bypass time 128 minutes (interquartile range, 91-185 min). A Pao2 of 313 mm Hg (hyperoxia) on cardiopulmonary bypass had highest sensitivity with specificity greater than 50% for association with operative mortality. Approximately, half of the population (237/469) had hyperoxia on cardiopulmonary bypass. Infants with hyperoxia were more likely to have acute kidney injury, prolonged postoperative length of stay, and mortality. They were younger, weighed less, had longer cardiopulmonary bypass times, and had higher Society of Thoracic Surgeons and the European Association for Cardio-Thoracic Surgery mortality scores. There was no difference in sex, race, preoperative creatinine, single ventricle physiology, or presence of genetic syndrome. On multivariable analysis, hyperoxia was associated with greater odds of mortality (odds ratio, 4.3; 95% CI, 1.4-13.2) but failed to identify an association with acute kidney injury or prolonged postoperative length of stay. Hyperoxia was associated with greater odds of mortality in subgroup analysis of neonatal patients. CONCLUSIONS: Hyperoxia occurred in a substantial portion of infants undergoing cardiopulmonary bypass for cardiac surgery. Hyperoxia during cardiopulmonary bypass was an independent risk factor for mortality and may be a modifiable risk factor. Furthermore, hyperoxia during cardiopulmonary bypass was associated with four-fold greater odds of mortality within 30 days of surgery. Hyperoxia failed to identify an association with development of acute kidney injury or prolonged postoperative length of stay when controlling for covariables. Validation of our data among other populations is necessary to better understand and elucidate potential mechanisms underlying the association between excess oxygen delivery during cardiopulmonary bypass and outcome.

Evaluation of the Central Effects of Systemic Lentiviral-Mediated Leptin Delivery in Streptozotocin-Induced Diabetic Rats.

Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.

Quantifying paediatric intensive care unit staffing levels at a paediatric academic medical centre: A mixed-methods approach.

AIM: To identify, simulate and evaluate the formal and informal patient-level and unit-level factors that nurse managers use to determine the number of nurses for each shift. BACKGROUND: Nurse staffing schedules are commonly set based on metrics such as midnight census that do not account for seasonality or midday turnover, resulting in last-minute adjustments or inappropriate staffing levels. METHODS: Staffing schedules at a paediatric intensive care unit (PICU) were simulated based on nurse-to-patient assignment rules from interviews with nursing management. Multivariate regression modelled the discrepancies between scheduled and historical staffing levels and constructed rules to reduce these discrepancies. The primary outcome was the median difference between simulated and historical staffing levels. RESULTS: Nurse-to-patient ratios underestimated staffing by a median of 1.5 nurses per shift. Multivariate regression identified patient turnover as the primary factor accounting for this difference and subgroup analysis revealed that patient age and weight were also important. New rules reduced the difference to a median of 0.07 nurses per shift. CONCLUSION: Measurable, predictable indicators of patient acuity and historical trends may allow for schedules that better match demand. IMPLICATIONS FOR NURSING MANAGEMENT: Data-driven methods can quantify what drives unit demand and generate nurse schedules that require fewer last-minute adjustments.