Navigating the Healthcare Conundrum: Leadership Perspective from a Premier Healthcare Organization in Loma Linda's Blue Zone.

Navigating the healthcare conundrum in the Blue Zone of Loma Linda, California, requires understanding the unique factors that make this region stand out in terms of health and longevity. But more important is understanding the healthcare system sustaining the Blue Zone in Loma Linda, California. In an era marked by soaring healthcare costs and diminishing reimbursement rates, hospitals and physicians face an unprecedented challenge: providing excellent patient care while maintaining financial sustainability. This leadership perspective publication paper delves into the multifaceted struggles encountered by healthcare and hospital leaders, exploring the root causes, implications, and potential solutions for this complex issue. As we examine the evolving healthcare landscape, we aim to shed light on the critical need for innovative approaches to sustain the future of healthcare excellence in one of the five original Blue Zones.

A pilot study on the biochemical effects of repeated administration of 24% oral sucrose vs. 30% oral dextrose on urinary markers of adenosine triphosphate degradation.

OBJECTIVES: Premature neonates often receive oral sucrose or dextrose before tissue-damaging procedures (TDPs). Previous work showed that a single dose of sucrose, but not dextrose, increased cellular energy utilization and ATP degradation. This pilot study probes the effects of repeated administration of sucrose or dextrose on energy metabolism. METHODS: Urinary markers of ATP metabolism (hypoxanthine, xanthine, uric acid) are measured in premature neonates randomized to receive: (a) standard of care, (b) 0.2 ml 24% oral sucrose, or (c) 0.2 ml 30% oral dextrose, before every painful procedure on days-of-life 3-7. RESULTS: Standard of care is associated with highest xanthine/creatinine and uric acid/creatinine, likely because of fewer pain treatments. Benefits of repeated oral sucrose are unclear. Neonates receiving oral dextrose had lower xanthine/creatinine and uric acid/creatinine. CONCLUSIONS: Repeated treatments of neonatal procedural pain with 30% oral dextrose are less energetically demanding. Larger clinical studies are needed for comparison with sucrose treatments.

The effect of whole-body cooling on brain metabolism following perinatal hypoxic-ischemic injury.

INTRODUCTION: Magnetic resonance imaging (MRI) and spectroscopy (MRS) have proven valuable in evaluating neonatal hypoxic-ischemic injury (HII). RESULTS: MRI scores in the basal ganglia of HII/HT(+) neonates were significantly lower than HII/HT(-) neonates, indicating less severe injury and were associated with lower discharge encephalopathy severity scores in the HII/HT(+) group (P = 0.01). Lactate (Lac) was detected in the occipital gray matter (OGM) and thalamus (TH) of significantly more HII/HT(-) neonates (31.6 and 35.3%) as compared to the HII/HT(+) group (10.5 and 15.8%). In contrast, the -N-acetylaspartate (NAA)-based ratios in the OGM and TH did not differ between the HII groups. DISCUSSION: Our data show that the HT was associated with a decrease in the number of HII neonates with detectable cortical and subcortical Lac as well as a decrease in the number of MRI-detectable subcortical lesions. METHODS: We retrospectively compared the medical and neuroimaging data of 19 HII neonates who received 72 h of whole-body cooling (HII/HT(+)) with those of 19 noncooled HII neonates (HII/HT(-)) to determine whether hypothermia was associated with improved recovery from the injury as measured by MRI and MRS within the first 14 days of life. MRI scores and metabolite ratios of HII/HT(+) and HII/HT(-) neonates were also compared with nine healthy, nonasphyxiated "control" neonates.

MRI assessment of ischemic liver after intraportal islet transplantation.

BACKGROUND: There is a recent focus on embolization of the portal vein by transplanted islets as a major cause of early graft loss. The resultant ischemia causes necrosis or apoptosis of cells within the liver. Thus, noninvasive assessment of the liver receiving the islet transplant is important to evaluate the status islet grafts. METHODS: This study used noninvasive magnetic resonance imaging (MRI) for assessment of the posttransplant ischemic liver. Syngeneic islets in streprozotocin-induced diabetic mice were used. MRI and morphological liver assessments were performed at 0, 2, and 28 days after transplantation. Histologic assessment of insulin, hypoxia induced factor 1-alpha, and apoptosis were undertaken at similar time points. RESULTS: Ischemic/necrotic regions in the liver were detected by MRI at 2 days but not at 28 days after transplantation and were confirmed histologically. Liver injury was quantified from high intensity areas on T2-weighted images. Insulin release peaked 2 days after transplantation. CONCLUSION: Onset and reversal of liver ischemia due to intraportal islet transplantation are detectable using T2-weighted MRI. These changes coincide with periods of maximum insulin release likely due to partial islet destruction. We propose that MRI, as a noninvasive monitor of graft-related ischemia, may be useful in assessment of liver and islet engraftment after intraportal islet transplantation in a clinical setting.

In vivo imaging demonstrates a time-line for new vessel formation in islet transplantation.

Vascularization of transplanted islets must be maintained to provide long-term graft function. In vivo assessment of new vessel formation in islet grafts has been poorly documented. The purpose of this study was to investigate whether neovascularization was detectable in vivo in a Feridex-labeled murine syngeneic subcapsular islet mass using DCE MRI over 180 days. Subcapsular transplants could be visualized at post-transplant days three, seven, 14, and 28 using T2-weighted MRI and at post-transplant day 180 by immunohistochemistry. Injection of the contrast agent gadolinium (Gd)-DTPA for DCE at three, seven, and 14 days showed increased signal in the transplant area consistent with new vessel formation. Areas under contrast enhancement curves suggested peak angiogenesis at 14 days. At 180 days, there was no observable change in signal intensity after contrast injection suggesting established vascularization or islet mass reduction. Immunohistochemistry confirmed MRI and DCE findings. These data suggest that islet angiogenesis occurs early after transplantation and is likely established after one month of transplantation. This study provides an in vivo time-line of neovascularization in subcapsular islet grafts. We anticipate that contrast extravasation captured by MRI may provide useful monitoring of graft angiogenesis if reproduced in a clinically relevant intraportal model.

Monitoring neovascularization of intraportal islet grafts by dynamic contrast enhanced magnetic resonance imaging.

Fifteen thousand youths are diagnosed yearly with type 1 diabetes mellitus. Pancreatic islet transplantation has been shown clinically to provide short-term (~1 year) insulin independence. However, challenges associated with early vascularization of transplanted islet grafts and long-term islet survival remain. We utilized dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to monitor neovascularization of islets transplanted into the right lobe of the liver in a syngeneic mouse model system. The left lobe received no islets and served as a control. DCE data were analyzed for temporal dynamics of contrast (gadolinium) extravasation and the results were fit to a Tofts two-compartment exchange model. We observed maximal right lobe enhancement at seven days post-transplantation. Histological examination up to 28 days was used to confirm imaging results. DCE-derived enhancement strongly correlated with immunohistochemical measures of neovascularization. To our knowledge, these results are the first to demonstrate using a FDA approved contrast agent that DCE MRI can effectively and non-invasively monitor the progression of angiogenesis in intraportal islet grafts.

Monitoring neovascularization of intraportal islet grafts by dynamic contrast enhanced magnetic resonance imaging.

Fifteen thousand youths are diagnosed yearly with type 1 diabetes mellitus. Pancreatic islet transplantation has been shown clinically to provide short-term (~1 year) insulin independence. However, challenges associated with early vascularization of transplanted islet grafts and long-term islet survival remain. We utilized dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to monitor neovascularization of islets transplanted into the right lobe of the liver in a syngeneic mouse model. The left lobe received no islets and served as a control. DCE data were analyzed for temporal dynamics of contrast (gadolinium) extravasation and the results were fit to a Tofts two-compartment exchange model. We observed maximal right lobe enhancement at seven days post-transplantation. Histological examination up to 28 days was used to confirm imaging results. DCE-derived enhancement strongly correlated with immunohistochemical measures of neovascularization. To our knowledge these results are the first to demonstrate, using a FDA approved contrast agent, that DCE MRI can effectively and non-invasively monitor the progression of angiogenesis in intraportal islet grafts.

An infant with Netherton syndrome and persistent pulmonary hypertension requiring extracorporeal membrane oxygenation.

Netherton syndrome is a rare genodermatosis characterized by ichthyosiform scaling, hair shaft abnormalities, and atopic features. Affected infants typically have delayed growth and development, immune abnormalities with recurrent infections, and intermittent aminoaciduria. We report a 23-day-old girl who presented with severe primary pulmonary hypertension, exfoliative erythroderma, and trichorrhexis invaginata. Genetic studies confirmed a premature termination mutation R350X in exon 12 of SPINK5. This mutation further supports the genotypic-phenotypic prediction that severe sequela result from premature termination mutations. To our knowledge, this is the first instance of Netherton syndrome associated with primary pulmonary hypertension to be reported. Further postulated is a possible link between excessive desquamation of fetal skin and respiratory failure in a neonate with Netherton syndrome.

Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants.

OBJECTIVE: To compare the incidence of low free T4 values reported by a direct equilibrium dialysis method to their incidence reported by 2 non-dialysis methods. STUDY DESIGN: Ninety-five infants, < or = 33 weeks gestational age at birth, admitted to Loma Linda University Children's Hospital before day 3 of life were studied. Infants were grouped by gestational age ranges: < or = 27, 28-30, and 31-33 weeks. Free T4 determinations were measured at 3, 7, and 14 days of life with 3 different free T4 methods. Gestational age-specific newborn reference ranges were available for the direct equilibrium dialysis method only. The only reference ranges available for the non-dialysis free T4 methods were not gestational age specific. Using available reference ranges we classified free T4 values as either low or not low. The incidence of low free T4 values was compared at 3, 7, and 14 days of life. RESULTS: Low direct equilibrium dialysis free T4 values were substantially less frequent than non-dialysis free T4 values. CONCLUSION: Substantial free T4 inconsistencies occur between dialysis and non-dialysis free T4 methods in preterm infants. It is unclear how much of this inconsistency is method dependent and how much is reference range dependent.

In vivo magnetic resonance imaging of vascularization in islet transplantation.

To evaluate changes in neovascularization of transplanted islets in vivo, dynamic contrast (gadolinium) enhanced magnetic resonance imaging (MRI) was used. Both iron (Feridex)-labeled and unlabeled syngeneic murine subcapsular islet grafts were studied. Differences in dynamic contrast enhancement of islet grafts were quantified after gadolinium injection at post-transplant days 3 and 14. Normalized contrast concentrations at day 14 in transplanted islets were increased relative with that on day 3. Time to peak contrast enhancement was faster by 12 min at day 14 compared to day 3 islets (while kidney and muscle peak times remained the same). Areas under the curve for contrast concentration versus time plots were larger in 14-day relative to 3-day islet grafts. In conclusion, noninvasive assessment of neovascularization is achievable. In vivo dynamic contrast-enhanced MRI can be used to detect and quantify changes in vascularization following islet transplantation. This technique may be useful in developing pro-angiogenic strategies to improve the transplantation outcome in experimental and clinical settings.

In vitro and in vivo improvement of islet survival following treatment with nerve growth factor.

BACKGROUND: Nerve growth factor (NGF) has been reported to play an important regulatory role in pancreatic beta-cell function. However, the usefulness of NGF in a transplantation setting is unknown. METHODS: A marginal number of islet cells (260 islet equivalents/recipient) cultured for 24 hr with NGF (500 ng/ml) was syngeneically transplanted under the kidney capsule of streptozotocin-induced diabetic Balb/c mice. Fluorescence microscopy was used to evaluate islet viability. Islet function was evaluated in vitro and in vivo by static assay and glucose tolerance test, respectively. RESULTS: In vitro, improved viability and survival were found in murine islets cultured in serum-free medium for 96 hr with 500 ng/ml NGF (P<0.05). NGF-treated islets had more insulin secretion than islets cultured without NGF in response to 2.8 mmol/L glucose (P<0.05), and 20 mmol/L glucose conditions. In vivo, 67% of recipients with a submarginal number of islets cultured in NGF attained normoglycemia for more than 120 days, whereas transplanted islets without NGF treatment survived a maximum of 13 days in control mice. At posttransplant day 4, recipients of NGF-cultured islets showed significant improvement of glucose tolerance. On immunohistochemistry, the kidney capsules containing NGF-cultured islets displayed higher insulin content, and more dilated neoplastic microvessels than control renal capsules. The number of apoptotic cells using TUNEL staining decreased by nearly 50% in NGF-cultured islet grafts in comparison to control islet grafts. CONCLUSIONS: The above data suggest potential advantages of NGF for islet survival following transplantation. This neurotrophic approach may prove beneficial in human islet transplantation.

Cerebral blood flow and oxygenation during venoarterial and venovenous extracorporeal membrane oxygenation in the newborn lamb.

BACKGROUND: Concern exists that extracorporeal membrane oxygenation (ECMO) may decrease cerebral blood flow (CBF), impair cerebral autoregulation, and thereby increase the risk of neurologic injury. OBJECTIVE: This study was undertaken in newborn lambs to compare the effects of initiation of venoarterial and venovenous ECMO on CBF and cerebral oxygen delivery as measured by laser-Doppler flowmetry. This study also evaluates the effects of carotid artery and jugular vein ligation on CBF. DESIGN: CBF, arterial blood pressure, sagittal sinus pressure, heart rate, cardiac output, arterial blood gases, and hemoglobin saturation were measured. After anesthesia, instrumentation, and a 1-2 hr stabilization period, values were recorded during a 30-min control period, and the carotid artery or jugular vein was cannulated. The animals were then studied during venoarterial or venovenous ECMO for 1 hr. MAIN RESULTS: Carotid ligation resulted in a transient decrease in right cortex CBF that resolved within 60 secs. Next, during a 60-min period of venoarterial ECMO (flow rate of 100 mL.min(-1).kg(-1), n = 11), cerebral resistance to flow increased, CBF decreased 25%, and cerebral oxygen delivery decreased by 30%. Native cardiac output and Paco(2) remained constant. Pulsatility in the lingual artery, representing the pulsatility of arterial flow to the brain, decreased throughout venoarterial ECMO. In contrast, in those lambs receiving ECMO in the venovenous mode (n = 7), resistance to flow, CBF, cerebral oxygen delivery, and pulsatility did not change. CONCLUSIONS: There was no sustained decrease in CBF after ligation of either the carotid artery or jugular vein. Venoarterial but not venovenous ECMO induced decreases of CBF that could not be attributed to changes in blood gases or blood pressure but that may relate to diminished pulsatility in cerebral resistance vessels or to differences in levels of circulating vasoactive compounds.

Incidence of low free T4 values in premature infants as determined by direct equilibrium dialysis.

BACKGROUND: The incidence of transient reductions in serum free T(4) (FT(4)) in premature infants may be overestimated because certain FT(4) analytical methods underestimate FT(4) concentrations. Transient reductions of FT(4) measurements have been reported in the majority of premature newborn infants. Direct equilibrium dialysis (DED) does not underestimate FT(4) concentrations and is the best available technique to measure serum FT(4) in the premature infant. OBJECTIVE: To evaluate the incidence of low FT(4) concentrations in premature infants using DED to measure FT(4). DESIGN/METHOD: We measured FT(4) by DED in infants with birth weight <1500 g. Infants were excluded if the following conditions were present: congenital anomalies or maternal thyroid disorders. Free T(4) was measured at 14 days of life. Low FT(4) was defined using a statistical definition of FT(4) measurements <10.3 pmol/l (0.8 ng/dl). RESULTS: Free T(4) was measured by DED in 114 infants. Low FT(4) levels were seen in nine infants (7.9%). CONCLUSION: The incidence of low FT(4) was much lower than previously reported when FT(4) was measured using DED indicating that methodological issues are involved in the variability among estimates of the frequency of transient reduction in FT(4).

Proton magnetic resonance spectroscopy improves outcome prediction in perinatal CNS insults.

OBJECTIVE: Prediction of neurologic outcome is difficult in neonates with acute nervous system injury. Previous studies using proton magnetic resonance spectroscopy ((1)H-MRS) have been used to predict short-term neurologic outcome in neonates with a variety of neurologic insults. We were interested in determining the effectiveness of combining clinical evaluation and spectroscopy obtained at the time of injury in predicting neurologic outcome at 24 months. STUDY DESIGN: We studied 33 neonates with acute central nervous system injury, 5.8+/-3.7 days of injury, owing to hypoxic-ischemic encephalopathy. Neonates were assessed using clinical variables (initial arterial pH, initial blood glucose, Sarnat score, electroencephalography) and spectroscopy (NAA/Cho, NAA/Cre, Cho/Cre, and lactate). Neonates were divided into two outcome groups: good/moderate and poor. Differences between the groups were assessed using chi(2) and t-test analyses. We analyzed the best predictors of outcome using discriminant analysis and calculated sensitivity, specificity, positive, and negative predictive values for each variable independently and in combination. RESULTS: There were significant differences between the good/moderate and poor outcome for the Sarnat score, EEG, lactate, and NAA/Cho. Spectroscopy combined with clinical variables improved sensitivity, but not specificity for predicting outcome. The presence of lactate had the best individual predictive value. Combination of the clinical with the MRS variables had the highest predictive value. CONCLUSION: Proton magnetic resonance spectroscopy done early after injury improves the ability to predict neurologic outcome at 24 months of age.

Comparison of 2 iron doses in infants receiving recombinant human erythropoietin therapy.

OBJECTIVE: To compare iron sufficiency in premature infants receiving high-dose recombinant human erythropoietin (r-HuEPO), 1200 IU/kg per week, supplemented with 6 or 12 mg/kg per day of enteral iron. DESIGN: We conducted a prospective, double-blind, controlled study of premature infants receiving r-HuEPO therapy, randomly assigned to receive 2 different doses of iron. Measurements of ferritin, iron, total iron-binding capacity, reticulocyte count, hemoglobin level, and hematocrit were obtained at baseline, 4, and 6 weeks. Transferrin saturation was calculated; the number of blood transfusions and the incidences of sepsis were recorded. SETTING: This study was performed in the neonatal intensive care unit at Loma Linda University Children's Hospital, Loma Linda, Calif. SUBJECTS: Infants with a gestational age of 32 weeks or younger, older than 7 days, and receiving r-HuEPO therapy from March 1, 1997, to June 30, 1998, were eligible for the study. Infants were randomly assigned to receive 6 mg/kg per day or 12 mg/kg per day of enteral iron during a course of r-HuEPO therapy for 4 to 6 weeks. RESULTS: Sixty-four infants were enrolled in the study. Twelve infants did not complete the study; 52 completed 4 weeks and 41 completed 6 weeks of the study. While ferritin levels and transferrin saturation decreased in both groups over the study period, there were no differences between the 2 study groups. CONCLUSIONS: Infants receiving high-dose r-HuEPO therapy (1200 IU/kg per week) decrease their ferritin levels (measure of iron stores) even when receiving high enteral iron supplementation. Given that the ferritin levels were similar between the 2 groups, we speculate that the additional iron either was not absorbed or was not stored.

QTc interval in infants receiving cisapride.

OBJECTIVE: To examine the effect of cisapride on the corrected QT (QTc) interval in infants over a 14-day period. STUDY DESIGN: A prospective cohort study of infants receiving cisapride (0.8 mg/kg per day). Twelve-lead electrocardiograms were obtained before and 3, 5, 7, and 14 days after cisapride initiation. RESULTS: Fifty infants completed the study; none had arrhythmias. Fifteen of 50 infants (30%) developed QTc interval > or =450 msec; QTc interval normalized in 13 of 15 infants. Infants with QTc interval on day 3 > or =2 standard deviations above the mean baseline QTc interval (401+40 msec) were more likely to develop prolonged QTc interval (p<0.0001). CONCLUSION: QTc interval prolongation was noted in 30% of infants. Subsequently, the majority of those infants had QTc interval normalization by day 14 of cisapride therapy. QTc interval 3 days following cisapride initiation may identify infants at risk for transient QTc interval prolongation. With appropriate monitoring, hospitalized infants receiving cisapride may have improved gastrointestinal motility without cardiac morbidity.