Validity of claims-based algorithms to identify neurodevelopmental disorders in children.

PURPOSE: To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference. METHODS: Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. RESULTS: PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD. CONCLUSIONS: PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases.

Prenatal exposure to cigarette smoke interacts with OPRM1 to modulate dietary preference for fat.

BACKGROUND: Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction. METHODS: We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. RESULTS: We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (-1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the "protective" (fat intake-lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (-3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). LIMITATIONS: A limitation of our study was its cross-sectional design. CONCLUSION: Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.

Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells.

Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose and is associated with oxidative stress. It has been implicated in hyperglycemia-induced ß-cell dysfunction and apoptosis. As high glucose and oxidative stress mediate diabetic nephropathy (DN), the contribution of TxNIP was investigated in renal mesangial cell reactive oxygen species (ROS) generation and collagen synthesis. To determine the role of TxNIP, mouse mesangial cells (MC) cultured from wild-type C3H and TxNIP-deficient Hcb-19 mice were incubated in HG. Confocal microscopy was used to measure total and mitochondrial ROS production (DCF and MitoSOX) and collagen IV. Trx and NADPH oxidase activities were assayed and NADPH oxidase isoforms, Nox2 and Nox4, and antioxidant enzymes were determined by immunoblotting. C3H MC exposed to HG elicited a significant increase in cellular and mitochondrial ROS as well as Nox4 protein expression and NADPH oxidase activation, whereas Hcb-19 MC showed no response. Trx activity was attenuated by HG only in C3H MC. These defects in Hcb-19 MC were not due to increased antioxidant enzymes or scavenging of ROS, but associated with decreased ROS generation. Adenovirus-mediated overexpression of TxNIP in Hcb-19 MC and TxNIP knockdown with siRNA in C3H confirmed the specific role of TxNIP. Collagen IV accumulation in HG was markedly reduced in Hcb-19 cells. TxNIP is a critical component of the HG-ROS signaling pathway, required for the induction of mitochondrial and total cell ROS and the NADPH oxidase isoform, Nox4. TxNIP is a potential target to prevent DN.

Use of a Sheath and Stylet for a Difficult Dorsal Root Ganglion Stimulation Lead Extraction: A Case Report.

Dorsal root ganglion stimulation (DRG-S) is a relatively new neuromodulation technique that has shown promising results in the treatment of chronic pain conditions. We present a case of a difficult lead extraction during the explantation of a DRG-S device. The lead was unable to be removed despite multiple attempts until a sheath and stylet were used to facilitate extraction. As DRG-S utilization becomes more widespread, DRG-S device explantation will inevitably become more common. The technique described in this report may be beneficial in certain cases of difficult DRG-S lead extraction.

Safety profiles and lesion size of different radiofrequency ablation technologies: a comparison of large tip, open and closed irrigation catheters.

INTRODUCTION: Different technologies have been developed for radiofrequency ablation (RFA), which include increasing electrode (tip) size and cooling the tip through irrigation either internally (closed-loop) with D5W or externally (open-loop) with saline. Although these catheters are widely used clinically, the propensity for adverse events and the lesion profiles of each of these catheter technologies have not been directly compared under a wide range of controlled conditions. METHODS AND RESULTS: Freshly excised canine thigh muscle was placed in a chamber filled with circulating, heparinized blood heated to 37 degrees C. Five different catheters were tested: 4 mm tip, 10 mm tip single thermistor, 10 mm tip multitemperature sensor, 4 mm closed-loop irrigated cooled-tip, and 4 mm open-loop irrigated cooled tip at several different contact and power settings. The catheter and tissue interface was continuously monitored with intracardiac echocardiography (echo) (Acuson). During the RFA, any bubbling generated from the tip and/or popping seen on echo was noted, and after each RFA, the catheter and lesion were examined for the presence of thrombus. For all of the catheters, complications correlated to the electrode tip temperature and power setting. All of the catheters experienced complications at any lesion size except for the open-irrigated catheter, which only had complications at the largest lesions. Overall, the cooled tip catheters experienced an at least sixfold greater odds of popping, bubbling, and impedance rises than the 4 mm, but the majority occurred at power levels greater than 20 W. The open-irrigated catheters created eccentric lesions that extended away from the tissue-catheter interface, in the direction of blood flow. In addition, it produced saline filled blisters at the lesion site in 16.7% of the burns. The 10 mm catheter had an at least twofold greater odds of thrombus, charring, and bubbling, but larger lesions than the 10 mm multitemperature sensor catheter. CONCLUSIONS: Catheter type, contact conditions, and power settings all play a role in lesion size and in the frequency of complications that occur during an RFA. Cooling the electrode tip, either internally or externally, does not prevent complications from occurring, especially at the higher power control settings. Adding more temperature sensors to the 10 mm seems to reduce the amount of complications that can occur.

Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation.

BACKGROUND: Altered conduction is associated with increased atrial fibrillation (AF) vulnerability in canine models of chronic mitral regurgitation (MR) and heart failure (HF). Rotigaptide (ZP123) augments gap junction conductance, improving cell-to-cell coupling. We studied the effects of rotigaptide on atrial conduction and AF vulnerability in the canine MR and HF models. METHODS AND RESULTS: Twenty-one dogs in 3 groups were studied: control (n=7), chronic MR induced by mitral avulsion (n=7), and HF induced by ventricular tachypacing (n=7). Epicardial mapping of both atria was performed with a 512-electrode array at baseline and at increasing rotigaptide doses (10, 50, and 200 nmol/L). Conduction velocity increased in both atria in control animals and MR animals (maximum percentage increase: 24+/-5%, 38+/-6% [P<0.001, <0.001] in the left atrium and 19+/-9%, 18+/-3% [P<0.001, <0.001] in the right atrium). Conduction velocity did not change in the left atrium of the HF group and increased minimally in the right atrium (3+/-3%, 17+/-5% [P=NS, P=0.001]). AF duration was increased at baseline in MR and HF animals (control: 16+/-25 seconds, MR: 786+/-764 seconds, HF: 883+/-684 seconds; P=0.013). At 50 nmol/L of rotigaptide, duration of AF markedly decreased in the MR animals (96% reduction, P<0.001), reducing AF duration to that of control animals (control: 9+/-11 seconds, MR: 14+/-16 seconds, HF: 1622+/-355 seconds; P=0.04). CONCLUSIONS: Gap junction modulation with rotigaptide reduces AF vulnerability in a canine MR model of AF to a level similar to control animals but does not affect AF vulnerability in the canine HF model. This may be a novel therapeutic target in some forms of AF.

Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure.

BACKGROUND: Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. METHODS AND RESULTS: We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-beta1 expression. CONCLUSIONS: Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

The effects of remodeling with heart failure on mode of initiation of ventricular fibrillation and its spatiotemporal organization.

PURPOSE: The effect of the heart failure substrate on the initiation of ventricular fibrillation (VF) and its resulting mechanism is not known. The objective of this study was to determine the effects of substrate on VF initiation and its spatiotemporal organization in the heart failure model. METHODS: Optical action potentials were recorded from LV wedge preparations either from structurally normal hearts (control, n = 11) or from congestive heart failure (CHF; n = 7), at the epicardial surface, endocardial surface which included a papillary muscle, and a transmural cross section. Action potential duration (APD(80)) was determined, and VF was initiated. A fast Fourier transform was calculated, and the dominant frequency (DF) was determined. RESULTS: The CHF group showed increased VF vulnerability (69 vs 26 %, p < 0.03), and every mapped surface showed an APD(80) gradient which included islands of higher APDs on the transmural surface (M cells) which was not observed in controls. VF in the CHF group was characterized by stable, discrete, high-DF areas that correlated to either foci or spiral waves located on the transmural surface at the site of the papillary muscle. Overall, the top 10 % of DFs correlated to an APD of 101 ms while the bottom 10 % of DFs correlated to an APD of 126 ms (p < 0.01). CONCLUSIONS: In the CHF model, APD gradients correlated with an increased vulnerability to VF, and the highest stable DFs were located on the transmural surface which was not seen in controls. This indicates that the CHF substrate creates unique APD and DF characteristics.

Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age.

BACKGROUND: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth. OBJECTIVE: We examined whether such alterations are present from birth through adolescence. METHODS: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447). RESULTS: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10-11) and CNTNAP2 (cg25949550, p = 4.0 × 10-9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)-significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort. CONCLUSIONS: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years-at least until adolescence.

Famotidine and long QT syndrome.

Numerous drugs have been implicated in causing a prolonged QT interval and Torsades de pointes. However, the association of famotidine and acquired long QT syndrome has rarely been reported. We report 2 cases of famotidine-associated acquired long QT syndrome.

Cigarette smoking and DNA methylation.

DNA methylation is the most studied epigenetic modification, capable of controlling gene expression in the contexts of normal traits or diseases. It is highly dynamic during early embryogenesis and remains relatively stable throughout life, and such patterns are intricately related to human development. DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors. Genetic variants at a specific locus can influence both regional and distant DNA methylation. The environment can have varying effects on DNA methylation depending on when the exposure occurs, such as during prenatal life or during adulthood. In particular, cigarette smoking in the context of both current smoking and prenatal exposure is a strong modifier of DNA methylation. Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases. As such, DNA methylation is a potential mechanistic link between current smoking and cancer, as well as prenatal cigarette-smoke exposure and the development of adult chronic diseases.

Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice.

Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.

Effectiveness of a pharmacist-led drug counseling on enhancing antihypertensive adherence and blood pressure control: a randomized controlled trial.

Adherence to antihypertensive medications represents a crucial success factor for optimal blood pressure (BP) control in clinical practice. This study evaluated whether an additional pharmacist-led medication counseling could achieve better optimal BP control and enhance compliance. In a designated family clinic in a region with similar resident characteristics to Hong Kong, patients taking ≥ one antihypertensive agent with suboptimal compliance were randomly allocated to a brief 3-minute drug advice (control; n = 161) or pharmacist counseling (intervention; n = 113). The two groups were compared by repeated measure ANOVA at 3-months and 6-months with BP control and medication compliance as outcome variables, respectively. The proportions of patients having optimal compliance increased from 0% to 41.1% at 3 months and 61.9% at 6 months (P < 0.001). The proportion of patients having optimal BP control improved from 64.1% at baseline to 74.0% at 3 months and 74.5% at 6 months (P = 0.023). There were no significant differences between the two groups in the changes of BP control and compliance levels. This study implied that even a brief 3-minute drug advice might lead to improved BP levels among patients on antihypertensive medications in general practice, but did not demonstrate additional effects by pharmacist counseling.

Supraventricular tachycardia--part I.

Supraventricular tachycardias (SVTs) affect all age groups and are a source of significant morbidity. They are frequently encountered in otherwise healthy individuals without structural heart disease. Advances in the understanding of their mechanisms and anatomical locations have led to highly effective pharmacologic and nonpharmacologic treatment strategies. Recognition, identification, and differentiation of the various SVTs are of great importance in formulating an effective treatment strategy. Developments over the past four decades have made possible the accurate diagnosis of SVTs. Today, advances in catheter design, energy delivery systems, mapping systems, and remote navigation systems have rendered the ablation of most SVTs safe and effective. This monograph provides an in-depth discussion of the history, presentation, mechanism, and treatment strategies of the most commonly encountered SVTs. The monograph is divided into two parts. The first part is presented here.

Supraventricular tachycardia-Part II: History, presentation, mechanism, and treatment.

Supraventricular tachycardias (SVTs) affect all age groups and are a source of significant morbidity. They are frequently encountered in otherwise healthy individuals without structural heart disease. Advances in the understanding of their mechanisms and anatomical locations have led to highly effective pharmacologic and nonpharmacologic treatment strategies. Recognition, identification, and differentiation of the various SVTs are of great importance in formulating an effective treatment strategy. Developments over the past four decades have made possible the accurate diagnosis of SVTs, and technological advances have led to ablative cures of most of these arrhythmias. This monograph provides an in-depth discussion of the history, presentation, mechanism, and treatment strategies of the most commonly encountered SVTs. The monograph is divided in two parts. Arrhythmias and related syndromes that are covered in detail in the first part include atrioventricular nodal reentrant tachycardia, Wolf-Parkinson-White syndrome, and atrioventricular reentrant tachycardia. The remaining SVTs are covered in the second part, which is presented here.

Failure of impedance monitoring to prevent adverse clinical events caused by fracture of a recalled high-voltage implantable cardioverter-defibrillator lead.

BACKGROUND: The Medtronic Sprint Fidelis implantable cardioverter-defibrillator high-voltage lead is prone to fracture. The October 2007 safety advisory recommended lead impedance monitoring to aid in identifying lead fractures. OBJECTIVE: The aim of this single-center study was to examine the effectiveness of impedance monitoring for detecting Sprint Fidelis lead failures before they caused adverse clinical events such as inappropriate shocks. METHODS: Impedance and sensing information were acquired during routine clinic and CareLink follow-up and at the time of lead failure using the Patient Alert, sensing integrity counter, nonsustained episode, and electrogram features in Medtronic pulse generators. RESULTS: Between September 2004 and February 2008, 17 of 514 Sprint Fidelis leads (3.3%) followed up at our center failed between 11 and 35 months after implantation (mean 23.0 +/- 8.0 months). Fifteen of these failures (88%) were caused by pace-sense conductor fractures, and 2 (12%) were caused by high-voltage conductor defects. Twelve of 15 patients (80%) with pace-sense conductor fractures received inappropriate shocks; of these, 4 had no significant increase in lead impedance before they were shocked, 2 were shocked <3 hours after their lead impedances exceeded the 1,000 Omega audible alert threshold, and 2 patients did not hear the alarm. All pace-sense conductor failures whose sensing function could be evaluated (13 of 15) had oversensing based on stored data, and oversensing usually (11 of 13) preceded impedances changes. CONCLUSION: Impedance monitoring did not prevent inappropriate shocks in two-thirds of our patients. Thus, pace-sense conductor impedance monitoring as currently implemented does not reliably forewarn patients of a lead malfunction. Consequently, patients who have Sprint Fidelis leads remain at risk for adverse clinical events associated with pace-sense conductor fracture.

Size-dependent volatility of diesel nanoparticles: chassis dynamometer experiments.

We analyzed the size-dependent volatility of nanoparticles in a diameter range of 30-70 nm in diesel exhaust emissions. The test system included a medium-duty diesel truck on a chassis dynamometer, a single-stage dilution tunnel, a tandem differential mobility analyzer (TDMA) equipped with an electric furnace, and a condensation particle counter. The size shifts of monodispersed diesel nanoparticles under changing furnace temperatures were measured by TDMA in the gas phase. Together with the reduction of average particle size and volume, we observed the development of bimodal size distributions resulting from the separation between semivolatile and nonvolatile species as the furnace temperature was increased. While 91-98% of the particles were found to be semivolatile species by total volume during the idling engine condition, only 6-9% were semivolatile during the one-half engine load condition. We also found that smaller particles contained a larger fraction of semivolatile species.