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This qualitative study sought to learn patients' perspectives on olaparib - including maintenance olaparib - in their own words.Olaparib-treated patients were interviewed by phone. A semi-structured interview guide that focused on symptoms and quality of life was formulated in alignment with the study objective. Interviews were transcribed and analyzed with content analysis.Twenty olaparib-treated patients were interviewed. Four themes emerged: (1) The Long Cancer Journey. Patients prescribed olaparib appear to have had a long cancer journey, sometimes with prior cancer ("I had breast cancer in 1996") and sometimes with a long interval from an ovarian cancer diagnosis; (2) Adherence. Despite this journey, patients were adherent to olaparib ("I set it for an alarm 15 min before I have to take [olaparib] and then exactly when I'm supposed to take it"); (3) Adherence Despite Challenges. Adherence continued despite side effects (although olaparib was "pretty tolerable"). This adherence also continued despite cost ("…for a month's supply, mine was $15,837… and my insurance covered some of it but not near enough"), and (4) Modifications in Perceptions of BRCA Status. Olaparib as cancer therapy influenced perceptions of BRCA mutations ("But I… I have to tell you, I'm grateful that I qualified to be on Lynparza®").Although oral maintenance therapy for ovarian cancer is relatively new, patients appear willing to take olaparib long term; and they seem to take great lengths to remain adherent, despite having sometimes had a long cancer journey.

ObjectiveIncreasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism.DesignWe created a mouse model ofPnlipp.T221M and characterised the structural and biochemical changes in the pancreas aged 1–12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR.ResultsWe demonstrated the hallmarks of human CP inPnlipp.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. ThePnlipp.T221M pancreas had increased ER stress evidenced by dilated ER, increasedHspa5(BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation ofDdit3(CHOP), nuclear factor-κB and cell death.ConclusionExpression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.

Summary Background There is a paucity of evidence to support safe and effective management of patients with acute severe ulcerative colitis during the COVID-19 pandemic. We sought to identify alterations to established conventional evidence-based management of acute severe ulcerative colitis during the early COVID-19 pandemic, the effect on outcomes, and any associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes. Methods The PROTECT-ASUC study was a multicentre, observational, case-control study in 60 acute secondary care hospitals throughout the UK. We included adults (≥18 years) with either ulcerative colitis or inflammatory bowel disease unclassified, who presented with acute severe ulcerative colitis and fulfilled the Truelove and Witts criteria. Cases and controls were identified as either admitted or managed in emergency ambulatory care settings between March 1, 2020, and June 30, 2020 (COVID-19 pandemic period cohort), or between Jan 1, 2019, and June 30, 2019 (historical control cohort), respectively. The primary outcome was the proportion of patients with acute severe ulcerative colitis receiving rescue therapy (including primary induction) or colectomy. The study is registered with ClinicalTrials.gov , NCT04411784 . Findings We included 782 patients (398 in the pandemic period cohort and 384 in the historical control cohort) who met the Truelove and Witts criteria for acute severe ulcerative colitis. The proportion of patients receiving rescue therapy (including primary induction) or surgery was higher during the pandemic period than in the historical period (217 [55%] of 393 patients vs 159 [42%] of 380 patients; p=0·00024) and the time to rescue therapy was shorter in the pandemic cohort than in the historical cohort (p=0·0026). This difference was driven by a greater use of rescue and primary induction therapies with biologicals, ciclosporin, or tofacitinib in the COVID-19 pandemic period cohort than in the historical control period cohort (177 [46%] of 387 patients in the COVID-19 cohort vs 134 [36%] of 373 patients in the historical cohort; p=0·0064). During the pandemic, more patients received ambulatory (outpatient) intravenous steroids (51 [13%] of 385 patients vs 19 [5%] of 360 patients; p=0·00023). Fewer patients received thiopurines (29 [7%] of 398 patients vs 46 [12%] of 384; p=0·029) and 5-aminosalicylic acids (67 [17%] of 398 patients vs 98 [26%] of 384; p=0·0037) during the pandemic than in the historical control period. Colectomy rates were similar between the pandemic and historical control groups (64 [16%] of 389 vs 50 [13%] of 375; p=0·26); however, laparoscopic surgery was less frequently performed during the pandemic period (34 [53%] of 64] vs 38 [76%] of 50; p=0·018). Five (2%) of 253 patients tested positive for SARS-CoV-2 during hospital treatment. Two (2%) of 103 patients re-tested for SARS-CoV-2 during the 3-month follow-up were positive 5 days and 12 days, respectively, after discharge from index admission. Both recovered without serious outcomes. Interpretation The COVID-19 pandemic altered practice patterns of gastroenterologists and colorectal surgeons in the management of acute severe ulcerative colitis but was associated with similar outcomes to a historical cohort. Despite continued use of high-dose corticosteroids and biologicals, the incidence of COVID-19 within 3 months was low and not associated with adverse COVID-19 outcomes. Funding None.

Evaluate association between fluid balance and intraventricular hemorrhage (IVH). Retrospective review of infants

Therapeutic hypothermia initiated within 6 hours of birth is currently the standard of care for the management of neonates with hypoxic-ischemic encephalopathy. Neonates undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy are also at risk for severe respiratory failure and need for extracorporeal life support. The risks and benefits of therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support are still not well defined. We report our experience of a case series of six neonates who underwent therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support. We also report long-term neurodevelopmental follow-up from 6 to 24 months and add to the current body of evidence regarding feasibility, clinical experience, and short-term complications.

We report a case of contrast-induced hypothyroidism in an extremely preterm infant after percutaneous patent ductus arteriosus (PDA) device closure. Iodine-induced hypothyroidism after exposure to iodine-containing antiseptics and contrast media has been previously reported in extremely preterm infants. However, this is the first report of contrast-induced hypothyroidism in an extremely preterm infant undergoing percutaneous PDA device closure. This is timely, given percutaneous PDA device closure is more frequently utilized. Guidelines for screening thyroid function pre and post contrast-requiring procedures may be warranted. Hypothyroidism if left untreated can have detrimental effects on developing brain, especially in the preterm population. Therefore, the earlier detection and treatment of iodine-induced hypothyroidism is imperative.

Digital image watermarking techniques are used to authenticate identity of owners and copyright protection of asset images. Asset medical images (AMI) specially require extreme care when embed a watermark message because additional information should affect the AMI quality and the changes in AMI gray levels may interfere with its interpretation. This paper introduces a hybrid encoded and adapted-tuned neural network (TNN) for AMI watermarking technique to cover almost essential watermarking requirements. To attain robustness, security and invisibility, uses human visual system (HVS) and TNN to tune the AMI and to find the maximum amount of adaptive watermark message before the watermark message becomes visible. To achieve transparency, enhance AMI using histogram equalization. Embedding is performed into the middle frequency coefficients of discrete cosine transform of the AMI, to avoid visual parts in the low frequency coefficient and the noise and attacks in high frequency to improve image robustness and increase capacity comparing to spatial domain.

The G20 (The Group of 20) is an international forum combining twenty major economies representing 19 countries and the European Union. The mission of the G20 is maintain an economic collaboration ensuring stable financial systems. While the member countries represent significant global GDP, trade, population and land area, criticism around bad representation of Africa within the G20 member countries of the G20 which is limited to South Africa. This publication with the embedded visualizations walks through the powerful economies of the G20 but also shows the poor representation of Africa., Website using google API which will require webserver to access the API data

Type 2 diabetes is a chronic progressive disease with increasing drug demands. It is comprised of a hereditary ß-cell dysfunction, (ßCD), insulin resistance (IR), and chronic systemic inflammation (CSI), which can be present with different degrees of severity. We have tested an alternative approach to the common drug escalation programs. DET (De-Escalation Treatment), temporary, multi-drug intervention targets to improve ß-Cell function and reverse disease progression. A personalized drug combination for a three-month treatment is determined based on a biomarker panel consisting of classic and new biomarkers. 22 patients (8 women, 14 men, age: 62±8 yrs., disease duration: 12±7 yrs., HbA1c: 7.8 %, BMI: 33.2±2.4 kg/m², treatment with 1 or 2 oral drugs) were treated with follow-up periods of up to 12 years. DET consisted of low doses each of basal insulin to address ßCD, treatment of IR (exercise and/or pioglitazone), a drug to reduce CSI (diet, GLP-1, or SGLTII) and a hypoglycemic intervention (metformin, or DPP-IV). The DET approach was well tolerated (nausea: 4 cases, edema: 1 case). All patients experienced a normalization or pronounced improvement of glycemic control without report of hypoglycemia. Mean HbA1c after 3 months was 5.9±0.4 %. Intact proinsulin decreased from 9.3±2.1 pmol/L to 2.3±0.6 pmol/L, adiponectin improved from 3.4±1.2 to 8.6±2.4 mg/dL, and mean body weight decreased by 2.4±1.1 kg (all: p11 years). Regeneration of ß-cell function by means of DET resulted in a temporary stop of chronic disease progression. A formal prospective clinical study to investigate the practicability of this approach in routine clinical practice is currently ongoing. Disclosure A. Pfützner: Consultant; Self; LifeCare, Inc., Novo Nordisk A/S. Research Support; Self; CNOGA Medical, Esperion Therapeutics, Inc. Speaker’s Bureau; Self; Sanofi-Aventis. A. Manessis: Research Support; Self; Novo Nordisk Inc., Sciema GmbH. L. Do: Research Support; Self; Sciema GmbH. M. Hanna: None. Funding Diabetes Treatment Centers International

Background Increased intact proinsulin in plasma is a highly specific biomarker for a major disruption of insulin-processing in the pancreatic β-cells with associated insulin resistance. Increased intact proinsulin in morning fasting plasma indicates not only incipient diabetes, but also increased risk of macrovascular events in the patient - of ten times before an actual diagnosis of diabetes - due to the convergence of β-cell dysfunction, insulin resistance, and chronic systemic inflammation. This has raised the question as to whether a marked increase in intact proinsulin levels after oral glucose load in healthy subjects might be considered as indicative for β-cell dysfunction and prediabetes. Methods A previous study from 2011 examined, inter alia, intact proinsulin levels in blood samples from twenty healthy study participants at baseline and two hours after an oral glucose tolerance test (OGTT) with 75 g glucose. Seventeen of the participants showed normal glucose levels at baseline and at two hours compared to 4 participants with normal intact proinsulin levels at baseline but increased intact proinsulin levels at two hours. Results All four patients went on to develop type 2 diabetes in the following 5 years. None of the other subjects from the previous investigation developed type 2 diabetes. Conclusions As also confirmed by recent literature, intact proinsulin provides a powerful, easily measured biomarker for β-cell dysfunction and insulin resistance in type 2 diabetes, as well as risk of future cardiovascular events regardless of the stage of diabetes.

There is a gap in knowledge about the postnatal growth of thyroid gland in preterm infants. To determine postnatal growth of thyroid gland in preterm infants. Thyroid gland volume was calculated in 57 prospectively enrolled preterm infants by measuring serial longitudinal, antero-posterior, and transverse dimensions of thyroid gland with ultrasound. Data were analyzed by using the Wilcoxon and independent t test. There was a significant correlation between thyroid volume (TV) and birthweight (BW) (p = 0.01), and between TV and gestational age (p = 0.02). However, unexpectedly, 12 infants had a decrease in TV between the first and second ultrasounds. Infants with late onset bacterial sepsis had lower TVs on their second ultrasounds than infants without sepsis. Thyroid ultrasound in preterm infants provides noninvasive and quick approach to determine TV and morphology. TV in preterm infants correlates positively with BW and gestational age. However, postnatal growth of thyroid gland is variable and may seemingly be affected by postnatal factors.

Advanced mechanical circulatory support is increasingly being used with more sophisticated devices that can deliver pulsatile rather than continuous flow. These devices are more portable as well, allowing patients to await cardiac transplantation in an outpatient setting. It is known that patients with renal failure are at increased risk for developing worsening acute kidney injury during implantation of a ventricular assist device (VAD) or more advanced modalities like a total artificial heart (TAH). Dealing with patients who have an implanted TAH who develop renal failure has been a challenge with the majority of such patients having to await a combined cardiac and renal transplant prior to transition to outpatient care. Protocols do exist for VAD implanted patients to be transitioned to outpatient dialysis care, but there are no reported cases of TAH patients with end stage renal disease (ESRD) being successfully transitioned to outpatient dialysis care. In this report, we identify a patient with a TAH and ESRD transitioned successfully to outpatient hemodialysis and maintained for more than 2 years, though he did not survive to transplant. It is hoped that this report will raise awareness of this possibility, and assist in the development of protocols for similar patients to be successfully transitioned to outpatient dialysis care.

IntroductionThrombotic microangiopathies (TMA) can be caused by diverse clinical entities of various etiologies. Thrombotic thrombocytopenic purpura (TTP) is caused by a lack of von Willebrand-fact...

BACKGROUND: We evaluated the epidemiology of fluid balance (FB) over the first postnatal week and its impact on outcomes in a multi-center cohort of premature neonates from the AWAKEN study. METHODS: Retrospective analysis of infants

Background: We evaluated the Wellion Galileo GLU/KET blood and ketone (s-Hydroxybutyrate, s-OHB) meter to demonstrate that it meets ISO15107:2015 regulatory approval criteria.Research Design and Me...

Systemic vascular endothelial growth factor (VEGF) inhibitions can induce worsening hypertension, proteinuria and glomerular diseases of various types. These agents can also be used to treat ophthalmic diseases like proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion and age-related macular degeneration. Recently, pharmacokinetic studies confirmed that these agents are absorbed at levels that result in biologically significant suppression of intravascular VEGF levels. There have now been 23 other cases published that describe renal sequela of intravitreal VEGF blockade, and they unsurprisingly mirror known systemic toxicities of VEGF inhibitors. We present three cases where stable levels of proteinuria and chronic kidney disease worsened after initiation of these agents. Two of our three patients were biopsied. The first patient’s biopsy showed diabetic nephropathy and focal and segmental glomerulosclerosis (FSGS) with collapsing features and acute interstitial nephritis (AIN). The second patient’s biopsy showed AIN in a background of diabetic glomerulosclerosis. This is the second patient seen by our group, whose biopsy revealed segmental glomerulosclerosis with collapsing features in the setting of intravitreal VEGF blockade. Though FSGS with collapsing features and AIN are not the typical lesions seen with systemic VEGF blockade, they have been reported as rare case reports previously. In addition to reviewing known elements of intravitreal VEGF toxicity, the cases presented encompass renal pathology data supporting that intravitreal VEGF blockade can result in deleterious systemic and renal pathological disorders.

Evaluate association between fluid balance and intraventricular hemorrhage (IVH).Retrospective review of infants30 weeks gestation admitted to Kentucky Children's Hospital Neonatal Intensive Care Unit.Infants with acute kidney injury (AKI) had a 2.4-fold increased risk of IVH (OR 2.38, 95% CI 1.46-3.87) and a 3.5-fold increased risk of severe IVH (OR 3.45, 95% CI 1.98-6.04). Infants above birthweight on day 4 had a 1.9-fold increased risk of IVH (OR 1.86, 95% CI 1.05-3.27) and a 2.0-fold increased risk of severe IVH (OR 1.96, 95% CI 1.03-3.74). When controlling for confounding factors, infants with AKI or above birthweight on day 4 had a 4.6-fold (aOR 4.60, 95% CI 1.80-11.78) and 3.0-fold (aOR 2.96, 95% CI 1.01-8.65) increased risk of severe IVH, respectively.Infants with AKI during the first week of life had a higher association of severe IVH even after controlling for confounding factors.

Background: In recent randomized clinical trials, an unusual reporting pattern of glycemic data and hypoglycemic events potentially related to an internet enabled blood glucose meter (MyGlucoHealth, BGM) was observed. Therefore, this clinical study was conducted to evaluate the system accuracy of the BGM in accordance with the ISO15197:2015 guidelines with additional data collection. Methods: To investigate system accuracy, 10 of 3088 devices and 6 of 23 strip lots, used in the trials, were selected by a randomization procedure and a standard repeatability assessment. YSI 2300 STAT Plus was used as the standard reference method. The samples were distributed as per the ISO15197:2015 recommendations with 20 additional samples in the hypoglycemic range. Each sample was tested with 6 devices and 6 strip lots with double determinations. Results: Overall, 121 subjects with blood glucose values 26-423 mg/dL were analyzed, resulting in 1452 data points. In all, 186/1452 readings (12.8%) did not meet the ISO acceptance criteria. Data evaluated according to the FDA guidelines showed that 336/1452 (23.1%) readings did not meet the acceptance criteria. A clear bias toward elevated values was observed for BG Conclusions: The results show that the BGM, although approved according to standard regulatory guidelines, did not meet the level of analytical accuracy required for clinical treatment decisions according to ISO 15197:2015 and FDA requirements. In general, caution should be exercised before selection of BGMs for patients and in clinical trials.

The structure and spectroscopic properties of the amide bond are a topic of fundamental interest in chemistry and biology. Herein, we report 17O NMR and 15N NMR spectroscopic data for four series of sterically-hindered acyclic amides. Despite the utility of 17O NMR and 15N NMR spectroscopy, these methods are severely underutilized in the experimental determination of electronic properties of the amide bond. The data demonstrate that a combined use of 17O NMR and 15N NMR serves as a powerful tool in assessing electronic effects of the amide bond substitution as a measure of electrophilicity of the amide bond. Notably, we demonstrate that steric destabilization of the amide bond results in electronically-activated amides that are comparable in terms of electrophilicity to acyl fluorides and carboxylic acid anhydrides.

Preterm birth is associated with increased risks of morbidity and mortality along with increased healthcare costs. Advances in medicine have enhanced survival for preterm infants but the overall incidence of major morbidities has changed very little. Abnormal renal development is an important consequence of premature birth. Acute kidney injury (AKI) in the neonatal period is multifactorial and may increase lifetime risk of chronic kidney disease.Traditional biomarkers in newborns suffer from considerable confounders, limiting their use for early identification of AKI. There is a need to develop novel biomarkers that can identify, in real time, the evolution of renal dysfunction in an early diagnostic, monitoring and prognostic fashion. Use of "omics", particularly metabolomics, may provide valuable information regarding functional pathways underlying AKI and prediction of clinical outcomes.The emerging knowledge generated by the application of "omics" (genomics, proteomics, metabolomics) in neonatology provides new insights that can help to identify markers of early diagnosis, disease progression, and identify new therapeutic targets. Additionally, omics will have major implications in the field of personalized healthcare in the future. Here, we will review the current knowledge of different omics technologies in neonatal-perinatal medicine including biomarker discovery, defining as yet unrecognized biologic therapeutic targets, and linking of omics to relevant standard indices and long-term outcomes.

Acute kidney injury (AKI) in the neonatal intensive care setting is multifactorial and is associated with significant morbidity and mortality. This study evaluates the utility of novel urinary biomarkers to predict the development and/or severity AKI in preterm infants. We performed a case-control study on a prospective cohort of preterm infants (

INTRODUCTION: Multi-disciplinary rounds in the neonatal intensive care unit (NICU) promote collaboration and communication between members of the health care team and has been shown to improve patient outcomes We implemented an E (remote) rounding platform in March 2020 to maintain the multidisciplinary approach while facilitating social distancing Objective: To evaluate perceptions of healthcare providers in the NICU regarding the implementation of multidisciplinary E-rounding during COVID-19 METHODS: An E-rounding platform was designed to allow only minimal members required at the bedside with the rest of the members of the multidisciplinary team rounding remotely using a video platform An IRB approved web-based survey was distributed to the NICU providers The survey included demographic questions and themes related to rounding efficiency, promotion of provider and patient safety, communication, and role utilization RESULTS: A total of 61 (16 physicians, 16 advanced practitioners, 22 nurses, 2 respiratory therapists, and 4 ancillary staff) providers participated in the study 46 62% had more than 7 year, 26 23% with 4-6 years, and 31 1% had less than 3 years' experience Age groups included 32 79% between 20-30 years, 36 07% between 31-40 years, 31 21% more than >40 years The majority (88%) had no previous experience with E-rounding A Likert scale of 1-5 (1 being much worse, 3 being the same and 5 much better) was utilized to evaluate themes related to provider role utilization, effectiveness, communication, and provider safety A majority reported (scale 3 and more)that E-rounding promoted patient safety (68 8%) and provider safety (90 1%), appropriate role utilization (72%), rounding efficiency (62%), and providing a foundation of trust with families (60%) compared to traditional rounds Only 50% reported that the ability to understand and communicate the patient plan was similar to or better than traditional rounding and 37 2% reported that they would not consider E-rounding if social distancing is not necessary CONCLUSIONS: E-rounding can be an effective tool to promote and continue the multidisciplinary rounding approach in the NICU during and after COVID-19, but adjustments need to be made to improve provider communication

To assess nutritional outcomes in preterm infants after the implementation of probiotics. Retrospective chart review of infants with birth weight⩽1250 grams and/or⩽28 weeks of gestational age admitted to the KCH-Neonatal Intensive Care Unit was done. Data were collected over two periods, period 1 (before probiotics) and period 2 (after probiotics) and included demographic data, daily weight gain, feeding strategies (type, amount, caloric content and frequency of feeds) and comorbidities affecting feedings (Patent ductus arteriosus, Sepsis). Primary outcomes—extra uterine growth restriction (EUGR) status and incidence of necrotizing enterocolitis (NEC) as well as secondary outcomes—time to reach full feeds, feeding intolerance episodes and weight gain were compared between the two groups. A total of 113 infants (period 1) were compared with 108 infants (period 2). The odds of EUGR was significantly lower with probiotics (odds ratio: 0.3, 95% confidence interval 0.138 to 0.611). Time to reach full feeds was significantly reduced and weight gain was significantly better in period 2. Significant reduction was also noted in number of total parental nutrition days, central line days, nil per os days and number of feeding intolerance episodes in period 2. There was no significant difference in the incidence of NEC. Probiotics improve feeding tolerance leading to better overall growth and decreases the incidence of EUGR in preterm infants.

Background Neonatal acute kidney injury (AKI) occurs in 40 to 70% of critically ill neonatal intensive care admissions. This study explored the differences in perceptions and practice variations among neonatologists and pediatric nephrologists in diagnostic criteria, management, and follow-up of neonatal AKI. Methods A survey weblink was emailed to nephrologists and neonatologists in Australia, Canada, New Zealand, India, and the United States. Questions consisted of demographic and unit practices, three clinical scenarios assessing awareness of definitions of neonatal AKI, knowledge, management, and follow-up practices. Results Many knowledge gaps among neonatologists, and to a lesser extent, pediatric nephrologists were identified. Neonatologists were less likely to use categorical definitions of neonatal AKI (p Conclusion Neonatal AKI is underappreciated, particularly among neonatologists. A lack of evidence on neonatal AKI contributes to this variation in response. Therefore, dissemination of current knowledge and areas for research should be the priority.

Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop

Omics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called "Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment" (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function.

Metabolomics, the latest of the "omics" sciences, refers to the systematic study of metabolites and their changes in biological samples due to physiological stimuli and/or genetic modification. Because metabolites represent the downstream expression of genome, transcriptome, and proteome, they can closely reflect the phenotype of an organism at a specific time. As an emerging field in analytical biochemistry, metabolomics has the potential to play a major role in monitoring real-time kidney function and detecting adverse renal events. Additionally, small molecule metabolites can provide mechanistic insights into novel biomarkers of kidney diseases, given the limitations of the current traditional markers. The clinical utility of metabolomics in the field of pediatric nephrology includes biomarker discovery, defining as yet unrecognized biological therapeutic targets, linking of metabolites to relevant standard indices and clinical outcomes, and providing a window of opportunity to investigate the intricacies of environment/genetic interplay in specific disease states.

This paper presents the fabrication, characterization, and modeling of electrodynamic microactuators. The actuators are piston-type devices, each comprising of a circular flexible polydimethylsiloxane membrane, a multi-turn Cu coil, and an integrated powder-based NdFeB permanent magnet. The devices are fully batch-fabricated in a single wafer using only three masks. Ranging in diameter from 2.5 to 5.2 mm, three different device designs are quasi-statically and dynamically characterized for their electromechanical performance. The resonant frequencies of the three actuators range from 224 to 820 Hz. The maximum displacements span from 4 to 64 μm for an input power ranging from 250 to 525 mW. The experimental results are supported by a parametric lumped element model of the transducer.

Patent ductus arteriosus (PDA) is common in preterm infants and is associated with significant morbidities. B type natriuretic peptide (BNP) is synthesized in the ventricles secondary to volume overload and excreted as urinary N-terminal pro-brain natriuretic peptide (NT-proBNP). We report an observational prospective study of 64 preterm infants with birth weight ⩽1000 g. Echocardiographic parameters were obtained from clinical echocardiograms performed in the first week of life. Urinary NT-proBNP/creatinine ratios (pg mg−1) were measured on the same day of the echocardiograms. Infants with medium to large PDA (n=39) had significantly higher NT-proBNP/creatinine levels compared with infants with small PDA (n=10) (median (IQ range): 2333 (792–6166) vs 714 (271–1632) pg mg−1, P=0.01) and compared with infants with no PDA (n=15) (2333 (792–6166) vs 390 (134–1085) pg mg−1, P=0.0003). Urinary NT-proBNP/creatinine ratios were significantly lower post treatment if PDA closed (n=17), P=0.001 or if PDA became smaller after treatment (n=9), P=0.004. Urinary NT-proBNP/creatinine levels correlated with ductal diameter (P⩽0.0001), but not with LA/Ao ratio (P=0.69) or blood flow velocity through the ductus (P=0.06). Our findings indicate that there is a positive correlation between ductal diameter and urinary NT-proBNP in preterm infants.

Introduction: Patients with peripheral artery disease (PAD) develop myofiber degeneration and fibrosis in their ischemic lower extremities, along with limb dysfunction. Walking performance improves with revascularization and exercise therapy, but effects on the myopathy are unknown. We previously showed fibrosis progresses with PAD and positively correlates with expression of vascular transforming growth factor-beta 1 (TGF-β1), a cytokine that stimulates collagen deposition. Hypothesis: We hypothesize that revascularization (RVS) and supervised exercise therapy (EXE) improve limb function in association with improved TGF-β1 dependent fibrosis. Methods: Gastrocnemius biopsies were collected from PAD patients (Fontaine Stage II; N=56) at baseline and 6 months after RVS (N=20), EXE (N=19), or no intervention (CTL; N=17). TGF-β1 expression was measured as grey scale units (gsu) by quantitative fluorescence microscopy of paraffin-embedded gastrocnemius sections. Collagen abundance was measured as optical density by quantitative multi-spectral bright-field microscopy of Masson Trichrome stained paraffin sections. Six Minute Walking Distance (SMWD), in meters, and Peak Walking Time (PWT), in seconds, were determined at baseline and 6 months. Relationships among TGF-β1, collagen, and limb function were assessed. Results: TGF-β1 expression and collagen density increased in CTL and EXE but not RVS patients. SMWD and PWT increased among RVS patients. PWT but not SMWD increased among EXE patients. SMWD and PWT were unchanged among CTL patients. The data are summarized in Table 1. Conclusions: RVS and EXE improved walking performance of patients with PAD, but only RVS prevented progression of fibrosis in the gastrocnemius of these patients. Over the same 6-month period, fibrosis increased in CTL muscle but was not sufficient to alter walking performance. The data suggest that benefits to the PAD leg may be greater with RVS compared to EXE.

Background Lower leg ischemia, myopathy, and limb dysfunction are distinguishing features of peripheral artery disease (PAD). The myopathy of PAD is characterized by myofiber degeneration in association with extracellular matrix expansion, and increased expression of transforming growth factor-beta 1 (TGF-β1; a pro-fibrotic cytokine). In this study, we evaluated cellular expression of TGF-β1 in gastrocnemius of control (CTRL) and PAD patients and its relationship to deposited collagen, fibroblast accumulation and limb hemodynamics. Methods Gastrocnemius biopsies were collected from PAD patients with claudication (PAD-II; N = 25) and tissue loss (PAD-IV; N = 20) and from CTRL patients (N = 20). TGF-β1 in slide-mounted specimens was labeled with fluorescent antibodies and analyzed by quantitative wide-field, fluorescence microscopy. We evaluated co-localization of TGF-β1 with vascular smooth muscle cells (SMC) (high molecular weight caldesmon), fibroblasts (TE-7 antigen), macrophages (CD163), T cells (CD3) and endothelial cells (CD31). Collagen was stained with Masson Trichrome and collagen density was determined by quantitative bright-field microscopy with multi-spectral imaging. Results Collagen density increased from CTRL to PAD-II to PAD-IV specimens (all differences p

Hypotonic saline solutions have been used for over five decades to treat children with diarrheal dehydration. However, concern has recently been raised about the potential for iatrogenic hyponatremia as a result of this therapy. We reviewed the medical records of 531 otherwise healthy children with gastroenteritis who had been admitted to the hospital for intravenous fluid therapy. We retrospectively collected data on 141 of these children who had received two serum electrolytes (one upon admission and the other 4-24 h thereafter). The remaining 390 children were excluded because their charts lacked the required data. We analyzed data in 124 of these 141 patients whose initial serum sodium (Na) level was between 130-150 mEq/l and excluded 17 patients whose admission serum sodium fell outside this range. All patients were treated with intravenous hypotonic fluids (5% dextrose in 0.2% saline, n = 4; 5% dextrose in 0.3% saline, n = 102; 5% dextrose in 0.45% saline, n = 18 patients) as maintenance fluid therapy or maintenance fluid plus deficit therapy; 100 of these children had received an initial saline bolus of 21.05 +/- 8.5 ml/kg upon admission. The serum Na level decreased by 1.7 +/- 4.3 mEq/l in the whole group. Of the 97 children with isonatremia (Na 139.5 +/- 2.7 mEq/l) on admission, 18 (18.5%) developed mild hyponatremia (Na 133.4 +/- 0.9 mEq/l, range 131-134), with a decrease in serum Na of 5.7 +/- 3.1 mEq/l, and 79 remained isonatremic (Na 138.3 +/- 2.7 mEq/l), with a decrease in serum Na of 1.8 +/- 3.4 mEq/l (p0.0005). There was no significant difference in type, rate, or amount of intravenous fluid or saline bolus (26.1 +/- 10.4 vs. 20.2 +/- 8.6 ml/kg, respectively) administered in these two groups. Children who became hyponatremic were older (5.8 +/- 2.7 years) than those who remained isonatremic (2.8 +/- 3.1 years) (p0.0005), but there was no statistical difference in gender, degree of dehydration, and severity of metabolic acidosis between the two groups. Although serum Na increased by 3.9 +/- 2.5 mEq/l in 19 patients with mild hyponatremia upon admission (Na 132.8 +/- 1.3 to 136.7 +/- 2.6 mEq/l) and 73% of these became isonatremic, hypotonic saline solutions have the potential to cause hyponatremia in children with gastroenteritis and isonatremic dehydration.

This study aims at examining the mechanical properties of MgB2 wires fabricated with PIT method by studying the effect of tensile and bending stresses on their current carrying capacity. Wires are mounted on a tensile machine and are subjected to different load increments within both the elastic and the plastic regions. The current carrying capacity is measured for each load and the behavior of Ic versus stress/strain is studied. Microstructures of MgB2 core are studied for different loads by using SEM. For bending tests, two cases are examined. The first case is to anneal MgB2 wires then wind them on mandrels with different diameters, while the second case is to wind un-annealed wires on the same mandrels with different diameters then anneal the winded wires. A comparison between both cases is made using SEM for all different diameters and measuring the corresponding Ic. The behavior of Ic versus bending strain is studied. This whole study aims at giving a clear picture of the optimum loading, bending and processing conditions at which MgB2 wires will possess a high current carrying capacity for practical applications.

Introduction: A six-month treatment with the Angiotensin-Converting Enzyme Inhibitor (ACEI) Ramipril improved the walking ability of Peripheral Artery Disease (PAD) patients, but the mechanism remains unknown. ACEI have been shown to reduce fibrosis in heart and kidney and improve arterial compliance. We have identified a myopathy in calf muscles of PAD patients, characterized by fibrosis and increased TGF-β1 produced exclusively in smooth muscle cells (SMC) of microvessels. These events were linked to myofiber oxidative damage and reduced myofiber cross-sectional area. Hypothesis: The myopathy of PAD patients taking ACEI is improved compared to patients who are not taking ACEI and this improvement is associated with improved walking ability. Methods: Calf muscle biopsies, from PAD patients (Fontaine Stage II) taking ACEI (ACEI+) and those who were not (ACEI-), were fixed, embedded in paraffin, sectioned at 4 microns and slide mounted. Oxidative damage (carbonyl groups) (N=13 for ACEI- and 22 for ACEI+) and TGF-β1 (N=13 for ACEI- and 20 for ACEI+) were analyzed by quantitative fluorescence microscopy and expressed as grey scale units (gsu). Myofiber cross-sectional area was determined from fluorescence-labeled sarcolemma. Fibrosis was determined as collagen density (gsu) by multi-spectral analysis of slide specimens (N=13 for ACEI- and 20 for ACEI+) stained with Mason Trichrome. Limb function was assessed by the six-minute walking distance (N=28 for ACEI- and 20 for ACEI+). Results: Compared to ACEI- patients, ACEI+ patients had reduced TGF-β1 (4.25 gsu +/- 0.69 vs. 1.51 gsu +/- 0.23; p = 0.001) and decreased collagen density (2067 gsu +/- 88 vs. 1671 gsu +/- 51; p < 0.001). Carbonyl adducts were reduced in myofibers of ACEI+ compared to ACEI- patients (1584 gsu +/- 55 vs. 1779 gsu +/- 58; p = 0.019) and myofiber cross sectional area was increased (4629 μm2 +/- 285 vs. 3816 μm2 +/- 267; p = 0.023). Six-minute walking distance was greater in ACEI+ compared to ACEI- patients (333 m +/- 20 vs. 266 m +/- 16; p = 0.011). Conclusions: Improved walking distance of PAD patients taking ACEI is associated with improved calf muscle myopathy, determined as reduced TGF-β1 production, collagen density, and myofiber oxidative damage, and increased myofiber cross-sectional area.

Working towards developing lightweight superconducting magnets for future space and other applications, we have successfully fabricated mono-core Ti-sheathed MgB2 wires by the powder-in-tube method. The wires were characterized by magnetization, electrical resistivity, x-ray diffraction, scanning electron microscopy, and energy dispersive spectrometry measurements. The results indicate that the Ti sheath does not react with the magnesium and boron, and the present wire rolling process can produce MgB2 wires with a superconducting volume fraction of at least 64% in the core. Using the Bean model, it was found that at 5 K, the magnetic critical current densities, Jc, measured in magnetic fields of 0, 5, and 8 T are about 4.2 × 105, 3.6 × 104, and 1.4 × 104 A cm−2, respectively. At 20 K and 0 T, the magnetic Jc is about 2.4 × 105 A cm−2. These results show that at zero and low fields, the values of the magnetic Jc for Ti-sheathed MgB2 wires are comparable with the best results available for the Fe-sheathed MgB2 wires. At high fields, however, the Jc for Ti-sheathed MgB2 wires appears higher than that for the Fe-sheathed MgB2 wires.

Multidisciplinary evaluation (MDE) of hepatocellular cancer (HCC) is the current standard, often provided through a tumor board (TB) forum; this standard is limited by oncology workforce shortages and lack of a TB at every institution. Virtual TBs (VTBs) may help overcome these limitations. Our study aim was to assess the impact of a regional VTB on the MDE process for patients with HCC.A retrospective cohort study was conducted, including patients with HCC referred to a tertiary cancer center from regional facilities (2009 to 2013). Baseline characteristics and outcomes were compared based on the referral mechanism: VTB versus subspecialty consultation (non-VTB). The primary outcome was comprehensive MDE (all required specialists present and key topics discussed). Secondary outcomes included timeliness of MDE and travel burden to complete MDE. Univariable and multivariable logistic regressions were performed to examine the association of a VTB with comprehensive MDE.A total of 116 patients were included in the study; 48 (41.4%) were evaluated through the VTB. A higher proportion of VTB patients received comprehensive MDE (91.7% v 64.7%; P = .001); the VTB was independently associated with higher odds of accomplishing comprehensive MDE (odds ratio, 6.0; 95% CI, 1.2 to 29.9; P = .02). VTB patients completed MDE significantly faster (median, 23 v 39 days; P.001), with lower travel burden (median, 0 v 683 miles traveled; P.001).This VTB program positively affected the process of care for patients with HCC by improving the quality and timeliness of the MDE process, while avoiding the burden arising from travel needs. Future studies should focus on implementation of VTB programs on a wider scale.

Background: ACE2 [vasoprotective axis of the renin angiotensin system (RAS)], plays a protective role in cardiovascular diseases. In addition, the number and function of EPCs is impaired in heart failure. These observations led us to hypothesize that DIZE would protect against myocardial infarction (MI) and improve EPC function. Methods: DIZE treatment (15 mg/kg/day, s.c.) was initiated in 8-week-old SD rats two days prior to MI surgery and continued throughout the study-period. Cardiac function was measured four weeks post-MI. The number of circulating rat EPCs (CD4 - /CD5 - /CD8 - /CD90 + ) was quantified via flow cytometry. EPCs were isolated from spleen mononuclear cells and function was assessed by ability to migrate towards SDF-1. Results: MI rats showed a 58% decrease in fractional shortening (FS,%) [control (C): 54.6 ± 3.0; DIZE alone (D) : 52.5± 4.8; MI: 22.5± 3.7], a 50% decrease in contractility (dP/dt max mmHg/s) (C: 9480 ± 425.3; D: 9585 ± 597.4; MI: 4716 ± 724.9), and a 27% increase in ventricular hypertrophy (VH, mg/mm) (C: 26.5 ± 1.5; D: 26.9 ± 1.4; MI: 33.4± 1.1). This was associated with 40% decrease in cardiac ACE2 activity (C: 246.2 ± 25.1; D: 254.2 ± 20.6; MI: 148.9 ± 29.2, RFU/min). There was a 23% decrease in the number of circulating EPCs (C: 4.3 ± 0.1%; D: 4.2 ± 0.2%; MI: 3.3 ± 0.1%) and 12% decrease in their migratory ability (MI: 20.0%). DIZE resulted in a 2.5 fold increase in ACE2 activity in MI heart, attenuated the MI-induced decrease in FS by 49%, improved dP/dt max by 49%, and reversed VH by 21%. In addition, DIZE increased the number of EPCs by 21% and improved their migratory ability by 9% in the MI rats. Furthermore, immunostaining for Islet-1, a marker for cardiac progenitor cells (CPCs) demonstrated that DIZE increased CPC number and decreased infiltration of macrophages in the peri-infarct area of the ischemic heart. All these beneficial effects were abolished by C-16, an ACE2 inhibitor. Conclusions: Collectively, our observations demonstrate that activation of endogenous ACE2 improves cardiac function and attenuates LV remodeling post-MI, increases EPC number and function, increases engraftment of CPCs and decreases inflammatory cells in peri-infarct cardiac regions. Thus, DIZE may represent a promising therapeutic strategy for treating MI.

Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazene aceturate (DIZE), a small molecule ACE2 activator, has been used to evaluate this hypothesis. DIZE (15 mg/kg per day, s.c.) was injected 2 days before MI surgery and continued throughout the study period. MI rats showed a 62% decrease in fractional shortening (%; control, 51.1±3.2; DIZE alone, 52.1±3.2; MI, 19.1±3.0), a 55% decrease in contractility (dP/dt max mm Hg/s; control, 9480±425.3; DIZE alone, 9585±597.4; MI, 4251±657.7), and a 27% increase in ventricular hypertrophy (mg/mm; control, 26.5±1.5; DIZE alone, 26.9±1.4; MI, 33.4±1.1). DIZE attenuated the MI-induced decrease in fractional shortening by 89%, improved dP/dt max by 92%, and reversed ventricular hypertrophy by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels but decreased ACE2 activity by 40% (control, 246.2±25.1; DIZE alone, 254.2±20.6; MI, 148.9±29.2; RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI, and restored normal balance of the cardiac renin–angiotensin system. In addition, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells, and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI.

Background Aminoglycoside exposure is a common cause of acute kidney injury (AKI). Delay in the diagnosis of AKI using conventional biomarkers has been one of the important obstacles in applying early effective interventions. We tested the hypothesis that urinary metabolomics could identify novel early biomarkers for toxic renal injury. Methods 3 days old rats were divided into 3 groups; they received a single daily injection of vehicle (0.9% NaCl solution) or gentamicin at a dose of 10 or 20 mg/kg/day for 7 days. Urine and blood were collected after 3 and 7days of injections. Urinary metabolites were evaluated using High-performance liquid chromatography and gas chromatography/ mass spectrometry. Results A distinct urinary metabolic profile characterized by glucosuria, phosphaturia and aminoaciduria was identified preceding changes in serum creatinine. At both gentamicin doses, urinary tryptophan was significantly (p