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Background: At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents.Study Design: Case series.Setting& Participants: 24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient.Outcome: Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring.Measurements: Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found.Results: A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented.Limitations: Size of patient group. No direct examination of RNA.Conclusion: Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to evaluate the effectiveness of directly integrating self-monitoring blood glucose (BG) information with insulin pump therapy on overall glycemic control. METHODS: In this randomized trial, 34 youth with type 1 diabetes using insulin pump therapy were trained on the use of the Deltec Cozmo Insulin Pump. Seventeen were randomized to use the CoZmonitor Blood Glucose Module, a device that attaches to the back of the pump using FreeStyle technology to perform BG tests which read directly on the pump screen. The remaining 17 (control group) used a FreeStyle Flash meter, a stand-alone BG meter, for their BG testing. At baseline, 3 and 6 months, the subjects filled out a questionnaire, had a hemoglobin A1c (HbA1c) test, and had pumps and meters downloaded. RESULTS: After 3 months of study, there were no changes in mean HbA1c (+/- SD) values for the experimental (8.7 +/- 1.1 to 8.6 +/- 1.1) or the control groups (9.1 +/- 1.4 to 9.2 +/- 1.5). There were also no significant differences in HbA1c values after 6 months. The average number of BG tests per day did not change significantly in either group during the study. After 3 and 6 months, the experimental group rated satisfaction with the use of the CoZmonitor at 4.4 and 3.8 (respectively) on a five-point Likert scale, with 5 being the most satisfied. CONCLUSIONS: Although significant changes in HbA1c values or the number of BG tests were not found, use of the BG module had a positive level of satisfaction. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity manifest as more severe disease in successive generations has been attributed to genetic anticipation in patients with autosomal dominant polycystic kidney disease (ADPKD). We evaluated variation in age at end-stage renal disease (ESRD) in ADPKD families for evidence of anticipation.Study Design: Retrospective.Setting& Participants: 413 families with ADPKD seen at our single center between 1985 and 2004 (including 95 families with documented polycystic disease type 1 [PKD1] and 213 ADPKD families with parents born before 1930).Predictor: Generational status.Outcome: Age at ESRD onset.Measurements: Time to ESRD was evaluated by using survival analysis, Cox regression, and descriptive statistics. Unstable trinucleotide repeat expansion was evaluated by means of genotyping in 6 PKD1 families.Results: We analyzed 413 ADPKD families (1,391 parent-offspring pairs) with known age at ESRD or last known age without ESRD (informative pairs). There was no difference in age at ESRD between parents and offspring by means of Cox regression after adjusting for correlations among family members and sex (hazard ratio, 1.019; 95% confidence interval, 0.919 to 1.13; P = 0.7). Similar analysis of PKD1 informative pairs and those with parents born before 1930 showed no differences in age at ESRD. Male ADPKD patients were 42% more likely to reach ESRD (P < 0.001), and male patients with documented PKD1 were 41% more likely to reach ESRD (P = 0.01) than female patients.Limitations: Hypertension treatment unknown.Conclusions: We found no evidence for anticipation of ESRD in patients with ADPKD; thus, the observed variation in age at ESRD may result from other genetic, sex, or environmental causes. [ABSTRACT FROM AUTHOR]

Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.Genes and Immunity (2007) 8, 628–633; doi:10.1038/sj.gene.6364425; published online 30 August 2007 [ABSTRACT FROM AUTHOR]

In this article the authors comment on a study by T. M. Bull, B. Clark, and K. McFann which associated pulmonary vascular dysfunction with acute lung injury. The authors assert that the study analyzed patients with acute lung injury who were enrolled in the Fluid and Catheter Treatment Trial (FACTT). They claim that one important finding of the study was the role of pulmonary vascular bed as a risk factor for mortality.

Abstract Background AKI is common following liver transplantation and is associated with significant morbidity and mortality. Biomarkers of AKI have not been well established in this setting but are needed to help guide patient care and facilitate development of novel therapeutics. Methods Serum creatinine, cystatin C, IL-6, and IL-8 and urine IL-18, NGAL, IL-6, and IL-8 were measured before and within 24 hours after liver transplantation in 40 patients. AKI was defined as a ≥50% sustained increase in creatinine above pre-operative values occurring within 24 hours of transplantation and persisting for at least 24 hours. Results Seven patients met criteria for AKI (17.5%), with mean creatinines of 0.81 mg/dL pre-operatively and 1.75 mg/dL post-operatively. While pre-operative biomarker levels in patients with AKI were similar to those in patients without AKI, differences were seen between the groups with regard to median post-operative serum IL-8 (pg/mL) (242.48 vs. 82.37, p = 0.0463) and urine NGAL (ng/mL) (386.86 vs. 24.31, p = 0.0039), IL-6 (pg/mL) (52 vs. 7.29, p=0.0532), IL-8 (pg/mL) (14.3 vs. 0, p = 0.0224), and IL-18 (pg/mL) (883.09 vs. 0, p = 0.0449). The areas under receiver operating characteristic (ROC) curves were 0.749 for urine IL-18, 0.833 for urine NGAL, 0.745 for urine IL-6, 0.682 for serum IL-6, 0.773 for urine IL-8, and 0.742 for serum IL-8. Post-operative cystatin C was not significantly different between AKI and no AKI groups. Conclusion Serum IL-8 and urine IL-18, NGAL, IL-6, and IL-8 are elevated in AKI within the first 24 hours following liver transplantation.

Abstract Background Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. Methods This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. Results Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. Conclusion Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.

Abstract Background Surveys have generally found that individuals more likely to use complementary and alternative medicine are female, live in the western United States, are likely to have a health complaint, and have a higher socioeconomic status than do nonusers. What is not known is the extent to which those who use complementary and alternative medicine also engage in positive health behaviors, such as smoking cessation or increased physical activity and/or exhibit fewer health risk factors such as obesity. This has been identified as a key research question in a recent Institute of Medicine report. In the present study we sought to determine whether the use of complementary and alternative medicine is associated with health behaviors or risk factors known to impact on health status. Methods The current study is a cross-sectional regression analysis using data from the 2002 National Health Interview Survey. Data were collected in-person from 31,044 adults throughout the 50 states and the District of Columbia. Results After controlling for a range of other factors, we found that engaging in leisure-time physical activity, having consumed alcohol in one's life but not being a current heavy drinker, and being a former smoker are independently associated with the use of CAM. Obese individuals are slightly less likely to use CAM than individuals with a healthy body-mass index. No significant associations were observed between receipt of an influenza vaccine and CAM use. Conclusion Those engaging in positive health behaviors and exhibiting fewer health risk factors are more likely to use CAM than those who forgo positive health behaviors or exhibit more health risk factors. The fact that users of CAM tend to pursue generally healthy lifestyles suggests that they may be open to additional recommendations toward optimizing their health.

Introduction: Noninvasive continuous blood pressure monitoring has the potential to improve patient treatment in the hospital setting. Such noninvasive devices can be applied earlier in the treatment process to empower nurses and clinicians to react more quickly to patient deterioration with the added benefit of eliminating the risks associated with invasive monitoring. However, emerging technologies must be capable of reproducing current clinical measures for medical decision making., Methods: This study aimed to determine the usability and willingness of nurses to implement a noninvasive continuous blood pressure monitoring device. The secondary aim directly compared the systolic blood pressure, diastolic blood pressure, and mean arterial pressure values recorded by the device (VitalStream; CareTaker Medical LLC, Charlottesville, VA) with the "gold standard" brachial cuff and arterial line measures recorded in the emergency department and intensive care unit settings., Results: VitalStream was similarly received by nurses in the emergency department and intensive care setting, but ultimately had greater promotion from emergency nurses. Despite some statistical similarity between measurement methodologies, all direct comparisons were found to not meet the Association for the Advancement of Medical Instrumentation 2008 and Association for the Advancement of Medical Instrumentation / European Society of Hypertension / International Organization for Standardization 2019 consensus statement criteria for acceptable blood pressure measure differences between the VitalStream and "gold standard" clinical measures. In all instances, the standard deviation of the Bland-Altman bias exceeded 8 mm Hg with less than 85% of paired differences falling within 10 mm Hg of the "gold standard.", Discussion: Taken together, the tested device requires additional postprocessing for medical decision making in trauma or emergent care., (Copyright © 2024 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Advanced Trauma Life Support (ATLS) focuses on care of injured patients in the first hour of resuscitation. Expanded demand for courses has led to a concurrent need for new instructors. Nurse practitioners and physician assistants (NPs/PAs) work on trauma services and duties include patient, staff, and outreach education. The goal of this project was to assess NP/PA self-reported knowledge and skills pertinent to ATLS and identify potential barriers to becoming instructors., Materials: This was a voluntary 91-question survey emailed to NP/PA lists obtained from professional societies and online social media channels. NPs/PAs completed a survey reflecting self-reported knowledge, experience, comfort level, and barriers to teaching ATLS interactive discussions and skills. Responses were recorded using a Likert scale and results were documented as percentages. Number of years of experience versus perceived knowledge and comfort teaching were compared using a χ 2 test of independence., Results: There were 1696 completed surveys. Most NPs/PAs thought they had adequate knowledge and experience to teach interactive discussions and skills. Those with more years of experience and those who completed more ATLS courses had higher percentages. The number 1 barrier to teaching was lack of formal teaching experience followed by perceived hierarchy concerns. Experience and comfort with skills that fell below 50% were pediatric airway (49.5%), needle and surgical cricothyrotomy (49.8% and 44.8%), diagnostic peritoneal lavage (21.6%), and venous cutdown (20.8%)., Conclusion: NPs/PAs with experience in trauma reported having the knowledge and skill to teach ATLS. A majority are comfortable teaching interactive discussions and skills for which they are knowledgeable. The primary barrier to teaching was lack of formal teaching experience, which is covered in the ATLS Instructor course. Training NPs/PAs to become instructors would increase the instructor base and allow for increased promulgation of ATLS and trauma education., Level of Evidence: IV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Post-acute sequelae of COVID-19 affects the quality of life of many COVID-19 survivors, yet the etiology of post-acute sequelae of COVID-19 remains unknown. We aimed to determine if persistent inflammation and ongoing T-cell activation during convalescence were a contributing factor to the pathogenesis of post-acute sequelae of COVID-19., Methods: We evaluated 67 individuals diagnosed with COVID-19 by nasopharyngeal polymerase chain reaction for persistent symptoms during convalescence at separate time points occurring up to 180 days post-diagnosis. Fifty-two of these individuals were evaluated longitudinally. We obtained whole blood samples at each study visit, isolated peripheral blood mononuclear cells, and stained for multiple T cell activation markers for flow cytometry analysis. The activation states of participants' CD4 + and CD8 + T-cells were next analyzed for each of the persistent symptoms., Results: Overall, we found that participants with persistent symptoms had significantly higher levels of inflammation at multiple time points during convalescence when compared to those who fully recovered from COVID-19. Participants with persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of proliferating effector T-cells (CD8 + Ki67 + ), and those with chest pain, joint pain, difficulty concentrating, and forgetfulness had higher levels of regulatory T-cells (CD4 + CD25 + ). Additionally, those with dyspnea had significantly higher levels of CD8 + CD38 + , CD8 + Granzyme B + , and CD8 + IL10 + cells. A retrospective comparison of acute phase inflammatory markers in adults with and without post-acute sequelae of COVID-19 showed that CD8 + Ki67 + cells were significantly higher at the time of acute illness (up to 14 days post-diagnosis) in those who developed persistent dyspnea., Discussion: These findings suggest continued CD8+ T-cell activation following SARS-CoV-2 infection in adults experiencing post-acute sequelae of COVID-19 and that the increase in T regulatory cells for a subset of these patients represents the ongoing attempt by the host to reduce inflammation., Competing Interests: BS is employed by Arcturus Therapeutics which is developing a COVID-19 vaccine. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 LaVergne, Dutt, McFann, Baxter, Webb, Berry, Tipton, Stromberg, Sullivan, Dunn, Henao-Tamayo and Ryan.)

Diagnostic Criteria Study BACKGROUND: The morbidity and mortality associated with ischemic stroke attributable to blunt cerebrovascular injury (BCVI) warrant aggressive screening. The Denver Criteria (DC) and Expanded Denver Criteria (eDC) have imprecise elements that can be difficult and subjective in application and can delay or prevent screening. We hypothesize these screening criteria lack adequate ability to consistently identify BCVI and that the use of a liberalized screening approach with CT angiography (CTA) is superior without increasing risk of acute kidney injury (AKI)., Methods: This was a multi-institutional retrospective cohort study of trauma patients who presented between 2015-2020 with radiographically confirmed BCVI diagnosed using each institutions' liberalized screening protocol, defined as automatic CTA of the head and neck for all patients undergoing head and neck CT. Outcomes of interest included AKI, stroke, and death due to BCVI. Outcomes were reported as frequency, percent, and 95% confidence interval as calculated by the Clopper-Pearson method. Incidence of medical follow-up within 1 year of first medical visit was quantified as the median and inter-quartile range of days to follow-up visit., Results: We identified 433 BCVI patients with a mean age of 45.2 (standard deviation 18.9) years, 256 men and 177 women, 1.73 m (0.10) tall, and weighed 80.3 kg (20.3). Forty-one patients had strokes (9.5% [95% confidence interval 6.9, 12.6] and 12 patients (2.8% [1.4, 4.5]) had mortality attributable to BCVI. Of 433 total cases, 132 (30.5% [26.2, 35.1]) would have been missed by DC and 150 (34.6% [30.2, 39.3]) by eDC. Incidence of AKI in our BCVI population was 6 (1.4% [0.01, 3.0])., Conclusions: BCVI would be missed over 30% of the time using the DC and eDC compared to liberalized use of screening CTA. Risk of AKI due to CTA did not occur at a clinically meaningful level, supporting liberal CTA screening., (Copyright © 2023. Published by Elsevier Ltd.)

Vitamin D deficiency is common in the United States and leads to altered immune function, including T cell and macrophage activity that may impact responses to SARS-CoV-2 infection. This study investigated 131 adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR and 18 adults with no COVID-19 diagnosis that were recruited from the community or hospital into the Northern Colorado Coronavirus Biorepository (NoCo-COBIO). Participants consented to enrollment for a period of 6 months and provided biospecimens at multiple visits for longitudinal analysis. Plasma 25-hydroxyvitamin D levels were quantified by LC-MS/MS at the initial visit (n = 149) and after 4 months (n = 89). Adults were classified as deficient (<30 nM or <12 ng/mL), insufficient (<30−50 nM or 12−20 ng/mL), or optimal (50−75 nM or >20 ng/mL) for 25-hydroxyvitamin D status. Fisher’s exact test demonstrated an association between disease severity, gender, and body mass index (BMI) at baseline. Mixed model analyses with Tukey-Kramer were used for longitudinal analysis according to BMI. Sixty-nine percent (n = 103) of the entire cohort had optimal levels of total 25(OH)D, 22% (n = 32) had insufficient levels, and 9% (n = 14) had deficent levels. Participants with severe disease (n = 37) had significantly lower 25-hydroxyvitamin D (total 25(OH)D) when compared to adults with mild disease (p = 0.006) or no COVID-19 diagnosis (p = 0.007). There was 44% of the cohort with post-acute sequalae of COVID-19 (PASC) as defined by experiencing at least one of the following symptoms after 60 days’ post-infection: fatigue, dyspnea, joint pain, chest pain, forgetfulness or absent-mindedness, confusion, or difficulty breathing. While significant differences were detected in 25-hydroxyvitamin D status by sex and BMI, there were no correlations between 25-hydroxyvitamin D for those without and without PASC. This longitudinal study of COVID-19 survivors demonstrates an important association between sex, BMI, and disease severity for 25-hydroxyvitamin D deficiency during acute stages of infection, yet it is not clear whether supplementation efforts would influence long term outcomes such as developing PASC.

Background: SARS-CoV-2 has infected millions across the globe. Many individuals are left with persistent symptoms, termed post-acute sequelae of COVID-19 (PASC), for months after infection. Hyperinflammation in the acute and convalescent stages has emerged as a risk factor for poor disease outcomes, and this may be exacerbated by dietary inadequacies. Specifically, fatty acids are powerful inflammatory mediators and may have a significant role in COVID-19 disease modulation., Objective: The major objective of this project was to pilot an investigation of plasma fatty acid (PFA) levels in adults with COVID-19 and to evaluate associations with disease severity and PASC., Methods and Procedures: Plasma from adults with ( N = 41) and without ( N = 9) COVID-19 was analyzed by gas chromatography-mass spectrometry (GC-MS) to assess differences between the concentrations of 18 PFA during acute infection (≤14 days post-PCR + diagnosis) in adults with varying disease severity. Participants were grouped based on mild, moderate, and severe disease, alongside the presence of PASC, a condition identified in patients who were followed beyond acute-stage infection ( N = 23)., Results: Significant differences in PFA profiles were observed between individuals who experienced moderate or severe disease compared to those with mild infection or no history of infection. Palmitic acid, a saturated fat, was elevated in adults with severe disease ( p = 0.04), while behenic ( p = 0.03) and lignoceric acid ( p = 0.009) were lower in adults with moderate disease. Lower levels of the unsaturated fatty acids, γ-linolenic acid (GLA) ( p = 0.03), linoleic ( p = 0.03), and eicosapentaenoic acid (EPA) ( p = 0.007), were observed in adults with moderate disease. Oleic acid distinguished adults with moderate disease from severe disease ( p = 0.04), and this difference was independent of BMI. Early recovery-stage depletion of GLA ( p = 0.02) and EPA ( p = 0.0003) was associated with the development of PASC., Conclusion: Pilot findings from this study support the significance of PFA profile alterations during COVID-19 infection and are molecular targets for follow-up attention in larger cohorts. Fatty acids are practical, affordable nutritional targets and may be beneficial for modifying the course of disease after a COVID-19 diagnosis. Moreover, these findings can be particularly important for overweight and obese adults with altered PFA profiles and at higher risk for PASC., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04603677]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Stromberg, Baxter, Dooley, LaVergne, Gallichotte, Dutt, Tipton, Berry, Haberman, Natter, Webb, McFann, Henao-Tamayo, Ebel, Rao, Dunn and Ryan.)

Background: Trauma performance improvement programs are required by the American College of Surgeons to review all nonsurgical admissions if the annual rate exceeds 10%. These reviews can have varying consistency between reviewers, are time consuming, and the consequent aggregate data are difficult to evaluate for trends., Objective: This study set forth to standardize nonsurgical admission review through validation of the Nelson tool, which is a published objective scoring tool to determine the appropriateness of nonsurgical admissions. We hypothesized that implementation of this tool would facilitate earlier identification of events resulting in meaningful intervention and a reduction of inappropriate nonsurgical admissions., Methods: The Nelson tool and scoring was integrated into the nonsurgical admission review process. A customized audit filter and report were built in the trauma registry. Data were reviewed with respect to scores and admitting service. Statistical analysis included using analysis of variance and t tests to examine differences between admitting services, χ2 test of independence or Fisher's exact to test the association of categorical variables, and ordinal logistic regression to test the ability of the total Nelson tool to predict appropriateness of admission., Results: Using the Nelson tool, scores resulted in appropriate admission service in over 90% of cases. Implementation of the tool resulted in a decreased performance improvement workload with a 78% reduction in nonsurgical admission cases required to go to secondary level of review., Conclusions: Utilization of a validated scoring tool decreases performance improvement workload without compromising patient safety., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Society of Trauma Nurses.)

Immune response dysregulation plays a key role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. In this study, we evaluated immune and endothelial blood cell profiles of patients with coronavirus disease 2019 (COVID-19) to determine critical differences between those with mild, moderate, or severe COVID-19 using spectral flow cytometry. We examined a suite of immune phenotypes, including monocytes, T cells, NK cells, B cells, endothelial cells, and neutrophils, alongside surface and intracellular markers of activation. Our results showed progressive lymphopenia and depletion of T cell subsets (CD3 + , CD4 + , and CD8 + ) in patients with severe disease and a significant increase in the CD56 + CD14 + Ki67 + IFN-γ + monocyte population in patients with moderate and severe COVID-19 that has not been previously described. Enhanced circulating endothelial cells (CD45 - CD31 + CD34 + CD146 + ), circulating endothelial progenitors (CD45 - CD31 + CD34 +/- CD146 - ), and neutrophils (CD11b + CD66b + ) were coevaluated for COVID-19 severity. Spearman correlation analysis demonstrated the synergism among age, obesity, and hypertension with upregulated CD56 + monocytes, endothelial cells, and decreased T cells that lead to severe outcomes of SARS-CoV-2 infection. Circulating monocytes and endothelial cells may represent important cellular markers for monitoring postacute sequelae and impacts of SARS-CoV-2 infection during convalescence and for their role in immune host defense in high-risk adults after vaccination., (Copyright © 2022 by The American Association of Immunologists, Inc.)

The longitudinal quality of life (QoL) of COVID-19 survivors, especially those with post-acute sequelae (PASC) is not well described. We evaluated QoL in our COVID-19 survivor cohort over 6 months using the RAND SF-36 survey. From July 2020-March 2021 we enrolled 110 adults from the United States with a positive SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) into the Northern Colorado Coronavirus Biobank (NoCo-COBIO). Demographic data and symptom surveillance were collected from 62 adults. In total, 42% were hospitalized, and 58% were non-hospitalized. The Rand SF-36 consists of 36 questions and 8 scales, and questions are scored 0-100. A lower-scale score indicates a lower QoL. In conclusion, hospitalization, PASC, and disease severity were associated with significantly lower scores on the RAND SF-36 in Physical Functioning, Role Limitation due to Physical Health, Energy/Fatigue, Social Functioning, and General Health. Long-term monitoring of COVID-19 survivors is needed to fully understand the impact of the disease on QoL and could have implications for interventions to alleviate suffering during recovery.

Background: SARS-CoV-2 has swept across the globe, causing millions of deaths worldwide. Though most survive, many experience symptoms of COVID-19 for months after acute infection. Successful prevention and treatment of acute COVID-19 infection and its associated sequelae is dependent on in-depth knowledge of viral pathology across the spectrum of patient phenotypes and physiologic responses. Longitudinal biobanking provides a valuable resource of clinically integrated, easily accessed, and quality-controlled samples for researchers to study differential multi-organ system responses to SARS-CoV-2 infection, post-acute sequelae of COVID-19 (PASC), and vaccination., Methods: Adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR are actively recruited from the community or hospital settings to enroll in the Northern Colorado SARS-CoV-2 Biorepository (NoCo-COBIO). Blood, saliva, stool, nasopharyngeal specimens, and extensive clinical and demographic data are collected at 4 time points over 6 months. Patients are assessed for PASC during longitudinal follow-up by physician led symptom questionnaires and physical exams. This clinical trial registration is NCT04603677 ., Results: We have enrolled and collected samples from 119 adults since July 2020, with 66% follow-up rate. Forty-nine percent of participants assessed with a symptom surveillance questionnaire (N = 37 of 75) had PASC at any time during follow-up (up to 8 months post infection). Ninety-three percent of hospitalized participants developed PASC, while 23% of those not requiring hospitalization developed PASC. At 90-174 days post SARS-CoV-2 diagnosis, 67% of all participants had persistent symptoms (N = 37 of 55), and 85% percent of participants who required hospitalization during initial infection (N = 20) still had symptoms. The most common symptoms reported after 15 days of infection were fatigue, loss of smell, loss of taste, exercise intolerance, and cognitive dysfunction., Conclusions: Patients who were hospitalized for COVID-19 were significantly more likely to have PASC than those not requiring hospitalization, however 23% of patients who were not hospitalized also developed PASC. This patient-matched, multi-matrix, longitudinal biorepository from COVID-19 survivors with and without PASC will allow for current and future research to better understand the pathophysiology of disease and to identify targeted interventions to reduce risk for PASC. Registered 27 October 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04603677 ., (© 2021. The Author(s).)

Background: Complicated appendicitis patients typically undergo appendectomy followed by antibiotics. The optimal course of antibiotics for complicated appendicitis is poorly defined., Methods: Data were collected from patients presenting with acute appendicitis and underwent appendectomy at the index hospitalization (2015-2017). Primary outcomes were readmission rate, superficial surgical site infection (SSI), deep space infection (DSI), which includes abscess. Length of post-operative antibiotic use was recorded and an average intent-to-treat (ITT) by operative grade was calculated., Results: Two hundred seventy-two patients (23%) were diagnosed with complicated appendicitis. SSI occurred in 4% of patients (n = 11); SSI rates ranged from 0% to 14.6% by ITT group with 3-4 days being the lowest (0%) and <3 days the highest (14.6%) ( P = .008). DSI including abscesses occurred in 27 (9.9%) patients; least frequently in the 5-6 day ITT group (7.4%). Length of stay (LOS) was significantly related to longer antibiotic use ( P < .001) and increasing operative grade ( P < .01)., Conclusions: Given the lower incidence of postoperative complications between 3 and 6 days and no added benefit for ITT >6 days, we recommend limiting antibiotic treatment to 3-6 days for all complicated appendicitis cases with additional workup warranted if infectious symptoms persist.

Objectives: The aim of our study was to describe the prevalence, characteristics, and outcomes of children with acute recurrent (ARP) or chronic (CP) pancreatitis with or without mutations in PRSS1, CFTR or SPINK1., Methods: Retrospective chart review of children with ARP or CP with and without testing for PRSS1, CFTR, and SPINK1. Demographics, clinical features, management, and outcome were collected. Analysis of variance was used to compare continuous variables and χ or Fisher exact test for categorical variables., Results: Ninety-one subjects with ARP (n = 77) or CP (n = 14) were identified and included in this study. Of these, 37 (41%) were male, 44 were white, and 30 were Hispanic. Thirty-three (36%) had at least 1 mutation identified (Pan-Mut): PRSS1 (7), CFTR (21), SPINK1 (3), SPINK/CFTR (2). Thirty-six were tested but had no mutation, and 22 were not tested. The Pan-Mut subjects were more likely to have a family history of pancreatitis but there were no differences in the clinical features, imaging or outcome., Conclusions: Mutations in CFTR, SPINK1 or PRSS1 are present in one third of pediatric ARP and CP with no other cause. No clinical features or outcomes differentiated between the Pan-Mut group and the no-mutation group. The Pan-Mut subjects were more likely to have a family history of pancreatitis. Pediatric ARP and CP without identified cause should undergo genetic testing.

Objective: Reduced testosterone, a recognized comorbidity of reduced insulin sensitivity (IS) and type 2 diabetes (T2D), has also been reported in adult males with type 1 diabetes (T1D). However, there are limited data on how early reduced testosterone occurs, and whether it is related to the reduced IS in T1D. Leptin, a modulator of the HPG-axis, may also influence testosterone in T1D. We hypothesized that IS and leptin would be associated with total testosterone (TT), and free androgen index (FAI) in adolescent males with T1D., Methods: T1D (n = 35), T2D (n = 13), lean (n = 13) and obese (n = 9) adolescent males had IS measured by hyperinsulinemic-euglycemic clamps (glucose infusion rate [GIR]), in addition to leptin, sex hormone binding globulin (SHBG), TT, and FAI. The cohort was stratified into those with T1D (n = 35) and those without (n = 35)., Results: TT and SHBG were lower in T2D boys vs. lean controls, and GIR and leptin correlated with FAI and TT in non-T1D participants. However, despite being insulin resistant, adolescent males with T1D had normal TT and FAI, unrelated to GIR. In T1D, leptin was inversely associated with TT (p = 0.005) and FAI (p = 0.01), independent of puberty, hemoglobin A1c (HbA1c), diabetes duration, body mass index (BMI) z-score and GIR., Conclusion: Leptin accounted for a significant proportion of the variability of testosterone in T1D. However, despite reduced IS, there was no association between IS and testosterone in T1D adolescents. These observations suggest that the mechanisms affecting testosterone may differ between adolescent males with and without T1D., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The optimal rate of fluid administration in pediatric diabetic ketoacidosis (DKA) is unknown., Objective: Our aim was to determine whether the volume of fluid administration in children with DKA influences the rate of metabolic normalization., Methods: We performed a randomized controlled trial conducted in a tertiary pediatric emergency department from December 2007 until June 2010. The primary outcome was time to metabolic normalization; secondary outcomes were time to bicarbonate normalization, pH normalization, overall length of hospital treatment, and adverse outcomes. Children between 0 and 18 years of age were eligible if they had type 1 diabetes mellitus and DKA. Patients were randomized to receive intravenous (IV) fluid at low volume (10 mL/kg bolus + 1.25 × maintenance rate) or high volume (20 mL/kg bolus + 1.5 × maintenance rate) (n = 25 in each)., Results: After adjusting for initial differences in bicarbonate levels, time to metabolic normalization was significantly faster in the higher-volume infusion group compared to the low-volume infusion group (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.0-3.9; p = 0.04). Higher-volume IV fluid infusion appeared to hasten, to a greater extent, normalization of pH (HR = 2.5; 95% CI 1.2-5.0; p = 0.01) than normalization of serum bicarbonate (HR = 1.2; 95% CI 0.6-2.3; p = 0.6). The length of hospital treatment HR (0.8; 95% CI 0.4-1.5; p = 0.5) and time to discharge HR (0.8; 95% CI 0.4-1.5; p = 0.5) did not differ between treatment groups., Conclusions: Higher-volume fluid infusion in the treatment of pediatric DKA patients significantly shortened metabolic normalization time, but did not change overall length of hospital treatment. ClinicalTrials.gov ID NCT01701557., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population., Study Design: BMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative)., Results: Children with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (β = -1.25 ± 0.85, P = .0016) and tTGA (β = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA., Conclusions: The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The American Diabetes Association (ADA) recommends that children with type 1 diabetes (T1D) see a multidisciplinary team and have hemoglobin A1c (A1C) levels measured every 3 months. Patients in rural areas may not follow guidelines because of limited specialty care access. We hypothesized that videoconferencing would result in equivalent A1C compared with in-person visits and increased compliance with ADA recommendations., Materials and Methods: The Barbara Davis Center (BDC) (Aurora, CO) telemedicine program provides diabetes care to pediatric patients in Casper and Cheyenne, WY, via remote consultation with annual in-person visits. Over 27 months, 70 patients were consented, and 54 patients completed 1 year in the study., Results: Patients were 70% male, with a mean age of 12.1 ± 4.1 years and T1D duration of 5.4 ± 4.1 years. There was no significant change between baseline and 1-year A1C levels for patients with data at both time points. Patients saw diabetes specialists an average of 2.0 ± 1.3 times per year in the year prior to starting telemedicine and 2.9 ± 1.3 times (P < 0.0001) in the year after starting telemedicine. Patients and families missed significantly less school and work time to attend appointments., Conclusions: Our study suggests telemedicine is equivalent to in-person visits to maintain A1C, whereas families increase the number of visits in line with ADA recommendations. Patients and families miss less school and work. Decreased financial burden and increased access may improve overall diabetes care and compliance for rural patients. Further study is needed to detect long-term differences in complications screenings and the financial impact of telemedicine on pediatric diabetes care.

Background and Objectives: Disease-specific treatment options for autosomal dominant polycystic kidney disease are limited. Clinical intervention early in life is likely to have the greatest effect. In a 3-year randomized double-blind placebo-controlled phase 3 clinical trial, the authors recently showed that pravastatin decreased height-corrected total kidney volume (HtTKV) progression of structural kidney disease over a 3-year period. However, the underlying mechanisms have not been elucidated., Design, Setting, Participants, & Measurements: Participants were recruited nationally from July 2007 through October 2009. Plasma and urine samples collected at baseline, 18 months, and 36 months from 91 pediatric patients enrolled in the above-mentioned clinical trial were subjected to mass spectrometry-based biomarker analysis. Changes in biomarkers over 3 years were compared between placebo and pravastatin-treated groups. Linear regression was used to evaluate the changes in biomarkers with the percent change in HtTKV over 3 years., Results: Changes in plasma concentrations of proinflammatory and oxidative stress markers (9- hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, and 15-hydroxyeicosatetraenoic acid [HETE]) over 3 years were significantly different between the placebo and pravastatin-treated groups, with the pravastatin group showing a lower rate of biomarker increase. Urinary 8-HETE, 9-HETE, and 11-HETE were positively associated with the changes in HtTKV in the pravastatin group., Conclusions: Pravastatin therapy diminished the increase of cyclooxygenase- and lipoxygenase-derived plasma lipid mediators. The identified biomarkers and related molecular pathways of inflammation and endothelial dysfunction may present potential targets for monitoring of disease severity and therapeutic intervention of autosomal dominant polycystic kidney disease., (Copyright © 2015 by the American Society of Nephrology.)

Background: Uric acid is associated with increased risk of cardiovascular disease and arterial stiffness in patients with hypertension or stroke. It remains unknown if uric acid is associated with arterial stiffness in the general population., Methods: We analyzed the association between serum uric acid levels and measures of arterial stiffness such as carotid-femoral pulse wave velocity (CF PWV), carotid-radial pulse wave velocity (CR PWV) and augmentation index (AI) in 4,140 participants from the Generation 3 Framingham cohort using linear regression., Results: Mean (SD) age was 40.0 (8.8) years and mean (SD) serum uric acid levels were 5.3 (1.5) mg/dl. Mean (SD) CF PWV was 7.0 (1.4) m/s. Individuals in the highest quartile of uric acid were more likely to be male, have a higher prevalence of hypertension, higher BMI, fasting glucose and insulin, and lower estimated glomerular filtration rate (eGFR). Multivariate adjusted means of CF PWV were 6.90, 6.94, 7.06, and 7.15 m/s for uric acid quartile 1, 2, 3, and 4 respectively. In unadjusted analysis each 1mg/dl increase in uric acid was associated with higher CF-PWV (β = 0.27; 95% CI = 0.25, 0.29; P < 0.0001). This was attenuated but remained significant after adjusting for age, sex, smoking, hypertension, BMI, fasting glucose, insulin, animal protein intake, and eGFR (β= 0.06; 95% CI = 0.02, 0.09; P < 0.0007). There was no association between serum uric acid levels and AI upon adjustment for cardiovascular risk factors., Conclusions: Serum uric acid levels are significantly associated with CF PWV and CR PWV in a younger Caucasian population., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Insulin resistance increases during adolescence in those with type 1 diabetes mellitus (T1DM), complicating glycemic control and potentially increasing cardiovascular disease (CVD) risk. Metformin, typically used in type 2 diabetes mellitus (T2DM), is a possible adjunct therapy in T1DM to help improve glycemic control and insulin sensitivity., Objective: We hypothesized that metformin would improve metabolic parameters in adolescents with T1DM., Design, Setting, and Participants: This randomized, double-blinded, placebo-controlled trial included 74 pubertal adolescents (ages: 13-20 yr) with T1DM. Participants were randomized to receive either metformin or placebo for 6 months. Glycated hemoglobin (HbA1c), insulin dose, waist circumference, body mass index (BMI), and blood pressure were measured at baseline, 3 and 6 months, with fasting lipids measured at baseline and 6 months., Results: Total daily insulin dose, BMI z-score and waist circumference significantly decreased at 3 and 6 months compared to baseline within the metformin group, even among normal-weight participants. In the placebo group, total insulin dose and systolic blood pressure increased significantly at 3 months and total insulin dose increased significantly at 6 months. No significant change was observed in HbA1c at any time point between metformin and placebo groups or within either group., Conclusions: Low-dose metformin likely improves BMI as well as insulin sensitivity in T1DM adolescents, as indicated by a decrease in total daily insulin dose. The decrease in waist circumference indicates that fat distribution is also likely impacted by metformin in T1DM. Further studies with higher metformin doses and more detailed measurements are needed to confirm these results, their underlying mechanisms, and potential impact on CVD in T1DM youth., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression., (Copyright © 2014 the American Physiological Society.)

Background: Standardization of the hemoglobin A1c (A1c) assay has led to its increasing utilization as a screening tool for the diagnosis of prediabetes and type 2 diabetes in youth. However, significant A1c assay variability remains and has implications for clinical management., Objective: To describe our center's experiences with A1c results in youth and to evaluate inter-method differences and their clinical implications., Subjects: Seventy-five youth (aged 10-18 yr old), body mass index (BMI) ≥85th‰ participated., Methods: Seventy-two participants had two A1c values performed on the same sample, one via immunoassay (DCA Vantage Analyzer, A1c1 ) and the other via high performance liquid chromatography (Bio-Rad Variant II, A1c2 ). Nineteen had A1c run on two immunoassay devices (A1c1 and Dimensions Vista, A1c3 )., Results: Mean age of participants was 13.9 years, BMI% 97.89%, 33% male, 16% white, 21% black, and 61% Hispanic (H). Mean A1c1 was 5.68% ± 0.38 vs. a mean A1c2 of 5.73% ± 0.39, p = 0.049. Concordance in diabetes status between methods was achieved in 79% of subjects. Nineteen subjects with A1c3 results had testing performed an average of 22 ± 9 days prior to A1c1 . Mean A1c3 was 6.24% ± 0.4, compared to a mean A1c1 of 5.74% ± 0.31, (p < 0.0001). A1c1 was on average systematically -0.5 ± 0.28 lower compared to A1c3 . There was poor agreement in diabetes classification between A1c1 and A1c3 , with a concordance in classification between methods of only 36.8%., Conclusions: Clinically significant inter-method A1c variability exists that impacts patient classification and treatment recommendations. In the screening of obese youth for diabetes, A1c results should be interpreted with caution., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Unlabelled: Insulin resistance is increasingly prevalent in children and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used phosphorus magnetic resonance spectroscopy (P-MRS), a noninvasive technique appealing for clinical research. P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly in those with a disease, is problematic because of variability in perception of effort and motivation. We therefore developed a method to predict MVC using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations., Methods: Data were collected from 66 sedentary 12- to 20-yr-old participants. Plantarflexion MVC was assessed using an MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from magnetic resonance images. Data from the first 26 participants were used to model the relation between MVC and MCSA (predicted MVC = 24.763 + 0.0047 MCSA). This model was then applied to the subsequent 40 participants., Results: MVC versus model-predicted mean MVC was 43.9 ± 0.8 kg versus 44.2 ± 1.81 (P = 0.90). P-MRS results when predicted and MVC were similar showed expected changes during MVC-based exercise. In contrast, MVC was markedly lower than predicted in four participants and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations., Conclusions: Compared with using MVC testing alone, using magnetic resonance imaging to predict muscle strength allows for a more accurate and standardized P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youths. These studies have importance as we seek to determine the role of mitochondrial function in youths with insulin resistance and diabetes and response to interventions.

Background Context: Blood loss in patients with adolescent idiopathic scoliosis (AIS) who are undergoing posterior spinal instrumentation and fusion (PSIF) varies greatly. The reason for this wide range is not clear. There are reports of unexpected massive hemorrhage during these surgeries. Many studies reflect authors' preferences for describing blood loss in terms of levels fused, weight, or percent blood volume., Purpose: We sought to define excessive blood loss clinically, determine its incidence in our study population, and identify associated variables. Results are intended to inform perioperative preparation for these cases. Results may be used to inform prospective study designs., Study Design: This was a retrospective uncontrolled case series., Patient Sample: A total of 311 consecutive AIS PSIF cases during the years 2005-2010 performed at Children's Hospital Colorado were studied., Outcome Measures: We measured estimated blood loss (EBL) and its association with multiple patient, surgical, and anesthetic variables., Methods: Thirty-one variables potentially related to blood loss were collected retrospectively from electronic medical records for analysis. When no cases of clearly excessive blood loss were identified on the basis of visual examination of EBL distribution, we chose to use the top 10% of blood loss cases as an arbitrary determinant of excessive blood loss. Three cut-off strategies captured the top 10% of EBL cases with little variation in who was selected: 1) >1,700 mL of EBL, 2) >50% EBL/estimated blood volume, and 3) >150 mL/level fused EBL. Variables were compared with the χ(2) test, Fisher exact, or t-tests, when appropriate. A generalized linear mixed logistic model was used to determine the probability of excessive blood loss based on the number of levels fused., Results: The average EBL was 89.17 mL/level fused (range, 45-133 mL). EBL fit a progressively wider distribution as surgical complexity (number of levels fused) increased. Number of levels fused (p<.0001), operative time (p=.0139), number of screws (p<.0001), and maximal preoperative Cobb angle (p=.0491) were significantly associated with excessive blood loss. The variable that was most strongly associated with excessive blood loss was the number of levels fused, with ≥12 levels having a probability of >10% of excessive hemorrhage., Conclusion: Excessive blood loss may be an arbitrary number until future research suggests otherwise. We show that the probability of exceeding one of our arbitrary definitions is approximately 10% when 12 or more levels are fused. If a 10% incidence of excessive blood loss is determined to be clinically relevant, teams might wish to pursue hematologic consultation and maximal blood conservation strategy when 12 or more levels are planned for fusion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Early morning blood pressure surge (MBPS) is a risk factor for cardiovascular events (CVEs), but the relationship with uric acid is not well understood. The authors aimed to determine the association between MBPS and increased uric acid and the effect of elevated MBPS and uric acid combination on CVEs. A total of 921 patients underwent 24-hour ambulatory blood pressure monitoring and were followed for a median of 40 months. During this period, 103 (11.2%) CVEs occurred. There was a significant relationship between increasing quartiles of serum uric acid level and increasing values of MBPS (P<.0001). Patients in the highest quartile stratified by elevated MBPS and serum uric acid level had a 3.55 odds of major CVE compared with patients in the lowest quartile. Serum uric acid is associated with MBPS and development of new CVEs., (©2014 Wiley Periodicals, Inc.)

Albuminuria is a strong, independent predictor of chronic kidney disease progression. We hypothesize that podocyte processing of albumin via the lysosome may be an important determinant of podocyte injury and loss. A human urine derived podocyte-like epithelial cell (HUPEC) line was used for in vitro experiments. Albumin uptake was quantified by Western blot after loading HUPECs with fluorescein-labeled (FITC) albumin. Co-localization of albumin with lysosomes was determined by confocal microscopy. Albumin degradation was measured by quantifying FITC-albumin abundance in HUPEC lysates by Western blot. Degradation experiments were repeated using HUPECs treated with chloroquine, a lysosome inhibitor, or MG-132, a proteasome inhibitor. Lysosome activity was measured by fluorescence recovery after photo bleaching (FRAP). Cytokine production was measured by ELISA. Cell death was determined by trypan blue staining. In vivo, staining with lysosome-associated membrane protein-1 (LAMP-1) was performed on tissue from a Denys-Drash trangenic mouse model of nephrotic syndrome. HUPECs endocytosed albumin, which co-localized with lysosomes. Choloroquine, but not MG-132, inhibited albumin degradation, indicating that degradation occurs in lysosomes. Cathepsin B activity, measured by FRAP, significantly decreased in HUPECs exposed to albumin (12.5% of activity in controls) and chloroquine (12.8%), and declined further with exposure to albumin plus chloroquine (8.2%, p<0.05). Cytokine production and cell death were significantly increased in HUPECs exposed to albumin and chloroquine alone, and these effects were potentiated by exposure to albumin plus chloroquine. Compared to wild-type mice, glomerular staining of LAMP-1 was significantly increased in Denys-Drash mice and appeared to be most prominent in podocytes. These data suggest lysosomes are involved in the processing of endocytosed albumin in podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases. Modifiers of lysosomal activity may have therapeutic potential in slowing the progression of glomerulosclerosis by enhancing the ability of podocytes to process and degrade albumin.