A Preliminary, Single-Center Retrospective Chart Review of Infusion Times of Intravenous Immune Globulin in Kawasaki Disease and Clinical Outcomes.

OBJECTIVE: Patients diagnosed with Kawasaki disease (KD) are at a high risk of developing coronary artery aneurysms. Intravenous immune globulin (IVIG) given in combination with aspirin is the standard of treatment for the prevention of coronary aneurysm. IVIG is recommended to be administered as a dose of 2 g/kg infused during 10 to 12 hours for the prevention of coronary aneurysms in KD; however, this does not always occur in practice. We aimed to investigate if an infusion time of <10 hours is associated with more coronary artery aneurysms than the recommended infusion time of 10 to 12 hours. METHODS: Patients with a diagnosis of and treated for KD with IVIG at the University of Chicago Medicine Comer Children's Hospital were identified by drug use reports that included patients who received IVIG between September 2008 and August 2018. Data were collected though chart review and patients were divided into 2 groups based on duration of infusion (<10 hours and 10-12 hours). The primary outcome was the incidence of coronary artery aneurysm. The secondary outcome was the time to defervescence. The safety outcome was the development of renal dysfunction. RESULTS: A total of 70 patients were screened and 44 were included in the analysis. Coronary aneurysm occurred in 2 of 33 patients (6.0%) in the <10-hour group and no patients in the 10- to 12-hour group (p = 0.558). The median time to defervescence was 0.5 hours in the <10-hour group and 0.95 hours in the 10- to 12-hour group (p = 0.166). The incidence of acute kidney injury was 6% (2 of 33 patients) in the 10-hour group and 9.1% (1 of 11 patients) in the 10- to 12-hour group (p = 0.588). CONCLUSIONS: All incidences of coronary artery aneurysm occurred in the patients who received IVIG with an infusion time of <10 hours. The incidence of acute kidney injury was numerically higher in the 10- to 12-hour group. Based on the recommendations in the American Heart Association KD guideline, our internal hospital policy, and our results, we recommend the infusion of IVIG be administered at a rate of 10 to 12 hours.

Acute Real-World Outcomes From the Phoenix Post-Approval Registry.

OBJECTIVES: An evaluation of the 30-day safety and performance outcomes of the Phoenix atherectomy system (Philips Volcano Corporation) was performed in real-world patients with peripheral artery disease (PAD). METHODS: The Phoenix Post-Approval Registry is an all-comer study that enrolled patients with infrainguinal PAD. Patients treated with the Phoenix atherectomy system were followed for 30 days to observe device-related complications. Outcomes evaluated include procedural (final target lesion(s) residual stenosis of ≤30% after treatment with Phoenix and any other adjunctive therapy) and technical success (defined as achieving a post-Phoenix [prior to any adjunctive therapy] residual diameter stenosis of ≤50%), target-vessel revascularization (TVR), target-lesion revascularization (TLR), target-limb amputation, ankle brachial index, Rutherford clinical category, and wound, ischemia, foot infection (WIfI) classification. RESULTS: Of the 500 patients enrolled, 259 had CLI, including 26.3% with Rutherford class 6. Procedural success rates were 97.3% for non-CLI patients and 98.2% for CLI patients. Technical success rates were 71.5% for non-CLI patients and 77.9% for CLI patients. Complication rates post Phoenix atherectomy were <1%. Through the 30-day follow-up, there were 6 patients (1.3%; 2 claudicants, 4 CLIs) who underwent TLR and 8 patients who underwent TVR. There were no major amputations in the non-CLI and CLI cohorts. In the CLI cohort, 16/235 (6.8%) underwent minor amputations. Higher stages of Rutherford class and WIfI classification were associated with amputations at 30 days. CONCLUSION: The Phoenix atherectomy system is a safe and effective treatment option in the acute setting for patients with PAD, including those with advanced Rutherford class. Randomized controlled trials are needed to confirm these results.

A New Generation of Functional Tagged Proteins for HIV Fluorescence Imaging.

During the last decade, there was a marked increase in the development of tools and techniques to study the molecular mechanisms of the HIV replication cycle by using fluorescence microscopy. Researchers often apply the fusion of tags and fluorophores to viral proteins, surrogate proteins, or dyes to follow individual virus particles while they progress throughout infection. The inclusion of such fusion motifs or surrogates frequently disrupts viral infectivity or results in a change of the wild-type phenotype. Here, we detail the construction and functional characterization of two new constructs where we fused fluorescent proteins to the N-terminus of HIV-1 Integrase. In the first, IN is recruited into assembling particles via a codon optimized Gag to complement other viral constructs, while the second is fused to a Gag-Pol expression vector fully capable of integration. Our data shows that N-terminal tagged IN is functional for integration by both recovery of integration of catalytically inactive IN and by the successful infectivity of viruses carrying only labeled IN. These tools will be important to study the individual behavior of viral particles and associate such behavior to infectivity.

Seizing the Moment: Policy Advocacy to End Mass Incarceration in the Time of COVID-19.

The mass human and economic casualties wrought by the COVID-19 pandemic laid bare the deep inequities at the base of the disproportionate losses and suffering experienced by diverse U.S. populations. But the urgency and enormity of unmet needs requiring bold policy action also provided a unique opportunity to learn from and partner with community-based organizations that often are at the frontlines of such work. Following a review of Kingdon's model of the policy-making process, we illustrate how a partnership in a large California county navigated the streams in the policy-making process and used the window of opportunity provided by the pandemic to address a major public health problem: the incarceration of over 2 million people, disproportionately African American and Latinx, in overcrowded, unsafe jails, prisons, and detention centers. We highlight tactics and strategies used, challenges faced, and implications for health educators as policy advocates during and beyond the pandemic.

Policy Determinants of Inequitable Exposure to the Criminal Legal System and Their Health Consequences Among Young People.

Criminalizing young people, particularly Black- and Brown-identified young people, has increasingly been a feature of US rhetoric, policies, and practices. Thus, the domains in which young people are exposed to the legal system have continued to expand, encompassing their communities, schools, and homes. Importantly, public health researchers have begun exploring links between legal system exposure and health, although this literature is primarily focused at the interpersonal level and assesses associations within a single domain or in adulthood.Using critical race theory and ecosocial theory of disease distribution, we identified potential policy-level determinants of criminalization and briefly summarized the literature on downstream health outcomes among young people. Our analysis suggests that policy decisions may facilitate the targeting of structurally marginalized young people across domains.Future research should (1) position these legislative decisions as primary exposures of interest to understand their association with health among young people and inform institutional-level intervention, (2) measure the totality of exposure to the criminal legal system across domains, and (3) use theory to examine the complex ways racism operates institutionally to shape inequitable distributions of associated health outcomes.

Endovascular Creation of Arteriovenous Fistulae for Hemodialysis Access with a 4 Fr Device: Clinical Experience from the EASE Study.

BACKGROUND: The use of arteriovenous fistula (AVF) is hampered by long surgical wait times, slow maturation, and upwards of 60% that do not mature. We describe our clinical experience in using a system with a 4F catheter profile for endovascular AVF creation in patients on hemodialysis. METHODS: This was a multioperator, single-center, single-arm, prospective study intended to evaluate safety and efficacy of a 4 Fr endovascular AVF (endoAVF) system for the creation of vascular access in hemodialysis patients. The study was performed after institutional review board approval at Italian Hospital (Asuncion, Paraguay). Patients were followed up at regular intervals through 6 months to determine procedural, maturation, and cannulation success as well as intervention rate and patency. RESULTS: From May to November 2016, 32 patients underwent the endoAVF procedure with no device-related adverse events. An endoAVF was successfully created in the proximal forearm for all 32 patients (20 between the radial artery and radial vein; 12 between the ulnar artery and ulnar vein). Wrist access was used for 72% (23/32) of the procedures for the arterial catheter and 59% (19/32) of the procedures for the venous catheter. The device successfully created an endoAVF in every patient for a technical success rate of 100% (32/32). The device- or procedure-related serious adverse event rate was 3% (1/32); one patient experienced a venous guidewire perforation successfully managed with a stent graft. Primary and cumulative patency rates through 6 months were 83% and 87%, respectively, with an intervention rate of 0.21 per patient-year. Physiological suitability, as defined by target flow rates ≥500 ml/min and cannulation vessel diameters ≥4 mm, was achieved in 91% (29/32) of patients by 90 days. Successful 2-needle cannulation was achieved in 78% (21/27) by 90 days, with mean time to cannulation of 43 ± 14 days. Functional cannulation, as defined by successful 2-needle cannulation for two-thirds of the dialysis sessions within 1 month, was achieved in 95% (20/21) of the patients who were successfully cannulated for an overall rate of 74% (20/27). All patients who achieved functional cannulation had their central venous catheters (CVCs) removed before the 90-day follow-up for a CVC removal rate of 74% (20/27). CONCLUSIONS: The 4 Fr endoAVF system allowed for multiple access and fistula creation site options to tailor the procedure to individual patient anatomy. Furthermore, the outcomes are comparable to previous generation endoAVF technology, with a potentially improved safety profile because of the use of arteries at the wrist for access.

Evaluation of the safety and efficacy of a novel product for the removal of impacted human cerumen.

BACKGROUND: This open-label study evaluated the safety and efficacy of a novel product for the removal of impacted cerumen in adult patients. METHODS: This was a prospective, single-center, single-arm, self-controlled clinical trial conducted in a community general practice setting. The novel product contains glycolic acid in an otologically-acceptable buffer containing sodium bicarbonate and glycerin and other buffering agents. The product was instilled into the ear canal prior to irrigation with warm water. Severity of cerumen impaction was graded using a 5-point scale. Improvement in tympanic membrane visualization was assessed after instillation and irrigation. RESULTS: A majority (83%, 25/30) of ears showed improvement with one application: with 53% (16/30) totally dissolved and gained 100% TM visualization. Total dissolution was observed in 80% (24/30) of the study ears per the intent-to-treat analysis and 86% (24/28) if irrigation instructions were followed. Most of the ears/participants that had cerumen blockage symptoms experienced significant improvement with the application. Feelings of fullness disappeared in 92% (11/12) of the affected ears; ears itching, 91% (10/11); water trapping or cracking, 78%, and decreased hearing disappeared in 71% (10/14). All (100%, 18) of the participants who completed the application satisfaction assessment were satisfied with the application process in terms of time needed and the overall rinse procedure. Only one mild adverse event (ear pruritis) occurred that was related to application. CONCLUSIONS: The tested cerumen removal product was effective and safe for removing moderate to severe blockage in patients with impacted cerumen. Procedure satisfaction for the product was high. TRIAL REGISTRATION: This trial is registered on http://www.clinicaltrials.gov/. The registration number is NCT02829294. The trial was retrospectively registered on July 8, 2016.

The Food and Drug Administration and pragmatic clinical trials of marketed medical products.

Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices (whether or not they are approved for marketing), and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.

Micelle Formation in Liquid Ammonia.

Perfluorinated long chain alkyl amides aggregate in liquid ammonia with increasing concentration which reflects micelle-type formation based on changes in (19)F NMR chemical shifts. The critical micelle concentrations (cmc) decrease with increasing chain length and give Kleven parameters A = 0.18 and B = 0.19. The micelles catalyze the ammonolysis of esters in liquid ammonia. The corresponding perfluorinated long chain alkyl carboxylates form ion pairs in liquid ammonia, but the equilibrium dissociation constants indicate favorable interactions between the chains in addition to the electrostatic forces. These perfluorinated carboxylates form micelles in aqueous solution, and their cmc's generate a Kleven B-value = 0.52 compared with 0.30 for the analogous alkyl carboxylates. The differences in hydrophobicity of CH2 and CF2 units in water and liquid ammonia are discussed, as is the possible relevance to life forms in liquid ammonia.

Examining the feasibility of a Microsoft Kinect ™ based game intervention for individuals with anterior cruciate ligament injury risk.

We describe a feasibility study in which the Microsoft Kinect is used for a game-based exercise to strengthen posterior chain muscles which are often weak in those at high risk of anterior cruciate ligament (ACL) injury. In the game, subjects perform a single posterior chain strengthening exercise. The game uses a side-scrolling video display driven by a hip abduction exercise while a player lies down on the floor. Leg lifts beyond a predetermined angle trigger the jumping action of an animated tiger. We describe the scene and game control, which uses depth images from the Kinect. Although Kinect-based skeletal data are used for many games, the skeletal model does not yield good estimates for positions on the floor. Our proposed system uses multiple leg angle estimators for different angle regions to recognize the player lying down and capture the angle between two legs. We conducted an experiment that validates our system with marker-based Vicon ground truth data. We also present results of an end-to-end test using the game, showing feasibility.

Broadband attenuation measurements of phospholipid-shelled ultrasound contrast agents.

The aim of this study was to characterize the frequency-dependent acoustic attenuation of three phospholipid-shelled ultrasound contrast agents (UCAs): Definity, MicroMarker and echogenic liposomes. A broadband through-transmission technique allowed for measurement over 2 to 25 MHz with a single pair of transducers. Viscoelastic shell parameters of the UCAs were estimated using a linearized model developed by N. de Jong, L. Hoff, T. Skotland and N. Bom (Ultrasonics 1992; 30:95-103). The effect of diluent on the attenuation of these UCA suspensions was evaluated by performing attenuation measurements in 0.5% (w/v) bovine serum albumin and whole blood. Changes in attenuation and shell parameters of the UCAs were investigated at room temperature (25°C) and physiologic temperature (37°C). The attenuation of the UCAs diluted in 0.5% (w/v) bovine serum albumin was found to be identical to the attenuation of UCAs in whole blood. For each UCA, attenuation was higher at 37°C than at 25°C, underscoring the importance of conducting characterization studies at physiologic temperature. Echogenic liposomes exhibited a larger increase in attenuation at 37°C versus 25°C than either Definity or MicroMarker.

Regulatory requirements of the Food and Drug Administration would preclude product claims based on observational research.

As norms of comparative effectiveness research are sought within the biomedical and health care communities, and the science of conducting and interpreting this research develops, the Food and Drug Administration (FDA) must balance diverse interests. The agency's overarching interest is the development of high-quality comparative effectiveness information that contributes to improved patient care. To further this interest, the FDA can provide expertise in trial design and postmarketing surveillance. The FDA can also ensure that manufacturers of medical products use comparative effectiveness information in product promotion in a manner consistent with regulatory requirements. In this article we observe that these requirements would preclude the manufacturer's use in a promotional context of comparative effectiveness findings derived from an observational study. The FDA recognizes, however, that there are ongoing efforts to address the methodological problems inherent in observational approaches and to foster consensus on enhanced methods. The FDA must work to navigate challenges that relate to both the science of comparative effectiveness research and the agency's statutory responsibilities to the public health.

The FDA's assessment of follow-on protein products: a historical perspective.

The scientific and regulatory issues that are associated with the possible introduction of 'follow-on' versions of protein drug products are the topic of considerable debate at present. Because of the differences between protein drug products and small-molecule drugs, the development of follow-on versions of protein products presents more complex scientific challenges than those presented by the development of generic versions of small-molecule drugs. Here, with a view to illustrating the Food and Drug Administration's (FDA's) scientific reasoning and experience in this area, we discuss past examples of the FDA's actions involving the evaluation of various types of follow-on and second-generation protein products and within-product manufacturing changes. The FDA believes its evaluation of the safety and effectiveness of follow-on protein products will evolve as scientific and technological advances in product characterization and manufacturing continue to reduce some of the complexity and uncertainty that are inherent in the manufacturing of protein products.