Medication fill duration in pediatric hypertension: adherence, blood pressure control, and disparities.

BACKGROUND: Medication nonadherence is a barrier to hypertension control. The Centers for Disease Control and Prevention recommends prescribing 90-day fills for maintenance medications yet antihypertensives are often dispensed as 30-day fills. Our objectives were to examine how often patients receive 30-day supplies of medication despite prescriptions for longer duration and to examine the effect of medication fill duration on adherence and hypertension control. METHODS: We conducted a retrospective cohort study of pediatric patients with hypertension over a 3-year period. For each patient, days prescribed per fill were compared to days dispensed per fill using pharmacy reports and insurance claim data. Proportion of Days Covered (PDC) was calculated to estimate adherence. Hypertension control was determined by provider assessment of control and blood pressure measurement at the final visit. RESULTS: Final cohort included 449 patients. A total of 70% had at least one prescription for ≥ 90 days but only 37% had at least one dispense for ≥ 90 days. There was no difference in the likelihood of being prescribed a 90-day fill by insurance type (public vs. private); however, patients with public insurance were less likely to be dispensed a 90-day fill (OR = 0.068, p < 0.001). Patients who received 90-day fills had better adherence (median PDC 77.5% vs. 58.1%, p < 0.001) and were more likely to have hypertension control based on provider assessment. CONCLUSIONS: Longer fill duration is associated with improved adherence and hypertension control. Patients with public insurance are markedly less likely to be dispensed 90-day fills, a modifiable barrier to improving adherence.

It Pays to Be Bumpy: Drag Reducing Armor in the Pacific Spiny Lumpsucker, Eumicrotremus orbis.

Armor is a multipurpose set of structures that has evolved independently at least 30 times in fishes. In addition to providing protection, armor can manipulate flow, increase camouflage, and be sexually dimorphic. There are potential tradeoffs in armor function: increased impact resistance may come at the cost of maneuvering ability; and ornate armor may offer visual or protective advantages, but could incur excess drag. Pacific spiny lumpsuckers (Eumicrotremus orbis) are covered in rows of odontic, cone-shaped armor whorls, protecting the fish from wave driven impacts and the threat of predation. We are interested in measuring the effects of lumpsucker armor on the hydrodynamic forces on the fish. Bigger lumpsuckers have larger and more complex armor, which may incur a greater hydrodynamic cost. In addition to their protective armor, lumpsuckers have evolved a ventral adhesive disc, allowing them to remain stationary in their environment. We hypothesize a tradeoff between the armor and adhesion: little fish prioritize suction, while big fish prioritize protection. Using micro-CT, we compared armor volume to disc area over lumpsucker development and built 3D models to measure changes in drag over ontogeny. We found that drag and drag coefficients decrease with greater armor coverage and vary consistently with orientation. Adhesive disc area is isometric but safety factor increases with size, allowing larger fish to remain attached in higher flows than smaller fish.

Probabilistic Neural Computing with Stochastic Devices.

The brain has effectively proven a powerful inspiration for the development of computing architectures in which processing is tightly integrated with memory, communication is event-driven, and analog computation can be performed at scale. These neuromorphic systems increasingly show an ability to improve the efficiency and speed of scientific computing and artificial intelligence applications. Herein, it is proposed that the brain's ubiquitous stochasticity represents an additional source of inspiration for expanding the reach of neuromorphic computing to probabilistic applications. To date, many efforts exploring probabilistic computing have focused primarily on one scale of the microelectronics stack, such as implementing probabilistic algorithms on deterministic hardware or developing probabilistic devices and circuits with the expectation that they will be leveraged by eventual probabilistic architectures. A co-design vision is described by which large numbers of devices, such as magnetic tunnel junctions and tunnel diodes, can be operated in a stochastic regime and incorporated into a scalable neuromorphic architecture that can impact a number of probabilistic computing applications, such as Monte Carlo simulations and Bayesian neural networks. Finally, a framework is presented to categorize increasingly advanced hardware-based probabilistic computing technologies.

A de novo paradigm for male infertility.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

PURPOSE: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. EXPERIMENTAL DESIGN: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). RESULTS: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. CONCLUSIONS: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.

A platysomid occurrence from the Tournaisian of Nova Scotia.

The Hangenberg extinction has been hypothesized as a first order event in vertebrate evolution; however, information on the earliest Carboniferous vertebrate fauna, crucial in evaluating biodiversity changes, is scarce. Post-extinction recovery has been suggested as the driver of ray-finned fish (actinopterygian) richness increase and differentiation in the Carboniferous. Under this model, actinopterygian postcranial morphology differentiates in the second stage of their radiation. Here, we report on a platysomid occurrence from the Tournaisian of Nova Scotia, Canada. Despite long-standing taxonomic issues with deep-bodied actinopterygians, this specimen represents the earliest known occurrence of one such fish. Its presence in the earliest Carboniferous indicates that actinopterygians were already postcranially differentiated in the aftermath of the Hangenberg. Moreover, this specimen suggests that earliest Carboniferous actinopterygians used multiple locomotory modes; recent data from later Carboniferous taxa suggest that actinopterygian locomotory modes proliferated throughout the Carboniferous. Taken together, these data suggest that early Carboniferous actinopterygians were morphologically, ecologically, and functionally diverse.

[Complications and emergencies in the recovery room]. / Komplikationen und Notfälle im Aufwachraum.

The recovery room as a central monitoring unit plays a crucial role in the perioperative care of patients. Here, the patient is monitored until the subsequent transfer to a further care ward; however, due to the previous anesthesia and surgery the recovery room also provides a high risk for (the development of) complications. The present article provides an overview of the most frequent complications to be expected in the recovery room (in adults), the diagnostics and the acute treatment.

Computed Tomography Guidance for Percutaneous Glycerol Rhizotomy for Trigeminal Neuralgia.

BACKGROUND: Percutaneous glycerol rhizotomy (PGR) is a well-described treatment for trigeminal neuralgia; however, the technique in using surface landmarks and fluoroscopy has not drastically changed since being first introduced. In this paper, we describe a protocol for PGR using computed tomography (CT) guidance based on an experience of over 7 yr and 200 patients. OBJECTIVE: To introduce an approach for PGR using CT guidance and, in doing so, demonstrate possible benefits over the traditional fluoroscopic technique. METHODS: Using a standard CT scanner, patients are placed supine with head in extension. Barium paste and a CT scout image are used to identify and plan a trajectory to the foramen ovale. A laser localization system built into the CT scanner helps to guide placement of the spinal needle into the foramen ovale. The needle position in the foramen is confirmed with a short-sequence CT scan. RESULTS: CT-guided PGR provides multiple benefits over standard fluoroscopy, including improved visualization of the skull base and significant reduction in radiation exposure to the surgeon and staff. Side benefits include improved procedure efficiency, definitive imaging evidence of correct needle placement, and potentially increased patient safety. We have had no significant complications in over 200 patients. CONCLUSION: CT-guided PGR is a useful technique for treating trigeminal neuralgia based on better imaging of the skull base, better efficiency of the procedure, and elimination of radiation exposure for the surgeon and staff compared to traditional fluoroscopic based techniques.

Use of a Laryngeal Mask Airway Decreases Radiation Exposure During Computed Tomography-Guided Percutaneous Glycerol Rhizotomy for Trigeminal Neuralgia.

BACKGROUND: We have been using computed tomography (CT) guidance for percutaneous glycerol rhizotomy (PGR) for the last 7 years. As a quality improvement exercise, we recently began using general anesthesia (GA) with the use of a laryngeal mask airway (LMA) because of our perception that the procedure went faster and that there was less radiation exposure because of less patient movement. We aim to compare PGR radiation exposure and procedural time between patients receiving local anesthetic with sedation and those receiving GA/LMA. METHODS: A single-center historical cohort study was performed using patients treated with PGR between 2017 and 2019. Ninety-two surgeries were conducted during the study period: 64 surgeries had local anesthetic with intravenous sedation, and 28 surgeries had deeper anesthetic with LMA. Data analyzed included the number of CT sequences obtained, needle placement time, and total radiation dose. RESULTS: Use of GA/LMA resulted in a 23% decrease in mean radiation dose (565.5 vs. 436.1 µGy × cm, P = 0.014), number of CT sequences required (7.4 vs. 5.7, P = 0.003), and needle placement time (12.8 vs. 9.8 minutes, P = 0.006). Additionally, 10 patients underwent multiple glycerol rhizotomies during the collection period with both anesthetic types being used at least once. Seven of 10 patients (70.0%) had a reduction in total radiation dose, number of CT sequences obtained, and needle placement time when GA/LMA was used. There were no procedure- or anesthetic-related complications in this patient cohort. CONCLUSIONS: The use of GA/LMA during PGR is associated with decreased radiation exposure without increased anesthetic complications.

Magnetic Source Imaging Using a Pulsed Optically Pumped Magnetometer Array.

We have developed a pulsed optically pumped magnetometer (OPM) array for detecting magnetic field maps originated from an arbitrary current distribution. The presented magnetic source imaging (MSI) system features 24 OPM channels, has a data rate of 500 S/s, a sensitivity of 0.8 p T / H z , and a dynamic range of 72 dB. We have employed our pulsed- OPM MSI system for measuring the magnetic field map of a test coil structure. The coils are moved across the array in an indexed fashion to measure the magnetic field over an area larger than the array. The captured magnetic field maps show excellent agreement with the simulation results. Assuming a 2D current distribution, we have solved the inverse problem, using the measured magnetic field maps, and the reconstructed current distribution image is compared to that of the simulation.

Parallel programming of an ionic floating-gate memory array for scalable neuromorphic computing.

Neuromorphic computers could overcome efficiency bottlenecks inherent to conventional computing through parallel programming and readout of artificial neural network weights in a crossbar memory array. However, selective and linear weight updates and <10-nanoampere read currents are required for learning that surpasses conventional computing efficiency. We introduce an ionic floating-gate memory array based on a polymer redox transistor connected to a conductive-bridge memory (CBM). Selective and linear programming of a redox transistor array is executed in parallel by overcoming the bridging threshold voltage of the CBMs. Synaptic weight readout with currents <10 nanoamperes is achieved by diluting the conductive polymer with an insulator to decrease the conductance. The redox transistors endure >1 billion write-read operations and support >1-megahertz write-read frequencies.

Computing with Spikes: The Advantage of Fine-Grained Timing.

Neural-inspired spike-based computing machines often claim to achieve considerable advantages in terms of energy and time efficiency by using spikes for computation and communication. However, fundamental questions about spike-based computation remain unanswered. For instance, how much advantage do spike-based approaches have over conventional methods, and under what circumstances does spike-based computing provide a comparative advantage? Simply implementing existing algorithms using spikes as the medium of computation and communication is not guaranteed to yield an advantage. Here, we demonstrate that spike-based communication and computation within algorithms can increase throughput, and they can decrease energy cost in some cases. We present several spiking algorithms, including sorting a set of numbers in ascending/descending order, as well as finding the maximum or minimum or median of a set of numbers. We also provide an example application: a spiking median-filtering approach for image processing providing a low-energy, parallel implementation. The algorithms and analyses presented here demonstrate that spiking algorithms can provide performance advantages and offer efficient computation of fundamental operations useful in more complex algorithms.

A primitive actinopterygian braincase from the Tournaisian of Nova Scotia.

The vertebrate fossil record of the earliest Carboniferous is notoriously poorly sampled, obscuring a critical interval in vertebrate evolution and diversity. Recent studies of diversity across the Devonian-Carboniferous boundary have proposed a vertebrate mass extinction at the end-Devonian, and recent phylogenies suggest that the origin of the actinopterygian crown may have occurred in the earliest Carboniferous, as part of a broader recovery fauna. However, the data necessary to test this are limited. Here, we describe a partial actinopterygian skull, including diagnostic elements of the posterior braincase, from the Tournaisian Horton Bluff Formation of Blue Beach, Nova Scotia. The braincase surprisingly shows a confluence of characters common in Devonian taxa but absent in Mississippian forms, such as an open spiracular groove; lateral dorsal aortae that pass through open broadly separated, parallel grooves in the ventral otoccipital region, posterior to the articulation of the first infrapharyngobranchial and an intertemporal-supratemporal complex. Phylogenetic analysis places it deep within the actinopterygian stem, among Devonian moythomasiids and mimiids, suggesting more phylogenetically inclusive survivorship of stem group actinopterygians across the end-Devonian mass extinction. With a high lineage survivorship in tetrapods and lungfish across the Devonian-Carboniferous boundary and high vertebrate diversity at Tournaisian localities, this hints at a more gradual turnover between Devonian and Carboniferous vertebrate faunas.

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer.

Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.

ADAM10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production.

BACKGROUND: Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells (DCs) initiate immune responses to common aeroallergens, and ADAM10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM10 on DCs in the development of allergic and anaphylactic responses. METHODS: In this study, we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata) and OVA-induced models of active anaphylaxis to determine the DC-specific function of ADAM10 and Notch signaling. To examine TH 1 and TH 17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium respectively, were used. RESULTS: Mice, which have ADAM10 deleted from DCs, have dramatic reductions in IgE production and do not develop significant TH 2 immune responses. Further, ADAM10DC-/- mice are resistant to IgE-mediated anaphylaxis. This response is selective for TH 2 immunity as TH 1 and TH 17 immunity is largely unaffected. Notch1, a known ADAM10 substrate, when knocked out of DCs (Notch1DC-/- ) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM10 and Notch1 signaling, DCs were unable to make cytokines that stimulate TH 2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM10DC-/- with the overexpression of the Notch1-intracellular domain, confirming the role of Notch signaling. CONCLUSIONS: Targeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating TH 2 immune responses and IgE production.

Reducing Length of Stay Using a Robotic-assisted Approach for Retromuscular Ventral Hernia Repair: A Comparative Analysis From the Americas Hernia Society Quality Collaborative.

OBJECTIVE: The aim of this study was to compare length of stay (LOS) after robotic-assisted and open retromuscular ventral hernia repair (RVHR). BACKGROUND: RVHR has traditionally been performed by open techniques. Robotic-assisted surgery enables surgeons to perform minimally invasive RVHR, but with unknown benefit. Using real-world evidence, this study compared LOS after open (o-RVHR) and robotic-assisted (r-RVHR) approach. METHODS: Multi-institutional data from patients undergoing elective RVHR in the Americas Hernia Society Quality Collaborative between 2013 and 2016 were analyzed. Propensity score matching was used to compare median LOS between o-RVHR and r-RVHR groups. This work was supported by an unrestricted grant from Intuitive Surgical, and all clinical authors have declared direct or indirect relationships with Intuitive Surgical. RESULTS: In all, 333 patients met inclusion criteria for a 2:1 match performed on 111 r-RVHR patients using propensity scores, with 222 o-RVHR patients having similar characteristics as the robotic-assisted group. Median LOS [interquartile range (IQR)] was significantly decreased for r-RVHR patients [2 days (IQR 2)] compared with o-RVHR patients [3 days (IQR 3), P < 0.001]. No differences in 30-day readmissions or surgical site infections were observed. Higher surgical site occurrences were noted with r-RVHR, consisting mostly of seromas not requiring intervention. CONCLUSIONS: Using real-world evidence, a robotic-assisted approach to RVHR offers the clinical benefit of reduced postoperative LOS. Ongoing monitoring of this technique should be employed through continuous quality improvement to determine the long-term effect on hernia recurrence, complications, patient satisfaction, and overall cost.

Rapid Nucleic Acid Extraction and Purification Using a Miniature Ultrasonic Technique.

Miniature ultrasonic lysis for biological sample preparation is a promising technique for efficient and rapid extraction of nucleic acids and proteins from a wide variety of biological sources. Acoustic methods achieve rapid, unbiased, and efficacious disruption of cellular membranes while avoiding the use of harsh chemicals and enzymes, which interfere with detection assays. In this work, a miniature acoustic nucleic acid extraction system is presented. Using a miniature bulk acoustic wave (BAW) transducer array based on 36° Y-cut lithium niobate, acoustic waves were coupled into disposable laminate-based microfluidic cartridges. To verify the lysing effectiveness, the amount of liberated ATP and the cell viability were measured and compared to untreated samples. The relationship between input power, energy dose, flow-rate, and lysing efficiency were determined. DNA was purified on-chip using three approaches implemented in the cartridges: a silica-based sol-gel silica-bead filled microchannel, nucleic acid binding magnetic beads, and Nafion-coated electrodes. Using E. coli, the lysing dose defined as ATP released per joule was 2.2× greater, releasing 6.1× more ATP for the miniature BAW array compared to a bench-top acoustic lysis system. An electric field-based nucleic acid purification approach using Nafion films yielded an extraction efficiency of 69.2% in 10 min for 50 µL samples.

A Combinatorial Model for Dentate Gyrus Sparse Coding.

The dentate gyrus forms a critical link between the entorhinal cortex and CA3 by providing a sparse version of the signal. Concurrent with this increase in sparsity, a widely accepted theory suggests the dentate gyrus performs pattern separation-similar inputs yield decorrelated outputs. Although an active region of study and theory, few logically rigorous arguments detail the dentate gyrus's (DG) coding. We suggest a theoretically tractable, combinatorial model for this action. The model provides formal methods for a highly redundant, arbitrarily sparse, and decorrelated output signal.To explore the value of this model framework, we assess how suitable it is for two notable aspects of DG coding: how it can handle the highly structured grid cell representation in the input entorhinal cortex region and the presence of adult neurogenesis, which has been proposed to produce a heterogeneous code in the DG. We find tailoring the model to grid cell input yields expansion parameters consistent with the literature. In addition, the heterogeneous coding reflects activity gradation observed experimentally. Finally, we connect this approach with more conventional binary threshold neural circuit models via a formal embedding.

Li-Ion Synaptic Transistor for Low Power Analog Computing.

Nonvolatile redox transistors (NVRTs) based upon Li-ion battery materials are demonstrated as memory elements for neuromorphic computer architectures with multi-level analog states, "write" linearity, low-voltage switching, and low power dissipation. Simulations of backpropagation using the device properties reach ideal classification accuracy. Physics-based simulations predict energy costs per "write" operation of <10 aJ when scaled to 200 nm × 200 nm.