Emergency Department Utilization and Patient Outcomes During the COVID-19 Pandemic in America.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic precipitated fear of contagion and influenced many people to avoid the emergency department (ED). It is unknown if this avoidance effected overall health or disease mortality. OBJECTIVE: We aimed to quantify the decreased ED volume in the United States, determine whether it occurred simultaneously across the country, find which types of patients decreased, and measure resultant changes in patient outcomes. METHODS: We retrospectively accessed a multihospital, multistate electronic health records database managed by HCA Healthcare to obtain a case series of all patients presenting to an ED during the early COVID-19 pandemic (March 1-May 31, 2020) and the same dates in 2019 for comparison. We determined ED volume using weekly totals and grouped them by state. We also recorded final diagnoses codes and mortality data to describe patient types and outcomes. RESULTS: The weekly ED volume from 160 facilities dropped 44% from 141,408 patients (week 1, March 1-7, 2020) to a nadir of 79,618 patients (week 7, April 12-18, 2020), before rising back to 105,667 (week 13, May 24-30, 2020). Compared with 2019, this overall decline was statistically significant (p < 0.001). The decline was universal across disease categories except for infectious disease and respiratory illnesses, which increased. All-cause mortality increased during the pandemic, especially for those with infectious disease, circulatory, and respiratory illnesses. CONCLUSIONS: The COVID-19 pandemic and an apparent fear of contagion caused a decrease in ED presentations across our hospital system. The decline in ED volume was associated with increased ED mortality, perhaps from delayed ED presentations.

The physical health of Indigenous and non-Indigenous patients participating in residential rehabilitation programs: a comparison study.

OBJECTIVE: To examine the differences in the physical health of Indigenous and non-Indigenous patients with severe mental illness (SMI) undergoing psychiatric rehabilitation. METHODS: An audit of the physical health of patients ( n = 361) in all publicly funded residential rehabilitation programs in Queensland was carried out in late 2014. Data collection focused on clinical and lifestyle factors associated with physical health. RESULTS: The prevalence of smoking, substance use and type 2 diabetes in Indigenous patients was significantly higher than rates found in non-Indigenous patients. Metabolic syndrome was also significantly higher in indigenous patients, with 66% of Indigenous patients compared to 46% of non-Indigenous patients meeting criteria for metabolic syndrome. CONCLUSIONS: Patients with SMI in residential rehabilitation programs have poor physical health. Our findings underscore the need for clinicians to develop and evaluate interventions aimed at improving the metabolic profile of those with SMI in residential rehabilitation programs. Historical factors and cultural traditions need to be considered when designing lifestyle interventions for Indigenous patients.

Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

Functional Vision in the Real-World Environment With a Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis.

Purpose: In a clinical trial (NCT03406416) of a second-generation (44-channel) suprachoroidal retinal prosthesis implanted in subjects with late-stage retinitis pigmentosa (RP), we assessed performance in real-world functional visual tasks and emotional well-being. Methods: The Functional Low-Vision Observer Rated Assessment (FLORA) and Impact of Vision Impairment-Very Low Vision (IVI-VLV) instruments were administered to four subjects before implantation and after device fitting. The FLORA contains 13 self-reported and 35 observer-reported items ranked for ease of conducting task (impossible-easy, central tendency given as mode). The IVI-VLV instrument quantified the impact of low vision on daily activities and emotional well-being. Results: Three subjects completed the FLORA for two years after device fitting; the fourth subject ceased participation in the FLORA after fitting for reasons unrelated to the device. For all subjects at each post-fitting visit, the mode ease of task with device ON was better or equal to device OFF. Ease of task improved over the first six months with device ON, then remained stable. Subjects reported improvements in mobility, functional vision, and quality of life with device ON. The IVI-VLV suggested self-assessed vision-related quality of life was not impacted by device implantation or usage. Conclusions: Subjects demonstrated sustained improved ease of task scores with device ON compared to OFF, indicating the device has a positive impact in the real-world setting. Translational Relevance: Our suprachoroidal retinal prosthesis shows potential utility in everyday life, by enabling an increased environmental awareness and improving access to sensory information for people with end-stage RP.

Substitution of the terminal chloride ligands of [Re(6)S(8)Cl(6)](4-) with triethylphosphine: photophysical and electrochemical properties of a new series of [Re(6)S(8)](2+) based clusters.

A systematic substitution of the terminal chlorides coordinated to the hexanuclear cluster [Re(6)S(8)Cl(6)](4-) has been conducted. The following complexes: [Re(6)S(8)(PEt(3))Cl(5)](3-) (1), cis- (cis-2) and trans-[Re(6)S(8)(PEt(3))(2)Cl(4)](2-) (trans-2), mer- (mer-3) and fac-[Re(6)S(8)(PEt(3))(3)Cl(3)](-) (fac-3), and cis- (cis-4) and trans-[Re(6)S(8)(PEt(3))(4)Cl(2)] (trans-4) were synthesized and fully characterized. Compared to the substitution of the halide ligands of the related [Re(6)S(8)Br(6)](4-) and [Re(6)Se(8)I(6)](3-) clusters, the chloride ligands are slower to substitute which allowed us to prepare the first monophosphine cluster (1). In addition, the synthesis of fac-3 was optimized by using cis-2 as the starting material, which led to a significant increase in the overall yield of this isomer. Notably, we observed evidence of phosphine isomerization taking place during the preparation of the facial isomer; this was unexpected based on the relatively inert nature of the Re-P bond. The structures of Bu(4)N(+) salts of trans-2, mer-3, and fac-3 were determined using X-ray crystallography. All compounds display luminescent behavior. A study of the photophysical properties of these complexes includes measurement of the excited state lifetimes (which ranged from 4.1-7.1 µs), the emission quantum yields, the rates of radiative and non-radiative decay, and the rate of quenching with O(2). Quenching studies verify the triplet state nature of the excited state.

Free Standing, Large-Area Silicon Nitride Membranes for High Toxin Clearance in Blood Surrogate for Small-Format Hemodialysis.

Developing highly-efficient membranes for toxin clearance in small-format hemodialysis presents a fabrication challenge. The miniaturization of fluidics and controls has been the focus of current work on hemodialysis (HD) devices. This approach has not addressed the membrane efficiency needed for toxin clearance in small-format hemodialysis devices. Dr. Willem Kolff built the first dialyzer in 1943 and many changes have been made to HD technology since then. However, conventional HD still uses large instruments with bulky dialysis cartridges made of ~2 m2 of 10 micron thick, tortuous-path membrane material. Portable, wearable, and implantable HD systems may improve clinical outcomes for patients with end-stage renal disease by increasing the frequency of dialysis. The ability of ultrathin silicon-based sheet membranes to clear toxins is tested along with an analytical model predicting long-term multi-pass experiments from single-pass clearance experiments. Advanced fabrication methods are introduced that produce a new type of nanoporous silicon nitride sheet membrane that features the pore sizes needed for middle-weight toxin removal. Benchtop clearance results with sheet membranes (~3 cm2) match a theoretical model and indicate that sheet membranes can reduce (by orders of magnitude) the amount of membrane material required for hemodialysis. This provides the performance needed for small-format hemodialysis.

Second Generation Nanoporous Silicon Nitride Membranes for High Toxin Clearance and Small Format Hemodialysis.

Conventional hemodialysis (HD) uses floor-standing instruments and bulky dialysis cartridges containing ≈2 m2 of 10 micrometer thick, tortuous-path membranes. Portable and wearable HD systems can improve outcomes for patients with end-stage renal disease by facilitating more frequent, longer dialysis at home, providing more physiological toxin clearance. Developing devices with these benefits requires highly efficient membranes to clear clinically relevant toxins in small formats. Here, the ability of ultrathin (<100 nm) silicon-nitride-based membranes to reduce the membrane area required to clear toxins by orders of magnitude is shown. Advanced fabrication methods are introduced that produce nanoporous silicon nitride membranes (NPN-O) that are two times stronger than the original nanoporous nitride materials (NPN) and feature pore sizes appropriate for middle-weight serum toxin removal. Single-pass benchtop studies with NPN-O (1.4 mm2 ) demonstrate the extraordinary clearance potential of these membranes (105 mL min-1 m-2 ), and their intrinsic hemocompatibility. Results of benchtop studies with nanomembranes, and 4 h dialysis of uremic rats, indicate that NPN-O can reduce the membrane area required for hemodialysis by two orders of magnitude, suggesting the performance and robustness needed to enable small-format hemodialysis, a milestone in the development of small-format hemodialysis systems.

Protein Separation and Hemocompatibility of Nitride Membranes in Microfluidic Filtration Systems.

Improving the health outcomes for end-stage renal Disease (ESRD) patients on hemodialysis (HD) requires new technologies for wearable HD such as a highly efficient membrane that can achieve standard toxic clearance rates in small device footprints. Our group has developed nanoporous silicon nitride (NPN) membranes which are 100 to 1000 times thinner than conventional membranes and are orders-ofmagnitude more efficient for dialysis. Counter flow dialysis separation experiments were performed to measure urea clearance while microdialysis experiments were performed in a stirred beaker to measure the separation of cytochrome-c and albumin. Hemodialysis experiments testing for platelet activation as well as protein adhesion were performed. Devices for the counter flow experiments were constructed with polydimethylsiloxane (PDMS) and a NPN membrane chip. The counter flow devices reduced the urea by as much as 20%. The microdialysis experiments showed a diffusion of ~ 60% for the cytochrome-c while clearing ~ 20% of the Albumin. Initial hemocompatibility studies show that the NPN membrane surface is less prone to both protein adhesion and platelet activation when compared to positive control (glass).

Modification of Nanoporous Silicon Nitride with Stable and Functional Organic Monolayers.

This study describes the formation of functional organic monolayers on thin, nanoporous silicon nitride membranes. We demonstrate that the vapor-phase carbene insertion into the surface C-H bonds can be used to form sub-5 nm molecular coatings on nanoporous materials, which can be further modified with monolayers of polyethylene glycol (PEG) molecules. We investigate composition, thickness, and stability of the functionalized monolayers and the changes in the membrane permeability and pore size distribution. We show that, due to the low coating thickness (~7 nm), the functionalized membrane retains 80% of the original gas permeance and 40% of the original hydraulic permeability. We also show that the carbene/PEG functionalization is hydrolytically stable for up to 48 h of exposure to water and that it can suppress nonspecific adsorption of the proteins BSA and IgG. Our results suggest that the vapor-phase carbenylation can be used as a complementary technology to the traditional self-assembly and polymer brush chemistries in chemical functionalization of nanoporous materials, which are limited in their ability to serve as stable coatings that do not occlude nanomembrane pores.

Towards an Implantable, Low Flow Micropump That Uses No Power in the Blocked-Flow State.

Low flow rate micropumps play an increasingly important role in drug therapy research. Infusions to small biological structures and lab-on-a-chip applications require ultra-low flow rates and will benefit from the ability to expend no power in the blocked-flow state. Here we present a planar micropump based on gallium phase-change actuation that leverages expansion during solidification to occlude the flow channel in the off-power state. The presented four chamber peristaltic micropump was fabricated with a combination of Micro Electro Mechanical System (MEMS) techniques and additive manufacturing direct write technologies. The device is 7 mm × 13 mm × 1 mm (<100 mm³) with the flow channel and exterior coated with biocompatible Parylene-C, critical for implantable applications. Controllable pump rates from 18 to 104 nL/min were demonstrated, with 11.1 ± 0.35 nL pumped per actuation at an efficiency of 11 mJ/nL. The normally-closed state of the gallium actuator prevents flow and diffusion between the pump and the biological system or lab-on-a-chip, without consuming power. This is especially important for implanted applications with periodic drug delivery regimens.

Nanoporous membrane robustness / stability in small form factor microfluidic filtration system.

The development of wearable hemodialysis (HD) devices that replace center-based HD holds the promise to improve both outcomes and quality-of-life for patients with end-stage-renal disease (ERD). A prerequisite for these devices is the development of highly efficient membranes that can achieve high toxin clearance in small footprints. The ultrathin nanoporous membrane material developed by our group is orders of magnitude more permeable than conventional HD membranes. We report on our progress making a prototype wearable dialysis unit. First, we present data from benchtop studies confirming that clinical levels of urea clearance can be obtained in a small animal model with low blood flow rates. Second, we report on efforts to improve the mechanical robustness of high membrane area dialysis devices.

ULTRATHIN SILICON MEMBRANES FOR IMPROVING EXTRACORPOREAL BLOOD THERAPIES.

Extracorporeal blood therapies such as hemodialysis and extracorporeal membrane oxygenation supplement or replace organ function by the exchange of molecules between blood and another fluid across a semi-permeable membrane. Traditionally, these membranes are made of polymers with large surface areas and thicknesses on the scale of microns. Therapeutic gas exchange or toxin cleara nce in these devices occurs predominantly by diffusion, a process that is described by an inverse square law relating a distance to the average time a diffusing particle requires to travel that distance. As such, small changes in membrane thickness or other device dimensions can have significant effects on device performance - and large changes can cause dramatic paradigm shifts. In this work, we discuss the application of ultrathin nanoporous silicon membranes (nanomembranes) with thicknesses on the scale of tens of nanometers to diffusion-mediated medical devices. We discuss the theoretical consequences of nanomembrane medical devices for patients, analyzing several notable benefits such as reduced device size (enabling wearability, for instance) and improved clearance specificity. Special attention is paid to computational and analytical models that describe real experimental behavior, and that in doing so provide insights into the relevant parameters governing the devices.

Analytical and Finite Element Modeling of Nanomembranes for Miniaturized, Continuous Hemodialysis.

Hemodialysis involves large, periodic treatment doses using large-area membranes. If the permeability of dialysis membranes could be increased, it would reduce the necessary dialyzer size and could enable a wearable device that administers a continuous, low dose treatment of chronic kidney disease. This paper explores the application of ultrathin silicon membranes to this purpose, by way of analytical and finite element models of diffusive and convective transport of plasma solutes during hemodialysis, which we show to be predictive of experimental results. A proof-of-concept miniature nanomembrane dialyzer design is then proposed and analytically predicted to clear uremic toxins at near-ideal levels, as measured by several markers of dialysis adequacy. This work suggests the feasibility of miniature nanomembrane-based dialyzers that achieve therapeutic levels of uremic toxin clearance for patients with kidney failure.

Ultrathin silicon membranes for wearable dialysis.

The development of wearable or implantable technologies that replace center-based hemodialysis (HD) hold promise to improve outcomes and quality of life for patients with ESRD. A prerequisite for these technologies is the development of highly efficient membranes that can achieve high toxin clearance in small-device formats. Here we examine the application of the porous nanocrystalline silicon (pnc-Si) to HD. pnc-Si is a molecularly thin nanoporous membrane material that is orders of magnitude more permeable than conventional HD membranes. Material developments have allowed us to dramatically increase the amount of active membrane available for dialysis on pnc-Si chips. By controlling pore sizes during manufacturing, pnc-Si membranes can be engineered to pass middle-molecular-weight protein toxins while retaining albumin, mimicking the healthy kidney. A microfluidic dialysis device developed with pnc-Si achieves urea clearance rates that confirm that the membrane offers no resistance to urea passage. Finally, surface modifications with thin hydrophilic coatings are shown to block cell and protein adhesion.

In-plane biocompatible microfluidic interconnects for implantable microsystems.

Small mammals, particularly mice, are very useful animal models for biomedical research. Extremely small anatomical dimensions, however, make design of implantable microsystems quite challenging. A method for coupling external fluidic systems to microfluidic channels via in-plane interconnects is presented. Capillary tubing is inserted into channels etched in the surface of a Si wafer with a seal created by Parylene-C deposition. Prediction of Parylene-C deposition into tapered channels based on Knudsen diffusion and deposition characterizations allows for design optimization. Low-volume interconnects using biocompatible, chemical resistant materials have been demonstrated and shown to withstand pressure as high as 827 kPa (120 psi) with an average pull test strength of 2.9 N. Each interconnect consumes less than 0.018 mm3 (18 nL) of volume. The low added volume makes this an ideal interconnect technology for medical applications where implant volume is critical.

Micro-molded cannulae for intracochlear infusions in small rodents.

The design, fabrication, and testing of micro-cannulae with integrated insertion stops is presented. The micro-cannulae were engineered through the use of a silicon micro-mold fabricated via bulk-silicon micro-machining techniques. The use of microelectronic fabrication techniques allows precise control of three critical parameters, insertion depth, interface contact area, and tubing out of round. Worst case variations were found to be 5microm for insertion depth, 502microm(2) for interface contact area, and 7% for tip out of round. Histological evaluation revealed the cannula to be located correctly within the basal portion of scala tympani.