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To describe the incidence and presentation of pancreatitis in Children with Medical Complexity (CMC) while evaluating severity of disease and outlining risk factors.This was a retrospective chart review between January 2010 and December 2019 of patients seen in the complex care clinic at Nationwide Children's Hospital (NCH) and Cincinnati Children's Hospital Medical Center (CCHMC). Data collected included sex, underlying diagnosis, family history of pancreatitis, type of pancreatitis, signs/symptoms, abdominal imaging, severity of attack, and presence of various risk factors associated with pancreatitis. Severity and diagnosis of pancreatitis was determined based on North American Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria.One hundred and twelve patients from both institutions were included, 62% from NCH, median age 11.5 [interquartile range (IQR): 5-16 years], 50% male. Most patients were less than 18 years of age with a median age of 8 years (IQR: 4-13 years). Underlying diagnoses included seizures (67%), cerebral palsy/spastic quadriplegia (65%), diabetes (3.6%), and mitochondrial disease (3%). Majority of patients were found to have multiple underlying diagnoses (88%). Incidence of pancreatitis for both institutions was 336 of 100,000 patients/year which is significantly higher than the general pediatric population ( P0.0001). Majority of first episodes of pancreatitis were mild (82%) with abdominal pain as the predominant symptom (50%). Adult patients were more likely to have pancreatitis related to medication use than pediatric patients (70% vs 38%, respectively P = 0.007).Individuals in the CMC population at our institutions have a high incidence of pancreatitis with unique risk factors compared to the general pediatric/young adult populations.

Varicella zoster virus (VZV) is responsible for chronic pain. VZV injection has similarities to herpes zoster (HZ) "shingles" pain in humans. In this study orofacial pain was induced by injecting male rats with the human VZV. The amygdala and parabrachial have been implicated to control affective/motivational orofacial pain. Recently our lab reported neurexin 3α (Nrxn3α) is expressed in the central amygdala and parabrachial. GABAergic neurons descend from the central amygdala to the lateral parabrachial region and Nrxn3α is important for presynaptic (γ-Aminobutyric acid) GABA release. Thus, we hypothesized that lateral parabrachial neuronal activity and orofacial pain are controlled by Nrxn3α within the central amygdala. To test the hypothesis Nrxn3α expression was knocked down (i.e., using short hairpin RNA or shRNA) in the central amygdala and GABA release and neuronal activity were quantitated in the parabrachial concomitant with measurement of the VZV induced pain response. Results revealed that attenuating Nrxn3 expression within the amygdala reduces GABA release in the parabrachial and increases neuronal activity within the lateral parabrachial region. Attenuating Nrxn3 expression also increases VZV associated orofacial pain. Activating GABAergic neurons within the central amygdala with opsins increase GABA release in the parabrachial and reduced the pain response after Nrxn3 shRNA treatment. These results are consistent with the idea that Nrxn3 within the central amygdala controls VZV associated pain by regulating GABA release in the lateral parabrachial that then controls the activity of ascending pain neurons.

Extracellular vesicles (EVs), including exosomes, microvesicles, and oncosomes, are nano-sized particles enclosed by a lipid bilayer. EVs are released by virtually all eukaryotic cells and have been shown to contribute to intercellular communication by transporting proteins, lipids, and nucleic acids. In the context of neurodegenerative diseases, EVs may carry toxic, misfolded forms of amyloidogenic proteins and facilitate their spread to recipient cells in the central nervous system (CNS). CNS-originating EVs can cross the blood–brain barrier into the bloodstream and may be found in other body fluids, including saliva, tears, and urine. EVs originating in the CNS represent an attractive source of biomarkers for neurodegenerative diseases, because they contain cell- and cell state-specific biological materials. In recent years, multiple papers have reported the use of this strategy for identification and quantitation of biomarkers for neurodegenerative diseases, including Parkinson’s disease and atypical parkinsonian disorders. However, certain technical issues have yet to be standardized, such as the best surface markers for isolation of cell type-specific EVs and validating the cellular origin of the EVs. Here, we review recent research using CNS-originating EVs for biomarker studies, primarily in parkinsonian disorders, highlight technical challenges, and propose strategies for overcoming them.

PURPOSE: Bullying, harassment, and discrimination (BHD) are prevalent in academic, scientific, and clinical departments, particularly orthopedic surgery, and can have lasting effects on victims. As it is unclear how BHD affects musculoskeletal (MSK) researchers, the following study assessed BHD in the MSK research community and whether the COVID-19 pandemic, which caused hardships in other industries, had an impact. METHODS: A web-based anonymous survey was developed in English by ORS Spine Section members to assess the impact of COVID-19 on MSK researchers in North America, Europe, and Asia, which included questions to evaluate the personal experience of researchers regarding BHD. RESULTS: 116 MSK researchers completed the survey. Of respondents, 34.5% (n = 40) focused on spine, 30.2% (n = 35) had multiple areas of interest, and 35.3% (n = 41) represented other areas of MSK research. BHD was observed by 26.7% (n = 31) of respondents and personally experienced by 11.2% (n = 13), with mid-career faculty both observing and experiencing the most BHD. Most who experienced BHD (53.8%, n = 7) experienced multiple forms. 32.8% (n = 38) of respondents were not able to speak out about BHD without fear of repercussions, with 13.8% (n = 16) being unsure about this. Of those who observed BHD, 54.8% (n = 17) noted that the COVID-19 pandemic had no impact on their observations. CONCLUSIONS: To our knowledge, this is the first study to address the prevalence and determinants of BHD among MSK researchers. MSK researchers experienced and observed BHD, while many were not comfortable reporting and discussing violations to their institution. The COVID-19 pandemic had mixed-effects on BHD. Awareness and proactive policy changes may be warranted to reduce/eliminate the occurrence of BHD in this community.

This document outlines the important aspects of caring for patients who have been diagnosed with advanced pelvic cancer. It is primarily aimed at those who are establishing a service that adequately caters to this patient group. The relevant literature has been summarized and an attempt made to simplify the approach to management of these complex cases.

Purpose Flat-detector computed tomography (FD-CT) is the standard for cochlear implant (CI) imaging. FD-CT systems differ in technical characteristics. Our aim was an evaluation of two different FD-CT generations with different protocols and hardware regarding image quality, radiation dose, and scan time. Methods Two temporal bone specimens (− / + CI = TB0/TB1) were scanned using three different scanners: two FD-CT systems with different scanning protocols (standard FD-CT: 20 s 70 kV, 20 s 109 kV; high-speed FD-CT [HS-FD-CT]: 7 s 109 kV, 9 s 109 kV, 14 s 72 kV) and MS-CT (5 s 120 kV). Acquired datasets were evaluated in consensus reading regarding qualitative and quantitative parameters: addressing CI- and cochlea-specific parameters, cochlea delineation, lamina spiralis ossea visibility, distinction of single CI electrodes, determination of intracochlear implant position, stapes delineation, and mastoidal septation were assessed. Addressing protocol-specific parameters, radiation dose (dose-length-product/DLP), and scan time were assessed. Results Two HS-FD-CT protocols (14 s/9 s) provide higher or equivalent diagnostic information regarding CI- and cochlea-specific parameters compared to both standard FD-CT protocols. The fastest HS-FD-CT protocol (7 s)—providing inferior diagnostic information compared to all other FD-CT protocols—still exceeds MS-CT. The highest DLP was recorded for the 14 s HS-FD-CT protocol (TB1 = 956 mGycm); the lowest DLPs were recorded for the 7 s HS-FD-CT protocol (TB0 = 188 mGycm) and for MS-CT (TB0 = 138 mGycm), respectively. HS-FD-CT allows a significant reduction of scan time compared to standard FD-CT. Conclusion High-speed FD-CT improves visualization of temporal bone anatomy and postoperative assessment of CIs by combining excellent image quality, fast scan time, and reasonable radiation exposure.

Iodothyronine deiodinases (DIO) are key enzymes that influence tissue-specific thyroid hormone levels during thyroid-mediated amphibian metamorphosis. Within the larger context of evaluating chemicals for thyroid system disrupting potential, chemical activity toward DIOs is being evaluated using high-throughput in vitro screening assays as part of U.S. EPA’s ToxCast program. However, existing data gaps preclude any inferences between in vitro chemical inhibition of DIOs and in vivo outcomes relevant to ecological risk assessment. This study aimed to generate targeted data in a laboratory model species (Xenopus laevis) using a model DIO inhibitor, iopanoic acid (IOP), to characterize linkages between in vitro potency, in vivo biochemical responses, and adverse organismal outcomes. In vitro potency of IOP toward DIOs was evaluated using previously developed in vitro screening assays, which showed concentration-dependent inhibition of human DIO1 (IC50: 97 µM) and DIO2 (IC50: 231 µM) but did not inhibit human or X. laevis DIO3 under the assay conditions. In vivo exposure of larval X. laevis to 0, 2.6, 5.3, and 10.5 µM IOP caused thyroid-related biochemical profiles in the thyroid gland and plasma consistent with hyperthyroxinemia but resulted in delayed metamorphosis and significantly reduced growth in the highest 2 exposure concentrations. Independent evaluations of dio gene expression ontogeny, together with existing literature, supported interpretation of IOP-mediated effects resulting in a proposed adverse outcome pathway for DIO2 inhibition leading to altered amphibian metamorphosis. This study highlights the types of mechanistic data needed to move toward predicting in vivo outcomes of regulatory concern from in vitro bioactivity data.

Background Congenital portosystemic shunts (CPSS) are rare vascular malformations and can be classified into extrahepatic and intrahepatic shunts. Extrahepatic CPSS, also termed Abernethy malformations are associated with severe long-term complications including portopulmonary hypertension, liver atrophy, hyperammoniemia and hepatic encephalopathy. We report a hitherto undescribed variant of Abernethy malformation requiring an innovative approach for interventional treatment. Case presentation We describe a 31-year-old patient following surgical repair of atrioventricular septal defect at the age of 6 years. In the long-term follow-up he showed persistent pulmonary hypertension which deteriorated despite dual pulmonary vasodilative treatment. When he developed arterial desaturation and symptomatic hyperammoniemia detailed reassessment revealed as underlying cause a hitherto undescribed variant of Abernethy malformation connecting the portal vein with the right lower pulmonary vein. Following interdisciplinary discussions we opted for an interventional approach. Since the malformation was un-accessible to interventional closure via antegrade venous or retrograde arterial access, a transhepatic percutaneous puncture of the portal vein was performed. Temporary balloon occlusion of the malformation revealed only a slight increase in portal venous pressure. Interventional occlusion of the large vascular connection was achieved via this transhepatic approach by successive implantation of two large vascular occluding devices. The postinterventional course was unremarkable and both ammonia levels and arterial saturation normalized at follow-up of 12 months. Conclusions Portal vein anomalies should be included in the differential diagnoses of pulmonary hypertension or pulmonary arterio-venous malformations. Based on careful assessment of the anatomy and testing of portal vein hemodynamics interventional therapy of complex Abernethy malformations can be performed successfully in specialized centers.

Infection-neutralizing antibody responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529), which is rapidly spreading worldwide. Here we report neutralizing antibody dynamics in a longitudinal cohort of coronavirus disease 2019 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying SARS-CoV-2 spike protein antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.

OBJECTIVE Total pancreatectomy with islet autotransplantation (TPIAT) is indicated to alleviate debilitating pancreas-related pain and mitigate diabetes in patients with acute recurrent and chronic pancreatitis when medical/endoscopic therapies fail. Our aim was to evaluate predictors of insulin requirement at 1 year following TPIAT in a cohort of children. RESEARCH DESIGN AND METHODS This was a review of 43 pediatric patients followed after TPIAT for 1 year or longer. Primary outcome was insulin use at 1 year, categorized as follows: insulin independent, low insulin requirement ( RESULTS At 1 year after TPIAT, 12 of 41 (29%) patients were insulin independent and 21 of 41 (51%) had low and 8 of 41 (20%) had high insulin requirement. Insulin-independent patients were younger than those with low and high insulin requirement (median age 8.2 vs. 14.6 vs. 13.1 years, respectively; P = 0.03). Patients with insulin independence had a higher number of transplanted islet equivalents (IEQ) per kilogram body weight (P = 0.03) and smaller body surface area (P = 0.02), compared with those with insulin dependence. Preoperative exocrine insufficiency was associated with high insulin requirement (P = 0.03). Higher peak C-peptide measured by stimulated mixed-meal tolerance testing (MMTT) at 3 and 6 months post-TPIAT was predictive of lower insulin requirement at 1 year (P = 0.006 and 0.03, respectively). CONCLUSIONS We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ per kilogram body weight transplanted, and smaller body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement.

γ-Glutamyl carboxylase (GGCX) catalyses γ-carboxylation of 15 different vitamin K dependent (VKD) proteins. Pathogenic variants in GGCX cause a rare hereditary bleeding disorder called Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1). In addition to bleedings, some VKCFD1 patients develop skin laxity and skeletal dysmorphologies. However, the pathophysiological mechanisms underlying these non-haemorrhagic phenotypes remain elusive. Therefore, we analyzed the effect of 22 GGCX pathogenic variants on γ-carboxylation of six non-haemostatic VKD proteins (UCMA/GRP, MGP, BGLAP, GAS6, PRGP1, TMG4) in a GGCX-/- HEK293T cell line by a functional ELISA. We observed that biallelic deficiency to γ-carboxylate Gla-rich protein lead to the development of skin laxity. Markedly reduced level of γ-carboxylated MGP is crucial but not exclusive for causing facial dysmorphologies. Moreover, we identified the vitamin K hydroquinone binding site in GGCX in an in silico model by docking studies, which was further validated by functional assays. Variants affecting this site result into loss-of-function or severely diminished ability to γ-carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype-phenotype analysis will help to develop new treatment options for VKCFD1 patients, where individualized therapy with γ-carboxylated VKD proteins may represent a promising strategy.

INTRODUCTION/AIMS Glucocorticoid-induced osteoporosis with vertebral fractures is frequent in patients with Duchenne muscular dystrophy (DMD). In this study, we evaluated the effects of oral bisphosphonate (BP) therapy on the prevalence and severity of vertebral fractures by vertebral morphometry assessment. METHODS We reviewed the records and radiographs of patients with DMD who had been treated with oral BP (weekly alendronate) and had undergone routine spine radiographic monitoring for glucocorticoid-induced osteoporosis at Cincinnati Children's Hospital Medical Center between 2010 and 2017. Study outcomes were thoracic and lumbar vertebral fracture prevalence and severity, assessed by Genant semiquantitative grading of vertebral morphometry, for up to 5 years of treatment. RESULTS Fifty-two patients (median age, 11.8 years; 88% prepubertal; 31% nonambulatory) had been treated with long-term glucocorticoids (median duration, 4.7 years at BP start). Most patients (75%) had mild vertebral height loss or fractures (Genant grade = 0 or 1) at baseline. The prevalence of vertebral fractures at each year of treatment was not statistically different from that at baseline (P = .08-1.00). Serial radiographs showed no longitudinal change in severity by Genant grade in most vertebrae (64%-80%). Improvement in vertebral fracture grade was observed in some patients. DISCUSSION We observed stable prevalence of vertebral fractures and no change in severity by Genant grade in most vertebrae for up to 5 years of treatment. Oral BP may mitigate development or progression of vertebral fractures and be beneficial for secondary prevention of glucocorticoid-induced osteoporosis in this population.

BACKGROUND: A single high-sensitive cardiac troponin (hs-cTn) can be used to rule-out acute myocardial infarction (MI) in patients presenting >3 hours (3 h) after chest pain onset to the emergency department. This study aimed to investigate the safety of ruling-out MI in early presenters with chest pain ≤3 h using a single hs-cTnI at admission.METHODS: We prospectively enrolled patients presenting with chest pain suggestive of MI. Hs-cTnI (Siemens ADVIA Centaur TNIH, Limit of detection: 2.2 ng/L) was measured at admission. Two physicians adjudicated final diagnosis. A diagnostic cut-off value 3 h).RESULTS: We included 1370 patients with available admission hs-cTnI results: median (Q1-Q3) age 65 (52-74), female sex: 43%, previous MI: 22%. We confirmed MI in 118 (8.6%) patients. Overall, 470 (34%) patients were classified as early, 770 (56%) as late presenters, and 130 (9%) patients had unknown onset. When applying the diagnostic cut-off value, MI was correctly ruled-out at admission in 370 (27%) patients: 134 (29%) early presenters, 206 (27%) late presenters and 30 (23%) patients with unknown onset. This resulted in an overall negative predictive value of 100% (95% CI: 99.0-100%), with both 100% (97.3-100%) for early and 100% (98.2-100%) for late presenters, respectively. Sensitivity was similarly high in the two groups.CONCLUSION: MI could be safely ruled-out in all patients presenting with chest pain ≤3 h when using a single hs-cTnI value TRIAL REGISTRATION NUMBER: NCT03634384.

Background. Chronic hepatitis C virus (HCV) infection is characterized by activation of natural killer (NK) cells. Here, we asked whether HCV elimination by sofosbuvir-based direct-acting antivirals (DAAs) and the addition of ribavirin (RBV) improve NK cell function in liver transplant (LTx) recipients. Methods. We analyzed NK cell degranulation and interferon (IFN)γ-response along with STAT1 and STAT4 phosphorylation in 29 HCV-infected LTx recipients and 17 HCV-infected patients during DAA treatment. Results. Compared with uninfected LTx recipients, NK cells from HCV-infected LTx recipients were polarized toward cytotoxicity with increased CD107a-degranulation (10.1% versus 14.6%; P = 0.0263) and reduced capacity to produce IFNγ (43.0% versus 26.7%; P = 0.0002). The altered phenotype of NK cells in HCV-infected LTx recipients was accompanied by increased STAT1 (44.6% versus 87.4%; P < 0.0001) and STAT1 phosphorylation (0.7% versus 8.9%; P = 0.0005) compared with pSTAT4 IFNα-induction (29.9% versus 17.6%; P = 0.0014). Successful DAA therapy did not affect CD107a-degranulation but decreased STAT1. RBV cotreatment with DAA therapy for HCV increased CD56Bright NK cell IFNγ-responses in LTx recipients (70.9% versus 89.2%; P = 0.002), and this correlated to an increase in the inducibility of pSTAT4 (MFI 157 versus 173; P = 0.0002). Conclusions. RBV cotreatment of HCV infection improved pSTAT4-dependent IFNγ-production in NK cells. This is relevant especially for immunocompromised patients such as LTx recipients or patients with end-stage liver disease.

The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile inflammatory conditions. NLRP3 activity is governed by two independent signals: the first signal primes NLRP3, rendering it responsive to the second signal, which then triggers inflammasome formation. Our understanding of how NLRP3 priming contributes to inflammasome activation remains limited. Here, we show that IKKβ, a kinase activated during priming, induces recruitment of NLRP3 to phosphatidylinositol-4-phosphate (PI4P), a phospholipid enriched on the trans-Golgi network. NEK7, a mitotic spindle kinase that had previously been thought to be indispensable for NLRP3 activation, was redundant for inflammasome formation when IKKβ recruited NLRP3 to PI4P. Studying iPSC-derived human macrophages revealed that the IKKβ-mediated NEK7-independent pathway constitutes the predominant NLRP3 priming mechanism in human myeloid cells. Our results suggest that PI4P binding represents a primed state into which NLRP3 is brought by IKKβ activity.

Introduction: Acute appendicitis is the most common non-obstetrical surgical emergency in pregnancy. Ultrasound is the imaging tool of choice, but its use is complicated due to anatomical changes during pregnancy and depends on the clinician’s expertise. In this study, our aim was to investigate the diagnostic accuracy of point-of-care ultrasound (POCUS) in suspected appendicitis in pregnant women. Methods: We conducted a retrospective analysis of all pregnant women undergoing POCUS for suspected appendicitis between June 2010–June 2020 in a tertiary emergency department. The primary outcome was to establish sensitivity, specificity, and likelihood ratios of POCUS in diagnosing acute appendicitis, overall and for each trimester. We used histology of the appendix as the reference standard in case of surgery. If appendectomy was not performed, the clinical course until childbirth was used to rule out appendicitis. If the patients underwent magnetic resonance imaging (MRI), we compared readings to POCUS. Results: A total of 61 women were included in the study, of whom 34 (55.7%) underwent appendectomy and in 30 (49.2%) an acute appendicitis was histopathologically confirmed. Sensitivity of POCUS was 66.7% (confidence interval [CI] 95% 47.1-82.7), specificity 96.8% (CI 95% 83.3-99.9), and positive likelihood ratio 20.7. Performance of POCUS was comparable in all trimesters, with highest sensitivity in the first trimester (72.7%). The MRI reading showed a sensitivity of 84.6% and a specificity of 100%. In the four negative appendectomies a MRI was not performed. Conclusion: Point-of-care ultrasound showed a high specificity and positive likelihood ratio in diagnosing acute appendicitis in pregnant women in all trimesters with suspected appendicitis. In negative (or inconclusive) cases further imaging as MRI could be helpful to avoid negative appendectomy.

Factors affecting outcomes in liver transplant (LTx) recipients with hepatocellular carcinoma (HCC) and hepatitis C viral (HCV) infection include the choice of immunosuppression. Here, we analyzed the HCV+ subgroup of patients from the randomized controlled, international SiLVER Study. We performed a post hoc analysis of 166 HCV+ SiLVER Study patients regarding HCC outcome after LTx. Control patients (group A: n=88) received mTOR inhibitor (mTORi)-free, calcineurin inhibitor (CNI)-based versus sirolimus-based immunosuppression (group B: n=78). We found no significant difference regarding HCV-RNA titers between group A and B. Since no effect in group B could be due to variable sirolimus dosing, we split group B into patients receiving sirolimus-based immunosuppression+CNIs for >50% (B1; n=44) or

Background A patent foramen ovale (PFO) has been associated with embolic strokes and transient ischemic attacks (TIAs). Catheter closure of PFO is effective in preventing recurrent events. Residual shunts and procedure or device related complications can occur, including atrial fibrillation and thrombus formation . This study examines the initial experience with a new PFO closure device, the IrisFIT PFO-Occluder (Lifetech Scientific, Shenzhen, China). Methods 95 patients with indications for PFO closure underwent percutaneous closure with the IrisFIT PFO-Occluder. The primary endpoint was the rate of accurate device placement with no/small residual shunt at 3 or 6 months follow-up. All patients underwent transoesophageal echocardiography (TEE) after 1 to 6 months. In case of a residual shunt, an additional TEE was performed after 12 months. Clinical follow-up was performed up to a mean of 33.1 ± 3.6 months. Results The device was successfully implanted in 95 (100%) patients with no relevant procedural complications. At final TEE follow-up (7.6 ± 3.9 months) the effective closure rate was 96.8% with 1 moderate and 2 large residual shunts. There were 8 cases of new onset atrial fibrillation and 2 TIAs. There were no cases of device embolization or erosion. Conclusion The IrisFIT occluder is a new PFO closure device with several advantages compared to other devices. In this small study cohort , technical success rate, closure rate and adverse event rate were comparable to other devices. The rate of new onset atrial fibrillation was higher in comparison to other studies and warrants further investigation.

Objectives To identify published economic evaluations of interventions aimed at preventing, diagnosing, or treating food allergies in children. Methods We examined economic evaluations published from 2000 to 2019. Data analyzed included: food allergy type, study population/setting, intervention/comparator, and economic evaluation details. Quality assessment used reporting and economic modeling checklists. Two reviewers simultaneously undertook article screening, data extraction, and quality assessment. Results 17 studies were included: 8 peanut allergy (PA) studies, 8 cow’s milk allergy (CMA) studies, and 1 egg allergy (EA) study. All PA studies reported incremental costs per quality-adjusted life-year gained for diagnostic strategies, management pathways for peanut exposure, and immunotherapies. Immunotherapies rendered inconsistent cost-effectiveness results. CMA studies reported costs per symptom-free day or probability of developing CMA tolerance. Cost-effectiveness of extensively hydrolyzed casein formula for CMA treatment was consistently demonstrated. Early introduction of cooked egg in first year of life dominated all EA prevention strategies. Quality assessment showed average noncompliance for 3.5 items/study (range 0-11) for modeling methods and 3.4 items/study (range 0-8) for reporting quality. Key quality concerns included limited justification for model choice, evidence base for model parameters, source of utility values, and representation of uncertainty. Conclusion Recent cost-effectiveness literature of interventions in PA, CMA, and EA is limited and diverse. Interventions for diagnosis and treatment of CMA and prevention of EA were generally cost-effective; however, results for PA were variable and dependent on effectiveness and utility values used. There is a need to expand economic evaluation of interventions for childhood food allergy and to improve methods and reporting.

Register-based studies indicate a possible association of monoclonal gammopathy of undetermined significance (MGUS) and prostate cancer (PCa). Aim of the present study was to investigate the relationship between MGUS and PCa considering potentially shared risk factors. Data from the prospective population-based Heinz Nixdorf Recall cohort study of 2.385 men (age 45–85) were analyzed. MGUS was determined at three points in time; cases of cancer were assessed annually. Potentially shared risk factors were assessed at baseline. Hazard ratios (HR), adjusted for age and educational attainment, and corresponding 95%-confidence intervals (95%-CI) were calculated. 157 cases of MGUS and 143 incident cases of PCa were detected. Of 19 participants diagnosed with both, MGUS and incident PCa, only in one case MGUS did not clearly occur before PCa. MGUS was associated with PCa presenting a HR of 2.00 (95%-CI: 1.23–3.25). Stratified by isotype, IgM-MGUS showed the strongest association with PCa. There was no relevant change of the effect estimate when adjusting for potentially shared risk factors. We were able to give supporting evidence for an association between MGUS and PCa and pointed out its temporality. There was no indication that the observed association is due to shared risk factors. The present study indicated that different isotypes of MGUS differ in the strength of the effect on PCa-risk. Based on these findings, future studies investigating the pathophysiological background of the association will be needed.

Aims An accelerated diagnostic algorithm for ruling-in or ruling-out myocardial infarction (MI) after 1 hour (1 h) has recently been derived and internally validated for the Siemens ADVIA Centaur TNIH assay. We aimed to validate the diagnostic performance of the TNIH 0 h/1 h algorithm ad modum Boeddinghaus in a Danish cohort. Methods and results Patients with chest pain suggestive of MI were prospectively enrolled. High-sensitive troponin I (TNIH) was measured at admission (0 h) and after 30 minutes (30 m), 1 h, and 3 hours (3 h). We externally validated the TNIH 0 h/1 h algorithm ad modum Boeddinghaus in Danish patients. Moreover, we applied the algorithm using the second TNIH measurement at 30 m instead of 1 h. We enrolled 1003 patients: median (Q1–Q3) age 64 (52–74) years, 42% female, and 23% with previous MI. Myocardial infarction was the final diagnosis in 9% of patients. Median (Q1–Q3) times from admission to 30 m and 1 h blood draw were 35 min (30–37 min) and 67 min (62–75 min), respectively. Using the 0 h and 1 h results, 468 (47%) patients were assigned to rule-out, 104 (10%) to rule-in, and 431 (43%) to the observational zone. This resulted in a negative predictive value of 100% (95% confidence interval: 99.2–100%), sensitivity of 100% (95.9–100%), positive predictive value of 79.8 (70.8–87.0%), and specificity of 97.7% (96.5–98.6%). The diagnostic performance after 30 m was similar. Conclusions The TNIH 0 h/1 h algorithm ad modum Boeddinghaus performed excellently for rule-out of MI in a Danish cohort. The Boeddinghaus algorithm also performed excellently after only 30 m. Trial registration number NCT03634384. Trial registry name and URL Rapid Use of High-Sensitive Cardiac Troponin I for Ruling-in and Ruling-out Acute Myocardial Infarction (RACING-MI), https://clinicaltrials.gov/ct2/show/NCT03634384.

Purpose To determine risk factors for coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs), characterize symptoms, and evaluate preventive measures against SARS-CoV-2 spread in hospitals. Methods In a cross-sectional study conducted between May 27 and August 12, 2020, after the first wave of the COVID-19 pandemic, we obtained serological, epidemiological, occupational as well as COVID-19-related data at a quaternary care, multicenter hospital in Munich, Germany. Results 7554 HCWs participated, 2.2% of whom tested positive for anti-SARS-CoV-2 antibodies. Multivariate analysis revealed increased COVID-19 risk for nurses (3.1% seropositivity, 95% CI 2.5–3.9%, p = 0.012), staff working on COVID-19 units (4.6% seropositivity, 95% CI 3.2–6.5%, p = 0.032), males (2.4% seropositivity, 95% CI 1.8–3.2%, p = 0.019), and HCWs reporting high-risk exposures to infected patients (5.5% seropositivity, 95% CI 4.0–7.5%, p = 0.0022) or outside of work (12.0% seropositivity, 95% CI 8.0–17.4%, p p = 0.00018) and the symptom taste disorder was strongly associated with COVID-19 (29.8% seropositivity, 95% CI 24.3–35.8%, p Conclusion Awareness of the identified COVID-19 risk factors and successful surveillance strategies are key to protecting HCWs against SARS-CoV-2, especially in settings with limited vaccination capacities or reduced vaccine efficacy.

One of the major obstacles preventing successful percutaneous pulmonary valve implantation (PPVI) is related to the close proximity of coronary artery branches to the expected landing zone. The aim of this study was to assess the frequency of coronary artery anomalies (CAAs) especially those associated with major coronary branches crossing the right ventricular outflow tract (RVOT) and to describe their relevance for the feasibility of percutaneous pulmonary valve implantation (PPVI). In our retrospective single-center study 90 patients were evaluated who underwent invasive testing for PPVI in our institution from 1/2010 to 1/2020. CAAs were identified in seven patients (8%) associated with major branches crossing the RVOT due to origin of the left anterior descending (LAD) or a single coronary artery from the right aortic sinus. In 5/7 patients with CAAs balloon testing of the RVOT and selective coronary angiographies revealed a sufficiently large landing zone distal to the coronary artery branch. While unfavorable RVOT dimensions prevented PPVI in one, PPVI was performed successfully in the remaining four patients. The relatively short landing zone required application of the “folded” melody technique in two patients. All patients are doing well (mean follow-up 3 years). CAAs associated with major coronary branches crossing the RVOT can be expected in about 8% of patients who are potential candidates for PPVI. Since the LAD crossed the RVOT below the plane of the pulmonary valve successful distal implantation of the valve was possible in 4/7 patients. Therefore these coronary anomalies should not be considered as primary contraindications for PPVI.

Aim Microanatomical evaluation of cochlear implant (CI) patients to identify anatomical risk factors for a scalar translocation. Methods CI patients with both a regular scala tympani spiralization (group A) and a scalar translocation (group B) were identified via postoperative flat-detector computed tomography (FD-CT). Then, the corresponding preoperative multislice computed tomography (MS-CT) and postoperative FD-CT datasets were assessed: First, the cochleae were separated in 6 segments of 45° each. Next, quantitative (cochlea height, length, depth, cochlear duct diameter [CD] per segment; percentual tapering of the CD per segment named cochlear geometry index [CGI]) and qualitative (identifiability of the CI model; CI-integrity; intracochlear array position) parameters were evaluated and compared for both groups. Receiver-operating-characteristics (ROC) analysis was performed for the CGI. Results In total, 40 preoperative MS-CT and postoperative FD-CT datasets (nA = 20; nB = 20) were analysed. Model “CI 512” was successfully identified and CI-integrity has been confirmed in all cases. Quantitative analysis showed a significant difference of both the CD at 0° (CD A 0°= 2.06 ± 0.23 mm; CDB 0°= 2.19 ± 0.18 mm; p0°= 0.04) and the CGI of the first segment (CGIA 0° -45°= 18.87 ± 6.04%; CGIB 0°-45°= 28.89 ± 8.58%; p0°-45°= 0.0001). For all other 5 cochlear segments there was no significant difference of CD and CGI; there was no significant difference of external cochlea diameters. The area under the curve (AUC) of the CGI0-45° was 0.864 with 24.50° as the optimal cut-off value to discriminate patients with a scala tympani spiralization and a scalar translocation. CGI0-45° of > 24.50° allowed the correct identification of 85% of patients with a scalar translocation. Conclusion CI insertion trauma is associated with a significantly higher narrowing of the proximal basal cochlea turn (BCT). The CGI as percentual tapering of the BCT turned out as reliable, clinically applicable parameter for identification of patients with an increased risk for a scalar translocation.

Nucleic acids (NAs) represent one of the most important classes of molecules recognized by the innate immune system. However, NAs are not limited to pathogens, but are also present within the host. As such, the immune system has evolved an elaborate set of pathogen recognition receptors (PRRs) that employ various strategies to recognize distinct types of NAs, while reliably distinguishing between self and non-self. The here-employed strategies encompass the positioning of NA-sensing PRRs in certain subcellular compartments that potentially come in contact with pathogens but not host NAs, the existence of counterregulatory measures that keep endogenous nucleic acids below a certain threshold, and also the specific identification of certain non-self patterns. Here, we review recent advances in the molecular mechanisms of NA recognition by TLRs, RLRs, and the cGAS-STING axis. We highlight the differences in NA-PRR interfaces that confer specificity and selectivity toward an NA ligand, as well as the NA-dependent induced conformational changes required for signal transduction. This article is protected by copyright. All rights reserved.

Objective This study aimed to provide an overview of the extent to which women with endometriosis are informed about, interested in, and make use of CAM, and to evaluate which of the methods are most often applied. Study Design A retrospective, two-center cohort study was conducted using a validated questionnaire among women with laparoscopically confirmed endometriosis at two urban teaching hospitals, certified as endometriosis centres. Results A total of 592 patients were included in the study and received the questionnaire; 114 (19.3 %) were included in the data analysis. Most of the women were not receiving hormone therapy at the time of the study (n = 60, 52.6 %). Most (n = 75, 65.8 %) were interested in CAM, but only a minority (n = 12, 10.5 %) had detailed knowledge about it. A total of 81 patients (71.1 %) had used at least one CAM method for disease management; the five most frequently used CAM methods were exercise (n = 55, 48.2 %), vitamins (n = 40, 35.1 %), yoga (n = 38, 33.3 %), homeopathy (n = 32, 28.1 %), and trace elements (n = 27, 23.7 %). Conclusions In our study population, women with endometriosis are strongly interested in using CAM, but have only limited information about it. Nevertheless, a majority of the patients had used at least one CAM method to relieve symptoms associated with the disease and the most often used was exercise.

Extended cut-off filtration by medium cut-off membranes (MCO) has been shown to be safe in maintenance hemodialysis (HD). The notion of using them for the control of chronic low-grade inflammation and positively influencing cellular immune aberrations seems tempting. We conducted an open label, multicenter, randomized, 90 day 2-phase cross over clinical trial (MCO- vs. high flux-HD). 46 patients underwent randomization of which 34 completed the study. Dialysate- or pre- and post-dialysis serum inflammatory mediators were assayed for each study visit. Ex vivo T cell activation was assessed from cryopreserved leucocytes by flow cytometry. Linear mixed models were used to compare treatment modalities, with difference in pre-dialysis serum MCP-1 levels after 3 months as the predefined primary endpoint. Filtration/dialysate concentrations of most mediators, including MCP-1 (mean ± SD: 10.5 ± 5.9 vs. 5.1 ± 3.8 pg/ml,P P P = 0.01) and PD1+ (P = 0.02) activated CD4+ T cells was striking. Thus, MCO-HD does not induce reduction of a broad range of inflammatory mediators studied here. Long-term reduction over a 3-month period was not possible. Increased single session filtration, as evidenced by increased dialysate concentrations of inflammatory mediators during MCO-HD, might eventually be compensated for by compartment redistribution or increased production during dialysis session. Nevertheless, lasting effects on the T-cell phenotype were seen, which deserves further investigation.

Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodiesviabinding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodiesin vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activityviaIgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.

Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis. Here, we show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures. Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids. ACMs are thus promising leads for potent anti-amyloid drugs in both T2D and AD while the supramolecular nanofiber co-assemblies should inform the design of novel functional (hetero-)amyloid-based nanomaterials for biomedical/biotechnological applications.

Purpose The aim of this study was to investigate the feasibility and reliability of transcutaneous ultrasound for the detection of complications after cochlear implantation. Methods In a single center retrospective cohort study, 115 consecutive cases of suspected complications after cochlear implantation (intervention group) were examined. The rate of pathologic ultrasound findings for specific leading symptoms and diagnoses was compared to a control group comprising twenty consecutive cochlear implants in symptom-free patients. Results Diagnostic ultrasound showed distinctly more pathologic findings in the intervention group (n = 67; 58.3%; p n = 1; 5%). Ultrasound revealed significantly more pathologic findings in haematoma or seroma around the implant (n = 17; 100%; p ϕ = 0.94) and magnet dislocation (n = 44; 97.7%; p ϕ = 0.92) confirmed by a strong effect. Ultrasound examination showed a medium to high effect size in patients presenting with local infections (n = 3; 21.4%; p = 0.283; ϕ = 0.25) and skin flap oedema (n = 2; 50%; p = 0.061; ϕ = 0.51). In contrast, ultrasound examinations displayed a low effect size in undefined cephalgia (0%; p = 0.444; ϕ = 0.17) and device malfunction or failure (0%; p > 0.999; ϕ = 0.13). Conclusion Transcutaneous ultrasound can be advocated as a feasible and effective method in the diagnostic work-up of magnet dislocation and haematoma or seroma around the implant following cochlear implantation. Contrary, ultrasound findings can be expected to be inconspicuous in patients presenting with undefined cephalgia and device malfunction or failure.

Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1 DR ) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1 DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1 DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING, also known as TMEM173) constitute the major signaling pathway in vertebrates that senses non-self DNA and elicits potent immune responses. At the core of this pathway, cGAS senses double-stranded DNA (dsDNA) and synthesizes cyclic GMP-AMP (cGAMP). cGAMP serves as a second messenger that relays its signal to downstream innate immune responses through STING. One of the major consequences triggered by the cGAS-STING pathway is the production of antiviral cytokines of the type I interferon family, which in turn induce expression of hundreds of interferon-stimulated genes (ISGs) with diverse antiviral functions. Recent studies have also revealed functional homologs across phylogenetic kingdoms with innate defense functions, suggesting an ancient evolutionary origin of cGAS-STING signaling. Aberrant activation of the cGAS-STING pathway by host DNA can lead to sterile inflammation associated with tissue damage, degeneration as well as premature aging. In this primer, we will introduce the basic principles of cGAS-STING signaling in the vertebrate system and highlight recent discoveries regarding its connection to other fundamental cellular processes in the context of human diseases.

Abnormal molecular processes occurring throughout the genome leave distinct somatic mutational patterns termed mutational signatures. Exploring the associations between mutational signatures and clinicopathological features can unravel potential mechanisms driving tumorigenic processes. We analyzed whole genome sequencing (WGS) data of tumor and peripheral blood samples from 37 primary breast cancer (BC) patients receiving neoadjuvant chemotherapy. Comprehensive clinico-pathologic features were correlated with genomic profiles and mutational signatures. Somatic mutational landscapes were highly concordant with known BC data sets. Remarkably, we observed a divergence of dominant mutational signatures in association with BC subtype. Signature 5 was overrepresented in hormone receptor positive (HR+) patients, whereas triple-negative tumors mostly lacked Signature 5, but expectedly overrepresented Signature 3. We validated these findings in a large WGS data set of BC, demonstrating dominance of Signature 5 in HR+ patients, mostly in luminal A subtype. We further investigated the association between Signature 5 and gene expression signatures, and identified potential networks, likely related to estrogen regulation. Our results suggest that the yet elusive Signature 5 represents an alternative mechanism for mutation accumulation in HR+ BC, independent of the homologous recombination repair machinery related to Signature 3. This study provides theoretical basis for further elucidating the processes promoting hormonal breast carcinogenesis.

A 64-year-old female patient presented with otalgia and hearing loss in the right ear. On otoscopy, the right tympanic membrane was highly vascularized and bulged into the anteroinferior quadrant. High-resolution computed tomography revealed an osteolytic lesion with occupation of the hypotympanum extending into the petrous apex and right parapharyngeal space as well as infiltration of the wall of the right internal carotid artery. MRI strengthened the suspicion of a jugulotympanic paraganglioma. The biopsy material obtained through exploratory tympanotomy was assessed as a low-grade polymorphic adenocarcinoma. The tumor was treated with definitive chemoradiotherapy. Posttherapeutic imaging after 4 months did not show any evidence of tumor progression.

The aim of this study was to characterize the educational quality and reliability of YouTube videos related to low back pain (LBP) as well as to identify factors associated with the overall video quality. A review of YouTube was performed using two separate search strings. Video-specific characteristics were analyzed for the first 50 videos of each string. Seventy-seven eligible videos were identified as a result. The mean Journal of the American Medical Association score was 2.25 ± 1.09 (range: 0-4) out of 4. The mean Global Quality Score (GQS) score was 2.29 ± 1.37 (range: 1-4) out of 5. The mean LBP score (LPS) score was 3.83 ± 2.23 (range: 0-11) out of 15. Video power index was a predictor of GQS score (β = 55.78, p = 0.048), whereas the number of likes (β = -2.49, p = 0.047) and view ratio (β = -55.62, p = 0.049) were associated with lower quality scores. Days since initial upload (β = 0.32, p = 0.042) as well as like ratio (β = 0.37, p = 0.019) were independent predictors of higher LPS scores. The results of this study suggest that the overall reliability and educational quality of videos uploaded to YouTube concerning LBP are unsatisfactory. More popular videos demonstrated poorer educational quality than their less popular counterparts. As the prevalence of LBP rises, more accurate and thorough educational videos are necessary to ensure accurate information is available to patients.

OBJECTIVE: To assess the impact and procedural input of intraoperative ultrasound (IOUS) with contrast-enhanced ultrasound (CEUS) and ultrasound elastography on surgical decision making during the procedure and consequently the out-come after hepato-pancreatico-biliary (HPB) surgery. MATERIALS AND METHODS: Data of 50 consecutive patients, who underwent HPB surgery from 04/2018 to 07/2018 were prospectively collected for this study. During surgery, IOUS with a high-resolution ultrasound device using CEUS after bolus injection of 2.4–5 ml Sulphur hexafluoride microbubbles using a 6–9 MHz probe and a share wave and strain elastography was performed by an experienced examiner. Process and time analysis were carried out using mobile phone timer. RESULTS: The IOUS with CEUS and elastography correctly identified 42 malignant tumors and 4 benign lesions. In 3 cases, the examination provided false positive result (identifying 3 benign lesions as malignant) and in 1 case a malignant lesion was incorrectly assessed as benign (sensitivity 97,7%, specificity 57,1%, PPV 93,3% and NPV 80%). The specific question by the surgeon could be answered successfully in 98% of the cases. In 76% of the cases, there was a modification (42%) or a fundamental change (34%) of the planned surgical approach due to the information provided by the IOUS. Within the last group, the IOUS had a major impact on therapy outcome. In 7 patients an additional tumor resection was required, in 5 patients the tumor was assessed as inoperable, and in total in 5 patients an intraoperative RFA (4/5) or postoperative RITA (1/5) was required. Regarding procedural input, there was only a slight, but significant difference between the transport and set-up times before the intraoperative use (mean: 14 min 22 s) and the return transport (mean 13 min 6 s), (p = 0,038). The average examination time was 14 minutes, which makes only one third of the overall time demand. CONCLUSION: Combination of IOUS with CEUS and elastography in oncological HPB surgery provides valuable information that affects surgical decision-making. The procedural input of about 45 minutes seems to be a good investment considering the improvement of the surgical procedure and a significant modification of the therapy approach in the majority of the cases.

Background Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX). VKCFD1 patients are treated life-long with high doses of vitamin K in order to correct the bleeding phenotype. However, normalization of clotting factor activities cannot be achieved for all VKCFD1 patients. Objective The current study aims to investigate the responsiveness to vitamin K for all reported GGCX mutations with respect to clotting factors in order to optimize treatment. Methods This study developed an assay using genetically engineered GGCX-/- cells, where GGCX mutations were analyzed with respect to their ability to γ-carboxylate vitamin K dependent pro-coagulatory and anti-coagulatory clotting factors by ELISA. Additionally, FVII activity was measured in order to proof protein functionality. For specific GGCX mutations immunofluorescent staining was performed to assess the intracellular localization of clotting factors with respect to GGCX wild-type and mutations. Results All GGCX mutations were categorized into responder and low responder mutations, thereby determining the efficiency of vitamin K supplementation. Most VKCFD1 patients have at least one vitamin K responsive GGCX allele that is able to γ-carboxylate clotting factors. In few patients, the hemorrhagic phenotype cannot be reversed by vitamin K administration because GGCX mutations on both alleles affect either structural or catalytically important sites thereby resulting into residual ability to γ-carboxylate clotting factors. Conclusion With these new functional data we can predict the hemorrhagic outcome of each VKCFD1 genotype thus recommending treatments with either vitamin K or Prothrombin Complex Concentrate.

Objective: To assess the degree, duration, mean absolute relative difference (MARD), and error analysis of discrepant values per continuous glucose monitoring (CGM) systems after hydroxyurea (HU) administration. Research Design and Methods: Inpatient glucometer and CGM data from 16 total pancreatectomy/islet autotransplantation patients using Dexcom Professional G4 and 12 patients using Dexcom G6 were analyzed after daily dosing with HU. Timing of HU dosing and median of 9.5 days of sensor and glucometer values were assessed per patient. Results: A large positive elevation of sensor readings was identified after HU dosing. The greatest discrepancy between glucometer and sensor readings occurred 0.5–2 h after HU administration [G4 (mean 3.0 mmol/L, median 2.4 mmol/L, MARD 55%), G6 (mean 4.2 mmol/L, median 4.6 mmol/L, MARD 91%)]. The discrepancy was

Background Duchenne muscular dystrophy is caused by mutations in the DMD gene, resulting in cardiomyopathy in all affected children by 18 years. Although cardiomyopathy is now the leading cause of mortality in these children, there is ongoing debate regarding timely diagnosis, secondary prevention, and treatment of this condition. The purpose of this study was to use exercise cardiac magnetic resonance imaging in asymptomatic young boys with Duchenne muscular dystrophy to describe their heart function and compare this with healthy controls. Methods We studied 11 boys with Duchenne muscular dystrophy aged 8.6 to 13.9 years and 11 healthy age- and sex-matched controls. Results Compared with the controls, boys with Duchenne muscular dystrophy had lower ejection fraction at rest (57% versus 63%; P = 0.004). During submaximal exercise, they reached similar peak tachycardia but increased their heart rate and cardiac output only half as much as controls (P = 0.003 and P = 0.014, respectively). End-systolic volume remained higher in boys with Duchenne muscular dystrophy both at rest and during exercise. When transthoracic echocardiography was compared with cardiac magnetic resonance imaging, 45% of the echocardiograms had suboptimal or poor views in the Duchenne muscular dystrophy group. Conclusions Boys with Duchenne muscular dystrophy had abnormalities in left ventricular systolic function that were exaggerated by exercise stress. Exercise cardiac magnetic resonance imaging is feasible in a select population of children with Duchenne muscular dystrophy, and it has the potential to unmask early signs of cardiomyopathy.