Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

Severe cardiac conduction disease associated with titin gene mutation.

Heart block is rare in pediatrics with many possible causes. An association between complete heart block (CHB) and pathogenic titin (TTN) mutations have not been previously described. We report a 9-year-old female with history of leukodystrophy and family history of atrial fibrillation who presented with syncope and conduction abnormalities, including CHB. She underwent pacemaker implantation and genetic testing demonstrated a pathogenic TTN mutation likely responsible for her cardiac findings. Our case suggests an association between TTN mutations and conduction disease and emphasizes broadening gene testing in assessing these patients, especially when a family history is present.

Protocol for UVC uridine actinometry.

Uridine contains the chromophore uracil, a base forming part of RNA. In the range 240-290 nm, the absorption spectra of uridine and DNA are very similar and correspond to the spectral inactivation sensitivity of almost all microorganisms. This makes the uridine (absorption maximum 262 nm) an ideal actinometer for determining the germicidal photon flux in the range of 240 to 290 nm. Uridine actinometry is a simple, environmental-friendly, and easy-to-operate actinometry. Thanks to the uridine absorbance spectrum, it was found to be a perfect fit for the photon flux validation of UVC systems. Conventional UV disinfection systems are generally based on low-pressure (LP) mercury lamps which emit at 254 nm. On the other hand, UV light-emitting diodes (UV-LEDs) are a relatively new source of UV light for water treatment, emitting at various wavelengths. This protocol suggests an accurate, simple, easy to operate and straightforward way to determine the photon flux of UVC systems. Contain between 1 and 3 bullet points highlighting the customization rather than the steps of the procedure.•Because of the uridine absorbance spectrum, it is an ideal actinometer for photon flux validation of UVC systems.•Initial uridine concentration and photoproduct absorbance impact the kinetic order and quantum yield.•The protocol for UVC uridine actinometry is appropriate for UV-LP and UV-LED sources for water disinfection.

Ectopic Atrial Tachycardia in Infants Following Congenital Heart Disease Surgery.

Although ectopic atrial tachycardia (EAT) is common following surgery for congenital heart disease (CHD), there are limited data regarding this arrhythmia. This study assessed risk factors and outcomes for patients less than one year of age with post-operative EAT. This was a retrospective analysis of infants undergoing CHD surgery from 2007 to 2020. Patients and surgeries with EAT were compared to controls without EAT. Out of 5372 infant CHD surgeries, EAT developed in 129 (2.5%). Compared to controls, the EAT cohort was younger (median 7 vs 85 days, p < 0.01), weighed less at time of surgery (3.3 vs 4.2 kg, p < 0.01), and was more likely to have DiGeorge syndrome (7.7% vs 3.0%, p < 0.01). Multivariate analysis revealed total anomalous venous connection (TAPVC) repair (odds ratio [OR] 2.8; 95% confidence interval 1.5-5.2), DiGeorge syndrome (OR 2.4; 1.1-5.2), Society of Thoracic Surgeons-European Association for Cardio-Thoracic surgery (STAT) category ≥ 4 (OR 2.1; 1.0-4.4), and longer cardiopulmonary bypass times (OR 1.1; 1.0-1.2) as independent risk factors for EAT. The onset of EAT occurred a median of 9 days (IQR 5-14 days) after CHD surgery. Antiarrhythmic treatment was initiated in 109/129 patients (84%) with propranolol (71%) and amiodarone (24%) the most commonly used medications. Although 15 (11.6%) patients did not survive to hospital discharge, EAT was not directly implicated in any deaths. EAT occurred after 2.5% of infant CHD surgeries. In addition to TAPVC repair, longer and more complex surgeries were associated with an increased the risk for the development of post-operative EAT.

Pediatric Electrophysiology Device Needs: A Survey from the Pediatric and Congenital Electrophysiology Society Taskforce on Pediatric-Specific Devices.

Background There are few US Food and Drug Administration (FDA)-approved devices specifically aimed at the pediatric patient with arrhythmia. This has led to a high off-label utilization of devices in this vulnerable population. The Pediatric and Congenital Electrophysiology Society (PACES), the international organization representing pediatric and congenital heart disease arrhythmia specialists, developed a task force to comprehensively address device development issues relevant to pediatric patients with congenital arrhythmia. Methods and Results As a first step, the taskforce developed a 26-question survey for the pediatric arrhythmia community to assess providers' understanding of the FDA approval process, specifically in regard to pediatric labeling. There were 92/211 respondents (44%) with a >90% completion rate. The vast majority of respondents believed there was a paucity of devices available for children (96%). More than 60% of respondents stated that they did not understand the FDA regulatory process and were not aware of whether the devices they used were labeled for pediatric use. Conclusions Pediatric electrophysiologists are keenly aware of the deficit of available pediatric devices for their patients. The majority do not understand the FDA approval process and could benefit from additional educational resources regarding this. A collaborative forum including PACES, FDA, patients and their families, and Industry would be an important next step in clarifying opportunities and priorities to serve this vulnerable population.

Pediatric Medical Device Development and Regulation: Current State, Barriers, and Opportunities.

Few medical devices are designed and marketed specifically for children. Instead, adult devices are often repurposed and used off-label in pediatrics. The innovation gap between pediatric and adult devices is complex and multifactorial. This review aims to summarize the medical device landscape, describe barriers to pediatric device development, and provide an update on current strategies to help overcome these limitations. Medical devices are regulated by the Food and Drug Administration. They are registered, cleared, or approved on the basis of a 3-tier risk classification system and a differentiated set of regulatory pathways. This includes some for products that receive special designations on the basis of specific aspects that warrant more rapid review and approval. Pediatric devices number only one-quarter of those developed for adults for multiple reasons. Clinically, innovators must adjust their products to address the smaller sizes, growth, and longer duration of use in children. Smaller sample sizes and population heterogeneity also challenge the ability to obtain sufficient safety data for regulatory submissions. Financial concerns stem from lower pediatric reimbursement rates coupled with a lack of nationally standardized coverage. There are a number of promising initiatives, including the Pediatric Device Consortia Program, Early Feasibility Studies, and the new System of Hospitals for Innovation in Pediatrics - Medical Devices. However, the gap will likely not be narrowed without broad cooperation across stakeholders from industry, academia, patient advocacy groups, health care providers, investors, payors, regulators, and Congress.

Third Trimester Fetal Heart Rates in Antibody-Mediated Complete Heart Block Predict Need for Neonatal Pacemaker Placement.

Congenital complete heart block (CCHB) affects 1 in 20,000 newborns. This study evaluates fetal and neonatal risk factors predictive of neonatal pacemaker placement in antibody-mediated complete heart block. The Children's Hospital Los Angeles institutional fetal, pacemaker, and medical record databases were queried for confirmed SSA/SSB cases of CCHB between January 2004 and July 2019. Cases excluded were those with a diagnosis beyond the neonatal period, diagnosis of a channelopathy, or if maternal antibody status was unknown. We recorded the gestational age (GA), birth weight (BW), fetal heart rates (FHRs) of the last echocardiogram before delivery, specific neonatal ECG and echocardiogram findings, age at pacemaker placement, and mortality. Of 43 neonates identified with CCHB, 27 had confirmed maternal antibody exposure. Variables associated with neonatal pacemaker implantation were FHRs < 50 bpm (p = 0.005), neonatal heart rates < 52 bpm (p = 0.015), and neonatal left ventricular fractional shortening (FS) percentages < 34% (p = 0.03). On multivariate analysis, FHR remained significant (p = 0.03) and demonstrated an increased risk of neonatal pacemaker placement by an odds ratio of 12.5 (95% CI 1.3-116, p = 0.05). The median GA at which the FHR was obtained was 34 weeks (IQR 26-35 weeks). Neonatal pacemaker placement was highly associated with a FHR < 50 bpm, neonatal HR < 52 bpm, and neonatal FS < 34%. FHRs at 34 weeks GA (IQR 26-35 weeks) correlated well with postnatal heart rates and were predictive of neonatal pacemaker placement.

Heat transfer of graphene foams and carbon nanotube forests under forced convection.

The effective dissipation of heat from electronic devices is essential to enable their long-term operation and their further miniaturization. Graphene foams (GF) and carbon nanotube (CNT) forests are promising materials for thermal applications, including heat dissipation, due to their excellent thermal conduction and low thermal interface resistance. Here, we study the heat transfer characteristics of these two materials under forced convection. We applied controlled airflow to heated samples of GF and CNT forests while recording their temperature using infrared micro-thermography. Then, we analyzed the samples using finite-element simulations in conjunction with a genetic optimization algorithm, and we extracted their heat fluxes in both the horizontal and vertical directions. We found that boundary layers have a profound impact on the heat transfer characteristics of our samples, as they reduce the heat transfer in the horizontal direction. The heat transfer in the vertical direction, on the other hand, is dominated by the material conduction and is much higher than the horizontal heat transfer. Accordingly, we uncover the fundamental thermal behavior of GF and CNT forests, paving the way toward their successful integration into thermal applications, including cooling devices.

Hypertrophic Cardiomyopathy in Adolescence: Application of Guidelines.

We present the course and management of an adolescent male with hypertrophic cardiomyopathy. The importance of family history, early screening, accurate evaluation of hypertrophy, and risk stratification for eligibility for a defibrillator in hypertrophic cardiomyopathy are emphasized. Learning points are seen in the light of new guidelines. (Level of Difficulty: Intermediate.).

Utility of Surveillance Ambulatory Rhythm Monitoring in the Pediatric Fontan Population.

Our institution established a Fontan surveillance plan, which included ambulatory rhythm monitoring (ARM) at 6, 10, 13, 16 and 19 years old, for early detection of Fontan-associated complications. We conducted a retrospective chart review of Fontan patients followed at our institution 2014-2018 to determine the utility of surveillance ARMs. 139 ARMs from 83 patients were included. ARMs with supraventricular tachycardia, sinus node dysfunction, accelerated junctional rhythm, > 1st degree atrioventricular block, and complex ventricular ectopy were classified as positive for arrhythmia. Arrhythmias were occult if detected on surveillance ARM. The ARM indication was surveillance in 78 (56%) and clinically indicated in 61 (44%). 52 (37%) ARMs in 27 (33%) patients had an arrhythmia. There was no difference in the age of patients with and without arrhythmias [median 10.9 (6.5, 17.1 years) vs. 8.8 (7, 13.6 years), p = 0.5]. Clinically indicated ARMs more frequently demonstrated arrhythmias than surveillance ARMs (52% vs. 26%, p < 0.01). Compared to patients without arrhythmias, those with arrhythmias were more likely to be female (48% vs. 23%, p = 0.02), have a single right ventricle (46% vs. 19%, p < 0.01) and longer QRS duration on ECG [100 (91, 116 ms) vs. 94 (84, 104 ms), p = 0.046]. Patients with occult arrhythmias were less likely to have moderate to severe atrioventricular valvar regurgitation (0% vs. 46%; p = 0.04) or ventricular dysfunction (0% vs. 46%; p = 0.04) than those with clinical arrhythmia(s). Arrhythmia findings resulted in change in management for 16/52 (31%) ARMs. The findings suggest the frequent presence of arrhythmias on periodic ARMs in patients following the Fontan procedure regardless of symptomatic status.

Characteristics of antegrade-only accessory pathways in children and adolescents.

There is minimal data regarding antegrade-only accessory pathways in young patients. Given evolving recommendations and treatments, retrospective analysis of the clinical and electrophysiologic properties of antegrade-only pathways in patients <21 years old was performed, with subsequent comparison of electrophysiology properties to age-matched controls with bidirectional pathways. Of 522 consecutive young patients with ventricular pre-excitation referred for electrophysiology study, 33 (6.3%) had antegrade-only accessory pathways. Indications included palpitations (47%), chest pain (25%), and syncope (22%). The shortest value for either the accessory pathway effective refractory period or the pre-excited R-R interval was taken for each patient, with the median of the antegrade-only group significantly greater than shortest values for the bidirectional group (310 [280-360] ms versus 270 [240-302] ms, p < 0.001). However, the prevalence of pathways with high-risk properties (effective refractory period or shortest pre-excited R-R interval <250 ms) was similar in both study patients and controls (13% versus 21%) (p = 0.55). Sixteen patients had a single antegrade-only accessory pathway and no inducible arrhythmia. Six patients had Mahaim fibres, all right anterolateral with inducible antidromic reciprocating tachycardia. However, 11 patients with antegrade-only accessory pathways and 3 with Mahaim fibres had inducible tachycardia due to a second substrate recognised at electrophysiology study. These included concealed accessory pathways (7), bidirectional accessory pathways (5), and atrioventricular node re-entry (2). Antegrade-only accessory pathways require comprehensive electrophysiology evaluation as confounding factors such as high-risk conduction properties or inducible Supraventricular Tachycardia (SVT) due to a second substrate of tachycardia are often present.

Multiwell plates for obtaining a rapid microbial dose-response curve in UV-LED systems.

UV light-emitting diodes (UV-LEDs) have emerged as a new technology for water disinfection. Multiwell plates are a common tool in biological research, but they have never been used for UVC/UVB-inactivation experiments of microorganisms. In this study, a novel, rapid and simple UVC/UVB-inactivation assay was developed for a UV-LED system using a multiwell plate setup (96- and 24-well plates). The relative incident irradiance distribution across the exposed area was examined by spectroradiometry and nitrate-nitrite uniformity assay. The two methods showed a good correlation and high distribution factors (>0.89 and >0.94 for 96- and 24-well plates, respectively). In addition, the potential of the new system for determining disinfection efficacy of E. coli and MS2 coliphage by UV-LEDs emitting at central wavelengths of 265 nm and 285 nm was demonstrated. The inactivation rate constants were comparable to those obtained using UV-LED systems with the conventional dish (or beaker) setup, but the multiwell plate method allowed for many more repetitions. The proposed system is an alternative for UV-inactivation dose-response assay, especially when screening assays are desired, since it has the advantage of being fast, comprehensive (with a large number of simultaneous replicates) and easily adapted to various applications as UV-LED based photocatalysis experiments, UV effect on biofilm formation and UV-based AOP degradation experiments.

Correction to: Life-threatening cardiac arrhythmias in congenital central hypoventilation syndrome.

The publisher regrets that in the original published version of this article, one of the author's name was incorrectly presented as "Yaniv Bar Cohen". The correct presentation should have been "Yaniv Bar-Cohen" and is now presented correctly in this article.

Life-threatening cardiac arrhythmias in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients are at risk for life-threatening cardiac arrhythmias, and presentation is dependent on their PHOX2B gene mutation. We describe the presentation of life-threatening arrhythmias in our cohort of CCHS patients. We reviewed the records of 72 CCHS patients seen at CHLA from 2004 to 2018. Data collected included demographics, PHOX2B genotype, ventilatory support, clinical symptoms, ambulatory cardiac monitoring results, and presence of cardiac pacemaker. Sixteen of 72 patients had evidence of potential life-threatening cardiac arrhythmias. PHOX2B genotypes were 20/25 polyalanine repeat expansion mutation (PARM), 20/26 PARM, 20/27 PARM, 20/32 PARM, and c.245C > T non-polyalanine repeat mutation. 11/16 patients were ventilated during sleep only. Symptoms included syncope, dizziness, chest pain, tingling in the left arm, and palpitations. 15/16 patients had recorded ambulatory cardiac monitoring. 5/16 patients were symptomatic without significant sinus pauses. 12/16 patients had implantation of cardiac pacemakers. 9/12 had significant sinus pauses on ambulatory monitoring, and 7/12 patients were symptomatic.Conclusion: CCHS patients have potential life-threatening arrhythmias requiring cardiac pacemaker implantation. Many of these patients are symptomatic with significant sinus pauses on ambulatory monitoring. However, some symptomatic patients with no significant pauses on ambulatory monitoring may still require cardiac pacemaker implantation.What is Known:• CCHS patients are at risk for life-threatening sinus pauses and require cardiac pacemaker implantation.What is New:• CCHS patients regardless of PHOX2B genotype are at risk for significant sinus pauses. Many CCHS patients with significant sinus pause on ambulatory cardiac monitoring are symptomatic and most present with syncope. Some symptomatic patients do not have significant sinus pauses but may still require cardiac pacemaker implantation.

LP-UV-Nano MgO2 Pretreated Catalysis Followed by Small Bioreactor Platform Capsules Treatment for Superior Kinetic Degradation Performance of 17α-Ethynylestradiol.

A successful attempt to degrade synthetic estrogen 17α-ethynylestradiol (EE2) is demonstrated via combining photocatalysis employing magnesium peroxide (MgO2)/low-pressure ultraviolet (LP-UV) treatment followed by biological treatment using small bioreactor platform (SBP) capsules. Reusable MgO2 was synthesized through wet chemical synthesis and extensively characterized by X-ray diffraction (XRD) for phase confirmation, X-ray photoelectron spectroscopy (XPS) for elemental composition, Brunauer-Emmett-Teller (BET) to explain a specific surface area, scanning electron microscopy (SEM) imaging surface morphology, and UV-visible (Vis) spectrophotometry. The degradation mechanism of EE2 by MgO2/LP-UV consisted of LP-UV photolysis of H2O2 in situ (produced by the catalyst under ambient conditions) to generate hydroxyl radicals, and the degradation extent depended on both MgO2 and UV dose. Moreover, the catalyst was successfully reusable for the removal of EE2. Photocatalytic treatment by MgO2 alone required 60 min (~1700 mJ/cm2) to remove 99% of the EE2, whereas biodegradation by SBP capsules alone required 24 h to remove 86% of the EE2, and complete removal was not reached. The sequential treatment of photocatalysis and SBP biodegradation to achieve complete removal required only 25 min of UV (~700 mJ/cm2) and 4 h of biodegradation (instead of >24 h). The combination of UV photocatalysis and biodegradation produced a greater level of EE2 degradation at a lower LP-UV dose and at less biodegradation time than either treatment used separately, proving that synergetic photocatalysis and biodegradation are effective treatments for degrading EE2.

Height and morphology dependent heat dissipation of vertically aligned carbon nanotubes.

The continuous miniaturization of electronic devices substantially increases their power density, and consequently, requires effective cooling of these components. Vertically aligned carbon nanotubes (VA-CNTs) constitute one of the most promising materials for use as a high-end heat dissipation element due to their high thermal conductivity and large surface area. However, the lack of a clear understanding of the heat transfer mechanisms of VA-CNTs has so far impeded their large-scale use as cooling elements. Our infrared micro-thermography analysis revealed that the heat dissipation of VA-CNTs is determined mainly by their height, such that the heat dissipation behavior of tall samples was dominated by convection from the carbon nanotube (CNT) sidewalls. The mechanism of heat transfer in short VA-CNTs, in contrast, was determined by their morphology. Short VA-CNTs with highly organized CNT formations or with low thermal conductance exhibited convective heat dissipation similar to that of tall VA-CNTs, while other short VA-CNTs exhibited heat transfer dominated by conduction along the CNTs. This study provides important guidelines regarding the parameters that can be changed to optimize the performances of VA-CNTs in thermal applications. These applications include cooling elements in electronic devices, where convection is required, or thermal interface materials, where conduction is required.

The involvement of superoxide radicals in medium pressure UV derived inactivation.

Today, two types of lamp systems dominate the UV disinfection industry: low-pressure (LP) UV lamps and medium-pressure (MP) polychromatic lamps. Both lamp types have their advantages and disadvantages in microorganism inactivation, with LP lamps being cheaper, having longer life, and working at lower temperature, hence reducing fouling, and MP lamps showing better inactivation per germicidal dose for certain microorganisms. Bacterium-based biosensors were used to compare LP and MP irradiation. These biosensors were Escherichia coli bacteria carrying the lux operon genes under the control of different stress-responding promoters, where activation of the specific promoter is manifested as bioluminescence. MP irradiation, considerably more than LP irradiation, resulted in activation of the superoxide dismutase expression, indicating the formation of superoxide radicals inside the cells. Accordingly, pre-exposure (immunization) of the bacteria to an activator that produces superoxide radicals resulted in lower inactivation and increased resistance to MP irradiation, but not to LP irradiation. This study shows that the difference in germicidal efficiency may result from the production of intracellular superoxide radicals by MP irradiation, at wavelengths other than 254 nm, as emitted by LP lamps.

Prenatal diagnosis and management of congenital complete heart block.

Congenital complete heart block (CCHB) is a life-threatening medical condition in the unborn fetus with insufficiently validated prenatal interventions. Maternal administration of medications aimed at decreasing the immune response in the fetus and beta-agonists intended to increase fetal cardiac output have shown only marginal benefits. Anti-inflammatory therapies cannot reverse CCHB, but may decrease myocarditis and improve heart function. Advances in prenatal diagnosis and use of strict surveillance protocols for delivery timing have demonstrated small improvements in morbidity and mortality. Ambulatory surveillance programs and wearable fetal heart rate monitors may afford early identification of evolving fetal heart block allowing for emergent treatment. There is also preliminary data suggesting a roll for prevention of CCHB with hydroxychloroquine, but the efficacy and safety is still being studied. To date, intrauterine fetal pacing has not been successful due to the high-risk invasive placement techniques and potential problems with lead dislodgement. The development of a fully implantable micropacemaker via a minimally invasive approach has the potential to pace fetal patients with CCHB and thus delay delivery and allow fetal hydrops to resolve. The challenge remains to establish accepted prenatal interventions capable of successfully managing CCHB in utero until postnatal pacemaker placement is successfully achieved.