Genetic and pharmacologic p32-inhibition rescue CHCHD2-linked Parkinson's disease phenotypes in vivo and in cell models.

BACKGROUND: Mutations in CHCHD2 have been linked to Parkinson's disease, however, their exact pathophysiologic roles are unclear. The p32 protein has been suggested to interact with CHCHD2, however, the physiological functions of such interaction in the context of PD have not been clarified. METHODS: Interaction between CHCHD2 and p32 was confirmed by co-immunoprecipitation experiments. We studied the effect of p32-knockdown in the transgenic Drosophila and Hela cells expressing the wild type and the pathogenic variants of hCHCHD2. We further investigated the rescue ability of a custom generated p32-inhibitor in these models as well as in the human fibroblast derived neural precursor cells and the dopaminergic neurons harboring hCHCHD2-Arg145Gln. RESULTS: Our results showed that wildtype and mutant hCHCHD2 could bind to p32 in vitro, supported by in vivo interaction between human CHCHD2 and Drosophila p32. Knockdown of p32 reduced mutant hCHCHD2 levels in Drosophila and in vitro. In Drosophila hCHCHD2 models, inhibition of p32 through genetic knockdown and pharmacological treatment using a customized p32-inhibitor restored dopaminergic neuron numbers and improved mitochondrial morphology. These were correlated with improved locomotor function, reduced oxidative stress and decreased mortality. Consistently, Hela cells expressing mutant hCHCHD2 showed improved mitochondrial morphology and function after treatment with the p32-inhibitor. As compared to the isogenic control cells, large percentage of the mutant neural precursor cells and dopaminergic neurons harboring hCHCHD2-Arg145Gln contained fragmented mitochondria which was accompanied by lower ATP production and cell viability. The NPCs harboring hCHCHD2-Arg145Gln also had a marked increase in α-synuclein expression. The p32-inhibitor was able to ameliorate the mitochondrial fragmentation, restored ATP levels, increased cell viability and reduced α-synuclein level in these cells. CONCLUSIONS: Our study identified p32 as a modulator of CHCHD2, possibly exerting its effects by reducing the toxic mutant hCHCHD2 expression and/or mitigating the downstream effects. Inhibition of the p32 pathway can be a potential therapeutic intervention for CHCHD2-linked PD and diseases involving mitochondrial dysfunction.

Ultrathin Bronchoscopy Without Virtual Navigation for Diagnosis of Peripheral Lung Lesions.

BACKGROUND: The increasing incidence of encountering lung nodules necessitates an ongoing search for improved diagnostic procedures. Various bronchoscopic technologies have been introduced or are in development, but further studies are needed to define a method that fits best in clinical practice and health care systems. RESEARCH QUESTION: How do basic bronchoscopic tools including a combination of thin (outer diameter 4.2 mm) and ultrathin bronchoscopes (outer diameter 3.0 mm), radial endobronchial ultrasound (rEBUS) and fluoroscopy perform in peripheral pulmonary lesion diagnosis? STUDY DESIGN AND METHODS: This is a retrospective review of the performance of peripheral bronchoscopy using thin and ultrathin bronchoscopy with rEBUS and 2D fluoroscopy without a navigational system for evaluating peripheral lung lesions in a single academic medical center from 11/2015 to 1/2021. We used a strict definition for diagnostic yield and assessed the impact of different variables on diagnostic yield, specifically after employment of the ultrathin bronchoscope. Logistic regression models were employed to assess the independent associations of the most impactful variables. RESULTS: A total of 322 patients were included in this study. The median of the long axis diameter was 2.2 cm and the median distance of the center of the lesion from the visceral pleural surface was 1.9 cm. Overall diagnostic yield was 81.3% after employment of the ultrathin bronchoscope, with more detection of concentric rEBUS views (93% vs. 78%, p < 0.001). Sensitivity for detecting malignancy also increased from 60.5% to 74.7% (p = 0.033) after incorporating the ultrathin scope into practice, while bronchus sign and peripheral location of the lesion were not found to affect diagnostic yield. Concentric rEBUS view, solid appearance, upper/middle lobe location and larger size of the nodules were found to be independent predictors of successful achievement of diagnosis at bronchoscopy. INTERPRETATION: This study demonstrates a high diagnostic yield of biopsy of lung lesions achieved by utilization of thin and ultrathin bronchoscopes. Direct visualization of small peripheral airways with simultaneous rEBUS confirmation increased localization rate of small lesions in a conventional bronchoscopy setting without virtual navigational planning.

Evaluating the Incidence and Risk Factors for Acute Cellular Rejection in a Steroid Sparing Liver Transplant Center.

BACKGROUND: Corticosteroids has been the mainstay of immunosuppression (IMS) following liver transplant (LT). With the advent of more potent IMS, complete steroid withdrawal has become possible after LT. However, there is limited data regarding the incidence and risk factors for acute cellular rejection (ACR) in LT recipients on steroid sparing regimens. OBJECTIVE: To identify the incidence and risk factors of ACR in LT recipients at an urban LT center utilizing a steroid-sparing IMS regimen. METHODS: This was a single center retrospective study evaluating incidence of ACR in adults (>18 years) who received a LT between 01/01/2008 and 6/30/2019 at a steroid-sparing liver transplant center. Data between patients who had ACR and patients who did not were compared and risk factors were identified by multivariate logistic linear regression. RESULTS: A total of 266 patients were included in this analysis, of which 18.4% experienced ACR within the first year of LT. Median time to first ACR was 134 (interquartile range [IQR]: 34-246) days. Black race (odds ratio [OR]: 4.39, P < 0.001), continued need for prednisone (OR: 2.80, P = 0.015) and cytomegalovirus (CMV) viremia (OR: 6.27, P < 0.001)) were independent risk factors for ACR. Tacrolimus use was associated with less ACR (OR: 0.33, P = 0.013). CONCLUSION AND RELEVANCE: Steroid sparing regimens for IMS post-LT were not associated with an increased incidence of ACR when compared to reported ACR rates in literature. Potential risk factors for ACR include Black race, the use of prednisone maintenance IMS therapy, and CMV viremia.

Barriers to Surgical Intervention and Factors Influencing Motor Outcomes in Patients with Severe Peripheral Nerve Injury: A Province Wide Cohort Study.

INTRODUCTION: Despite the importance of timing of nerve surgery after peripheral nerve injury, optimal timing of intervention has not been clearly delineated. The goal of this study is to explore factors that may have a significant impact on clinical outcomes of severe peripheral nerve injury that requires reconstruction with nerve transfer or graft. MATERIALS AND METHODS: Adult patients who underwent peripheral nerve transfer or grafting in Alberta were reviewed. Clustered multivariable logistic regression analysis was used to examine the association of time to surgery, type of nerve repair, and patient characteristics on strength outcomes. Cox proportional hazard regression analysis model was used to examine factors correlated with increased time to surgery. RESULTS: Of the 163 patients identified, the median time to surgery was 212 days. For every week of delay, the adjusted odds of achieving Medical Research Council strength grade ≥ 3 decreases by 3%. An increase in preinjury comorbidities was associated with longer overall time to surgery (aHR 0.84, 95% CI 0.74-0.95). Referrals made by surgeons were associated with a shorter time to surgery compared to general practitioners (aHR 1.87, 95% CI 1.14-3.06). In patients treated with nerve transfer, the adjusted odds of achieving antigravity strength was 388% compared to nerve grafting; while the adjusted odds decreased by 65% if the injury sustained had a pre-ganglionic injury component. CONCLUSION: Mitigating delays in surgical intervention is crucial to optimizing outcomes. The nature of initial nerve injury and surgical reconstructive techniques are additional important factors that impact postoperative outcomes.

A novel GNAS variant presents with disorders of GNAS inactivation and cardiomyopathy.

The GNAS gene (OMIM#139320), located on chromosome 20q13.2, encodes for the alpha-subunit of the stimulatory signaling protein, Gsα protein. GNAS variants with inactivating properties are associated with Albright's hereditary osteodystrophy (AHO) and when maternally inherited, pseudohypoparathyroidism 1a (OMIM#103580), which includes multiple hormone resistance. In this clinical report we describe a novel GNAS variant, c.159A>G, p.K53N, in an individual with features consistent with AHO and pseudohypoparathyroidism 1a and its segregation through multiple maternal relatives, including two genotype positive maternal first cousins who also display features classic for AHO. The proband developed unique features including cardiomyopathy which required a heart transplant at 5 years old and immune dysregulation resulting in multisystem organ failure and ultimately, death at the age of 18 years. Additional investigations exploring alternative explanations for the proband's presentation were pursued including whole genome sequencing which was negative. We postulate that the atypical features seen in the proband may have resulted from dysregulated Gsα signaling in cardiac tissue. Future studies are needed to explore the properties of the K53N GNAS variant and this proposed mechanism.

Incidence and risk factors for the development of cytomegalovirus viremia in a steroid sparing liver transplant center.

BACKGROUND: Cytomegalovirus (CMV) is a common opportunistic infection in patients after liver transplant (LT). Guidelines recommend 900 mg daily of valganciclovir; however, valganciclovir commonly causes dose-dependent hematologic toxicities. Use of a low-dose valganciclovir (450 mg) has been used to prevent these adverse effects, but the data regarding this dosing strategy are not as robust in a steroid sparing LT center. METHODS: Retrospective chart review of adult LT recipients between January 1, 2008 and June 30, 2019. All patients received low-dose valganciclovir 450 mg PO daily for CMV prophylaxis. Primary outcome was the incidence of CMV viremia in LT recipients at 12 months post-LT. Secondary outcomes include time to CMV viremia, risk factors for the development of CMV viremia, and incidence of breakthrough CMV viremia while on valganciclovir prophylaxis. RESULTS: A total of 266 patients were included. Overall, the majority were male (63.2%) and Caucasian (45.5%). The most common indication for transplant was decompensated cirrhosis (82%). The incidence of CMV at 1 year posttransplant was 7.9%. Independent risk factors included high risk status (OR 5.97, 95% CI 2.14-16.61, p = .001) as well as having an episode of rejection (OR 5.99, 95% CI 2.16-16.66, p = .001). CONCLUSION: Low-dose valganciclovir can be effective in the prevention of CMV viremia in LT patients and may be a beneficial strategy for CMV prophylaxis in a steroid-sparing transplant center. Further studies may be needed to determine appropriate length of prophylaxis therapy for different risk groups.

Selective internal radiation therapy for hepatocellular carcinoma: A 15-year multicenter Australian cohort study.

BACKGROUND AND AIM: The exact place for selective internal radiation therapy (SIRT) in the therapeutic algorithm for hepatocellular carcinoma (HCC) is debated. There are limited data on its indications, efficacy, and safety in Australia. METHODS: We performed a multicenter retrospective cohort study of patients undergoing SIRT for HCC in all Sydney hospitals between 2005 and 2019. The primary outcome was overall survival. Secondary outcomes were progression-free survival and adverse events. RESULTS: During the study period, 156 patients underwent SIRT across 10 institutions (mean age 67 years, 81% male). SIRT use progressively increased from 2005 (n = 2), peaking in 2017 (n = 42) before declining (2019: n = 21). Barcelona Clinic Liver Cancer stages at treatment were A (13%), B (33%), C (52%), and D (2%). Forty-four (28%) patients had tumor thrombus. After a median follow-up of 13.9 months, there were 117 deaths. Median overall survival was 15 months (95% confidence interval 11-19). Independent predictors of mortality on multivariable analysis were extent of liver involvement, Barcelona Clinic Liver Cancer stage, baseline ascites, alpha fetoprotein, and model for end-stage liver disease score. Median progression-free survival was 6.0 months (95% confidence interval 5.1-6.9 months). Following SIRT, 11% of patients were downstaged to curative therapy. SIRT-related complications occurred in 17%: radioembolization-induced liver disease (11%), pneumonitis (3%), gastrointestinal ulceration, and cholecystitis (1% each). Baseline ascites predicted for radioembolization-induced liver disease. CONCLUSION: We present the largest Australian SIRT cohort for HCC. We have identified several factors associated with a poor outcome following SIRT. Patients with early-stage disease had the best survival with some being downstaged to curative therapy.

Discussion: can upper extremity (deltoid) near infrared spectroscopy be used to assess cerebral tissue bed saturation on femorally cannulated veno-arterial extracorporeal membrane oxygenation patients?

Continuous cerebral tissue saturation monitoring with near infrared spectroscopy may help clinicians identify cerebral desaturation early; however, patients have reported discomfort from near infrared spectroscopy monitoring pads on the forehead. This study aims to compare upper extremity near infrared spectroscopy monitoring to cerebral near infrared spectroscopy monitoring to assess its viability as a surrogate for cerebral saturation. A retrospective analysis of 10 femorally cannulated veno-arterial extracorporeal membrane oxygenation patients was performed comparing left (L) and right (R) upper extremity (deltoid) near infrared spectroscopy monitoring to cerebral near infrared spectroscopy monitoring (n = 20 data sets, 10 left and 10 right) and right radial blood gasses. Deltoid and cerebral near infrared spectroscopy values were recorded every 15 minutes for at least 24 hours when possible, were plotted on scatter grams, and were analyzed using Pearson product-moment coefficient (r). Based on the concept of covariance, a moderate-good relationship r = 0.50-0.75 was noted in 10% (n = 2) of the study group. A fair relationship r = 0.25-0.50 was noted in 50% (n = 10), and little or no relationship was noted in 40% (n = 8). None of the study group displayed a good to excellent relationship (r = 0.75 or above). In addition, coefficient of multiple determination for multiple regression R2 was calculated and strong fit of the regression line was not noted. Although cerebral near infrared spectroscopy monitoring has been extremely helpful in identifying low cerebral tissue saturation on veno-arterial extracorporeal membrane oxygenation patients, the use of upper extremity (peripheral deltoid) tissue monitoring does not provide adequate correlation and should not be used as a surrogate to cerebral monitoring.

Normal Hemoglobin A1c Variability in Early Adolescence: Adult Criteria for Prediabetes Should Be Applied with Caution.

American Diabetes Association adult criteria are used to screen youth for diabetes, but little is known about normal glycemia in youth. In the HEALTHY Study (total n = 8814), hemoglobin A1c was ≥5.7% in 2% of normal weight youth. This suggests need for cautious interpretation of prediabetes hemoglobin A1s in youth.

Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure.

OBJECTIVE: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and ß-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. ß-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS: In TODAY, ß-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.

Screening for cystic fibrosis-related diabetes and prediabetes: Evaluating 1,5-anhydroglucitol, fructosamine, glycated albumin, and hemoglobin A1c.

OBJECTIVE: Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers-hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)-as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG). METHODS: Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined. RESULTS: Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC's for all alternate markers were low for CFPD (0.52-0.67) and CFRD (0.56-0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45-0.94) and 41% specificity (95% CI: 0.28-0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42-0.8). CONCLUSIONS: All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG.

Endocrine Complications of Cystic Fibrosis: A Multisystem Disease of the Endocrine Organs.

Cystic fibrosis (CF) is one of the most common life-limiting genetic disorders. Although CF is typically considered primarily as a pulmonary disease, the CF conductance transmembrane regulator is present throughout the body. From an endocrine perspective, this multisystem disease manifests primarily in the pancreas as a unique form of diabetes (CF-related diabetes mellitus), as bone disease, and as reproductive health issues in people with CF. These complications have become ever more concerning to people with CF as treatment for pulmonary disease improves and lifespans lengthen, increasing the impact of nonpulmonary complications. Our understanding of the management of these concerns continues to evolve, and, although there are some effective treatments, there is great opportunity for continued investigation into the pathophysiology of the endocrine complications of CF and their treatment.

Characterizing idiopathic pulmonary fibrosis patients using US Medicare-advantage health plan claims data.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare life-threating interstitial lung disease (ILD). This study characterizes demographics, health care utilization, and comorbidities among elderly IPF patients and estimates prevalence and incidence rates for selected outcomes. METHODS: Cohort study using a large US health insurance database (Optum's Medicare Advantage plan). INCLUSION CRITERIA: ≥ 1 diagnosis code for IPF (2008 - 2014), age ≥65 years, no diagnosis of IPF or other ILD in prior 12 months. Demographics, health care utilization, comorbidities and incidence rates for various outcomes were estimated. Follow-up continued until the earliest of: health plan disenrollment, death, a claim for another known cause of ILD, or end of the study period. RESULTS: 4,716 patients were eligible; 53.4% had IPF diagnostic testing. Median age was 77.5 years, 50.3% were male, median follow-up time was 0.8 years. Incidence rates ranged from 1.0/1,000 person-years (lung transplantation) to 374.3/1,000 person-years (arterial hypertension). Baseline characteristics and incidence rates were similar for cohorts of patients with and without IPF diagnostic testing. CONCLUSIONS: Elderly IPF patients experience a variety of comorbidities before and after IPF diagnosis. Therapies for IPF and for the associated comorbidities may reduce morbidity and associated health care utilization of these patients.

Transcranial Doppler is an effective method in assessing cerebral blood flow patterns during peripheral venoarterial extracorporeal membrane oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) can be life-saving in refractory cardiogenic shock but carries a risk of neurologic complications such as stroke and hemorrhage. As little is known about the effects of different peripheral VA-ECMO cannulation sites on cerebral blood flow (CBF), transcranial Doppler (TCD) was used to determine whether the cannulation site affects CBF. METHODS: Thirty-seven patients receiving VA-ECMO for cardiogenic shock via axillary or femoral artery cannulation were prospectively enrolled. Measured bilateral middle cerebral artery (MCA), mean flow velocities (MFV), and pulsatility indices (PI) were the primary outcomes and adverse neurologic events were secondary outcomes. RESULTS: The median age was 58 years (IQR 51-66) with 26 (70%) males. Median VA-ECMO flow was 3.8 L/min (IQR 3.2-4.9) with mean arterial pressures of 80 mm Hg (IQR 75-86). Nineteen patients received right axillary artery cannulation while 18 underwent femoral cannulation. Compared with the femoral group, MFV was higher in the axillary group in the right MCA (46 cm/s [IQR 26-57] vs 27 [17-36], P = 0.03) and left (43 [IQR 35-60] vs 29 cm/s [16-48], P = 0.05). Axillary PI was significantly lower compared with the femoral group (right: 0.48 cm/s [0.25-0.65] vs 0.83 [0.66-0.93], P = 0.02; left: 0.41 cm/s [0.29-0.63] vs 1.02 [0.7-1.3], P = 0.004). One axillary patient experienced a stroke with deficits. CONCLUSIONS: TCD appears to be an effective tool for indirect monitoring of CBF in patients with ECMO with limited pulsatility. Axillary artery cannulation seems to provide higher cerebral flow rates without any difference in neurologic outcomes. Future studies may incorporate TCD into regulating ECMO flows to achieve physiologic CBF.

Immune-mediated graft dysfunction in liver transplant recipients with hepatitis C virus treated with direct-acting antiviral therapy.

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls-33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.

Reduced insulin sensitivity is correlated with impaired sleep in adolescents with cystic fibrosis.

BACKGROUND: Prevalence of cystic fibrosis-related diabetes (CFRD) rises sharply in adolescence/young-adulthood and is associated with increased morbidity/mortality. Sleep may be a modifiable risk factor for diabetes but its relationship with metabolic function has not been fully examined in youth with CF. The aim of the study was to examine the relationship between objectively measured sleep and glucose metabolism in youth with CF. METHODS: Adolescents (43 with CF and 11 healthy controls) completed 1-week of concurrent home continuous glucose monitoring (CGM) and actigraphy. Fasting labs and an oral glucose tolerance test were obtained. T-tests and analysis of variance (ANOVA) were used to test differences between actigraphy outcomes in CF participants and controls. Spearman's rank correlation coefficients were used to test for correlations between actigraphy, CGM, and insulin sensitivity (IS) measures. RESULTS: All participants averaged insufficient sleep (mean = 7.5 hours per night) compared to the 8 to 10 hours recommended for this age group. CF participants had poorer sleep by actigraphy measures than healthy controls. Higher minimum daytime glucoses on CGM correlated with shorter total sleep time (TST) and worse sleep efficiency (SE). Reduced IS in CF participants with dysglycemia was correlated with shorter TST, longer sleep latency, more wake after sleep onset, and poorer SE. CONCLUSIONS: Poor sleep appears to correlate with higher blood glucose and lower IS in CF adolescents with dysglycemia. Further research is needed to better understand the mechanisms and directionality behind this relationship.

An Analysis of Risk Factors for Hemolysis in Children on Extracorporeal Membrane Oxygenation.

OBJECTIVES: Hemolysis is a known complication of pediatric extracorporeal membrane oxygenation associated with renal failure and mortality. We sought to identify predictors of hemolysis in pediatric extracorporeal membrane oxygenation patients and determine its influence on outcomes. DESIGN: Retrospective, single-center study. SETTING: Urban, quaternary care center pediatric and neonatal ICU. PATIENTS: Ninety-six patients requiring extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily measurements of plasma-free hemoglobin were obtained while patients were on extracorporeal membrane oxygenation. Patients with a prior extracorporeal membrane oxygenation run, on extracorporeal membrane oxygenation for less than 24 hours, or without complete medical records were excluded from the study. Ninety-six patients met inclusion criteria, of which, 25 patients (26%) had plasma-free hemoglobin greater than 30 mg/dL. Of those patients, 15 of 25(60%) had plasma-free hemoglobin greater than 50 mg/dL, and 21 of 25(84%) occurred during the first 7 days on extracorporeal membrane oxygenation. Compared with patients without hemolysis, those with hemolysis were younger (0.2 mo [0.06-3.2 mo] vs 8.2 mo [0.6-86 mo]; p < 0.001), had a higher pericannulation international normalized ratio (3.9 [3.5-5.5] vs 2.6 [1.8-3.7]; p = 0.003), lower pericannulation platelet count (33 × 10/µL [22-42 × 10/µL] vs 61 × 10/µL [38-86 × 10/µL]; p < 0.001), and had a less negative inlet pressure (-3.5 mm Hg [-14 to 11.5 mm Hg] vs -19 mm Hg [-47 to 0 mm Hg]; p = 0.01). A greater proportion of patients with hemolysis had a heparin assay less than 0.2 mg/dL (50% vs 17%; p = 0.001) and had fluid removal via slow continuous ultrafiltration (32% vs 6%; p < 0.001). Patients with hemolysis had increased risk of in-hospital mortality (odds ratio 10.0; 95% CI 3.4-32; p < 0.001). On multivariable analysis, continuous ultrafiltration (odds ratio, 8.0; 95% CI, 1.9-42; p = 0.007) and pericannulation international normalized ratio greater than 3.5 (odds ratio, 7.2; 95% CI, 2.3-26; p = 0.001) were significantly associated with hemolysis. CONCLUSIONS: Hemolysis is a common complication of pediatric extracorporeal membrane oxygenation. We found that patients with hemolysis (plasma-free hemoglobin > 30 mg/dL) had a 10-fold increase in in-hospital mortality. In our study cohort, hemolysis was associated with continuous ultrafiltration use, but not continuous renal replacement therapy. Additionally, our results suggest that the degree of coagulopathy (international normalized ratio > 3.5) at the time of cannulation influences hemolysis. Additional prospective studies are necessary to define further strategies to prevent hemolysis and improve outcomes in pediatric extracorporeal membrane oxygenation patients.

Using near-infrared reflectance spectroscopy (NIRS) to assess distal-limb perfusion on venoarterial (V-A) extracorporeal membrane oxygenation (ECMO) patients with femoral cannulation.

BACKGROUND: Patients requiring V-A ECMO who receive femoral cannulation have an associated risk of distal, lower-limb hypoperfusion and ischemia of the cannulated leg. This pilot study evaluated the usefulness of non-invasive lower-limb oximetry, using near-infrared reflectance spectroscopy (NIRS) to detect limb ischemia. METHODS: Between June 2016 and January 2017, 25 patients receiving femoral V-A ECMO were continuously monitored using the CASMED Fore-Sight Elite (CAS Medical Systems Inc., Branford, CT) tissue oximeter. A retrospective pilot study was conducted to review the correlation between NIRS tissue saturations (StO2) and clinical indications of limb ischemia. Patients were monitored for StO2s less than 50% for more than four minutes or StO2 differentials between the cannulated and non-cannulated legs greater than 15%. RESULTS: Twenty-five patients (age 22-78) were monitored with NIRS. Six patients had clinical indications of lower-limb ischemia: cold limb, mottled skin and pulseless Doppler ultrasound. All six patients had StO2s below 50% that persisted for longer than four minutes. Of the 25 patients, one patient had a false-positive indication of hypoperfusion with StO2 below 50% for more than four minutes due to a venous saturation below 30%. Another patient had a false-positive pulseless Doppler ultrasound caused by high doses of pressor support. The StO2 was greater than 60%, which confirmed the clinical determination of adequate perfusion. Five patients had StO2s below 50% for less than four minutes and none of these patients had clinical indications of lower-limb hypoperfusion. All patients with cannula-related obstruction of flow to the distal portion of the leg had StO2 differentials greater than 15%. No patients without cannula-related obstruction to flow had StO2 differentials greater than 15%. CONCLUSION: Advancements in NIRS technology seem to have improved its accuracy for continuous, non-invasive monitoring of regional tissue and may provide clinicians with an additional metric to protect the distal portion of the cannulated leg.

Use of Continuous Glucose Monitoring in Youth-Onset Type 2 Diabetes.

PURPOSE OF REVIEW: Continuous glucose monitoring (CGM) technology has long been accepted as a tool for managing glycemia in type 1 diabetes (T1D) and is receiving increased attention as a tool for monitoring glucose patterns in patients with other forms of diabetes, in particular type 2 diabetes (T2D). Recent studies in adults with T2D have shown benefits of CGM in the investigation of glycemic variability, as well as utility as a tool for improving glycemic control. The literature on CGM use in youth-onset T2D, however, is sparse. This paper reviews the various roles for CGM in T2D, with a focus on published reports of CGM use in youth-onset T2D. The gaps in knowledge are highlighted, along with a discussion regarding need for future studies of potential applications for CGM in this younger population. RECENT FINDINGS: CGM systems provide insight into glycemic abnormalities in obese youth with and at risk for T2D. This technology has enabled examination of the relationship between free-living glycemic profiles and traditional diabetes screening tests, as well as markers of cardiometabolic risk in this high-risk population. Investigators are incorporating CGM technology into the study of T2D in youth, but interventional studies of CGM as a tool for glycemic control in youth-onset T2D are limited. Youth with T2D face a more aggressive disease than adults with T2D, and further studies utilizing advances in glucose monitoring technology to improve outcomes in this population are needed.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.