Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy. Pancreatic cancer (PanCa) is the fourth highest cause among cancer-related deaths  in 2018 in the United States. It was also estimated that about 23,800 men and 21,950 women were diagnosed with this disease. PanCa accounts for only ~3% of all cancers but it contributes ~7% of cancer deaths. PanCa accounts for very poor overall median survival, i.e., 5 to 6 months. The 5-year survival rate for patients with pancreatic cancer is only 6 to 8% [Chemotherapy is expected to provide substantial local control and prolong survival. However, there is no efficient and standard treatment for advanced and metastatic pancreatic cancer. Gemcitabine, a deoxycytidine nucleoside analog , has shown a broad spectrum of anticancer activity against various tumors, including pancreatic, lung, and breast cancers. GEM activity depends on its entry into cells and immediate phosphorylation by deoxycytidine kinase (DCK) takes place which results in monophosphate and diphosphate (dFdCDP) ,8. The a2 five times daily led to fever and fatal hypotension while a phase II trial (150 mg/m2 twice weekly) showed flu, fever, rigors, and malaise as its side effects which led towards the withdrawal of GEM [2/week) which resulted in positive activity with minor side effects [Gemcitabine as a chemotherapeutic agent is not instantaneous due to severe systemic side effects. For example, a phase I trial with a maximum dose of 9 mg/ml of GEM . Dissati effects . SubsequGEM is considered a gold-standard treatment for pancreatic cancer. It has also exhibited a broad spectrum of anticancer activity against various cancers. However, chemoresistance is one of the leading problems associated with this drug. To overcome the side effects caused by GEM, it has been formulated in other forms for effective administration and therapeutic outcome. Problems associated with GEM therapy also opened platforms to administer drugs such as OXA, CIS, and other chemotherapeutic drugs to be administered with GEM, which are being successfully used at the clinical level, as described later in the article.® is a hydrochloride salt of GEM being produced by Eli Lilly which is extensively used against pancreatic cancer both as a single therapeutic agent and in combination with many other anticancer agents. Although it is not immediately life-threatening but Gemzar induces numerous side effects such as pale skin, easy bruising or bleeding, numbness, tingly feeling, weakness, nausea, vomiting, stomach upset, diarrhea, constipation, headache, swelling in hands/ankles/feet, skin rash, drowsiness, and hair loss [Gemzarair loss .The major drawback associated with the delivery of Gemzar is the formation of inactive metabolite difluorodeoxyuridine in the presence of enzyme deoxycytidine deaminase which exists abundantly in the liver and blood. Deoxycytidine monophosphatase causes deamination and conversion of Gemzar to its diphosphate and triphosphate forms. This conversion causes rapid clearance and a reduced half-life of the drug up to 15 min . 2 weekly × 7 followed by 1 week of rest, then weekly × 3 every 4 weeks thereafter (for 63 patients), or 5-FU 600 mg/m2 once weekly (for 63 patients). The expected result was to alleviate at least one parameter associated with symptoms which could help in increasing patient survival rates without causing additional side effects. A significant change in survival rate was observed in 23.8% of patients treated with GEM compared with just 4.8% clinical benefits in patients under the influence of 5-FU, which concluded the comparatively high therapeutic activity of GEM [The efficacy of Gemzar as a first-line treatment for pancreatic cancer was done by conducting clinical studies and comparing Gemzar with 5-Fluoro-Uracil. During the experiment, clinical data were obtained from 126 patients suffering from pancreatic cancer with significant symptoms. The drug dose given was either GEM 1000 mg/my of GEM .N-(2-hydroxypropyl)methacrylamide) (PHPMA) is a copolymer which is widely used to formulate various anticancer drugs. HPMA copolymer formulation provides prolonged GEM by utilizing enhanced permeability and retention effects which localizes the drug at the tumor site [Poly in presence of enzyme cytidine deaminase being present abundantly in the liver and plasma . Gemlip The use of single chemotherapeutic agents has shown limitations caused by their poor stability and bioavailability, drug-resistance, and high systemic toxicity. Co-delivery of dual or multiple/cocktail drugs have come up with synergistic therapeutic action and minimized side effects . Though A significant number of literatures is available in PubMed suggesting that co-administration of GEM with other drugs has vast clinical significance in treating pancreatic cancer .Detailed review reports discussing the superiority and complexity of regiments to increase the overall survival of pancreatic patients are shown in Altogether, co-administration of GEM with other drugs  depict s®, Celgene) doxorubicin liposomal formulation , micellar formulation of PTX ) and clinically evaluated nanoformulations obey EPR delivery characteristics [Gemcitabine co-administration with various chemotherapeutic drugs have shown significant effects and positive outcome at clinical level  and has eristics . Upon reeristics . This cheristics . Cellulaeristics , can be eristics . Various synthetic approaches, both topdown and bottom-up, of nanocarrier development via nanoprecipitation, double emulsion, solvent evaporation, self-assembly, layer-by-layer approaches, polymer micellization, and gelation are suitable with the appropriate engineering surface chemistry. All these approaches offer pre-determined particle size range and distribution, hydrophobicity–hydrophilicity balance, porosity, and polymer chain/gel network, drug encapsulation capacity, sustained/stimuli-responsive drug release as a function of formulation characteristics. 2 and mean volume of distribution of 632 L/m2, GEM with a half-life of 42–94 min, mean total clearance of 30.7–92.2 L/h/m2 and mean volume of distribution of 50 L/m2) [co-MA-GFLG-Gemcitabine-co-MA-GFLG-doxorubicin-co-MA-TyrNH2) is a construct of a HPMA polymer conjugated with 6.4 wt % GEM and 5.7 wt % of DOX with 1 mol.% tyrosinamide (known as P-GEM-DOX) which exhibited a superior cytotoxicity effect. The efficacy of GEM and DOX was enhanced using this multi-drug targeting formulation without an increase in its level of toxicity. Effect of the formulation on tumor growth was compared using a control group where the results showed that the formulations with a 50% maximum tolerated dose regimen of P-GEM-DOX showed a 50% reduced tumor growth and formulation with 75% MTD showed a reduction in the tumor up to 60%, which was significantly higher than the control group and the groups with a low dose of P-GEM-DOX. There was no significant decrease in body weight of control group and the group with a low dose of P-GEM-DOX with a maximum of 5% loss in the body weight of groups treated with 50% and 75% maximum tolerated dose regimens of P-GEM-DOX [Liposomes are the vehicles commonly used for drug delivery applications . Liposom50 L/m2) ,58. Thes50 L/m2) ,60. Co-e50 L/m2) . EndoTAG50 L/m2) . Poly network polymeric structures which can offer drug depot and controlled drug release for targeted drug delivery . Nanogeladiation . GEM andadiation . Use of b-PCC-g-GEM-g-DC-g-TEPA and conjugated with the EGFR targeting Cetuximab antibody. This formulation is efficient to target GEM at pancreatic tumor sites. Both in vitro studies on MIAPaCa-2 and in vivo studies on MIAPaCa-2 orthotopic mouse models showed enhanced drug uptake in the group treated with formulations containing Cetuximab as the targeting antibody than the control group. Mice showed low tumor volume when treated with the GEM-miR-205-Cetuximab conjugated formulation with no alteration in body weight, suggesting negligible drug-based toxicity [b-PAC and PEG-b-PUC through hydrogen bonding and ionic interaction) shows a high drug loading capacity with an ability to incorporate GEM and Phenformin, exhibiting good activity against cancer stem cells [Polymeric micelles possess a unique shell-like structure. For drug delivery purposes, micelles are modified copolymers with a hydrophobic core and a hydrophilic shell. Mondal et al.  showed ttoxicity . GEM andtoxicity . Though toxicity . The useem cells ,71. The em cells ,73. CD44em cells . Micelleem cells .® or nab-PTX) is a formulation which has overcome the limitations associated with the paclitaxel drug with a satisfactory solubility in water. Paclitaxel, when combined with Gemcitabine, has shown an increase in the level of Gemcitabine within tumor cells by decreasing the activity of cytidine deaminase, an enzyme with an ability to decrease Gemcitabine metabolism. nab-PTX possesses an ability to distort the stroma of PanCa cells which assist in activating angiogenesis, thereby increasing circulation, making it easier for GEM to reach targeting sites. Despite these advantages, this drug combination has shown significant toxicity which demands efficient studies and trials for drug approval [2 GEM with 125 mg/m2 of nab-PTX given for a 3-week period in repetition every 4 weeks. Overall survival, total response rate, and the maximum tolerated dose obtained from these studies were quite higher. According to their preclinical study, the nab-PTX is intended for the destruction of the peritumoral desmoplastic stroma, therefore, they increased the intra-tumoral concentration of GEM within the treated mice group used for their study. Although these studies gave a direction in using this combination effectively against PanCa, a randomized phase III clinical trial was much needed to bring up this combinational therapy as an acceptable therapy for the significant treatment of PDAC [Albumin bound paclitaxel  can enhance chemotherapy activity. Hyperthermia plays a vital role in enhancing the chemotherapeutic efficiency of drugs by alleviating the temperature of cancer cells, and, as a result, enhancing their sensitivity towards chemotherapeutic drugs. GEM + Cis-based thermosensitive liposomes have been formulated using DPPC/HSPC/Chol/DSPE-PEG2000 polymers. These liposomes when modified with polymer to lead to multi-functional nano formulation have a phase transition temperature of 42 °C which makes the formulation release its therapeutic moiety only when triggered with hyperthermia . The norNanoparticles have been functionally modified to come up with chemotherapeutic formulations with significant pharmacokinetic property, non-toxicity, and biocompatibility. Liposomes, solid nanoparticles, polymer conjugates, micelles and etc. have come up as an emerging source for drug delivery; but to get established clinically, various trials are still needed for validation. Therefore, in a broader way liposome and polymeric nanoparticles are the formulations which are being clinically used for drug delivery in a broad sprectrum of different drug and drug combinations . HoweverCo-delivery mechanisms with GEM can be an effective tool for enhancing the survival rate of PanCa patients and decreasing the problems associated with dual drug co-administration. The recent research conducted with the co-delivery of GEM has shown promising outcomes such as the ability to decrease individual drug doses, incorporating drugs of different physicochemical properties together, which warrants further investigation. Although there are certain limitations with co-delivery techniques such as overcoming the barrier of the physical/chemical features of two different types of specific drugs or therapies when applied together, it is imperative to find alternative solutions to improve the efficacy of the combination. Also, uniform drug loading capacity, the stability of the drug combination, and higher uptake capabilities should also be taken into account. The availability of various drug delivery options has opened up scope to work on the approach of how the delivery vehicle can be fabricated in a better way to limit the curbs associated with the delivery of GEM with other drug cocktails. Combining both hydrophilic and hydrophobic drugs into a single system can prove to be an efficient technique for the treatment of PanCa patients. Based on the current research and success profiles of various co-delivery techniques, significant GEM-based co-delievry formulations based on polymeric micelle has been noticed; therefore, further work on these nanocarriers could help to promote polymeric micelles as an excellent source of GEM-based co-delivery. This can also help in designing polmeric carriers in such a way that it can have the properties of different carriers altogether such as liposome and hydrogel properties within itself, which can make polymeric micelles more efficient in delivering GEM and other drugs; therefore, these carriers could be nearer to clinical trials than the other carriers which are being studied now although more advanced studies are required in this direction to reduce the limitations which are still present with the different nanocarriers, which would possibly enable more concrete findings to proceed to clinical trials.


Silicone wristbands have been used to measure exposure to pesticides and other chemicals among children and younger farm workers, but not in older adults. Thus, we aimed to examine exposure to pesticides using silicone wristbands in a small cohort of older adults living on agricultural land, with variable contact with fields and pesticides. We also investigated correlations between pesticide levels on wristbands and urinary pesticide metabolites. Organophosphate (OPH) pesticides and several organochlorines were measured in wristbands worn by 15 males age 70+ (10 farmers using pesticides and 5 non-farmers with no recent pesticide use). Wristbands were worn continuously for 5-days. End-of-day urine samples were collected on days 1-3-5. Spearman correlations and Wilcoxon Scores were calculated. Five pesticides were quantified in the wristbands and detection frequencies ranged from 40-90%. In urine,12 OPH metabolites were quantified, but only 5 were detected in >50% of the samples. None of 5 urinary herbicides were detected. Imputation was performed by dividing minimum-detect by square-root-2. Malathion was only detected in farmers compared to non-farmers. Correlations between OPH urinary metabolites and wristband were examined but only two were significant and were negative in direction. Notably, organochlorine DDE on the wristbands was significantly correlated with 3 OPH metabolites. These unexpected relationships, based on small numbers, suggest a need to replicate this work in a larger study sample to explore potential for confounding or mixtures in future studies of pesticides and health in older farmers.


Balance impairment is a common problem among older adults. Poor balance in older adults is often associated with mobility impairments, activity limitations and fear of falling in older adults. Thus, balance assessment is useful for early detection of postural control deficits to prevent mobility impairments and falls in older adults. The aim of this study was to assess if balance measures based in center of pressure (COP) parameters during one-legged stance could differentiate between older adults with and without falls in the past 12 months. One-hundred and seventy older adults  performed three 30s one-legged stance trials with eyes open on a force platform with 30s of rest between each trial. The following variables were evaluated: COP 95% elliptical area, COP velocity in the anterior-posterior and medio-lateral directions, and test duration . Fallers had poorer balance than non-fallers (P ≤0.004). The COP parameters presented an area under the curve between 0.65-0.72, with sensitivity varying from 66 to 78% and specificity from 54 to 68%. There were no significant differences between fallers and non-fallers on test duration . The findings showed that the fallers had similar duration time, but poorer balance than the non-fallers during one-legged stance. The COP parameters were able to differentiate the balance between fallers and non-fallers with acceptable area under curve, sensitivity and specificity.


Mechanical, materials, and biological causes of intracortical probe failure have hampered their utility in basic science and clinical applications. By anticipating causes of failure, we can design a system that will prevent the known causes of failure. The neural probe design was centered around a bio-inspired, mechanically-softening polymer nanocomposite. The polymer nanocomposite was functionalized with recording microelectrodes using a microfabrication process designed for chemical and thermal process compatibility. A custom package based upon a ribbon cable, printed circuit board, and a 3D-printed housing was designed to enable connection to external electronics. Probes were implanted into the primary motor cortex of Sprague-Dawley rats for 16 weeks, during which regular recording and electrochemical impedance spectroscopy measurement sessions took place. The implanted mechanically-softening probes had stable electrochemical impedance spectra across the 16 weeks and single units were recorded out to 16 weeks. The demonstration of chronic neural recording with the mechanically-softening probe suggests that probe architecture, custom package, and general design strategy are appropriate for long-term studies in rodents. Intracortical neural interfaces enable both fundamental neuroscience advances and engineering strategies to restore motor, sensory, and cognitive functions to individuals who have suffered neurological injury or disease. Though electrical interfaces have dominated the field , recent Ebrain ~ 10 kPa) [Epolymer ~ 2–4 GPa) than standard silicon-based devices (ESi ~ 160 GPa) or tungsten microwire (EW ~ 411 GPa) arrays [Solutions to poor long-term intracortical interface reliability largely focus on addressing the biological tissue response through geometric or materials design of neural probes ,18,19,20 10 kPa) . Intraco 10 kPa) ,27, whic 10 kPa) ,29, pary 10 kPa) ,31,32,33 10 kPa) ,35,36,37) arrays ,39, ther) arrays ,41. Seve) arrays ,33,42. A) arrays  or with ) arrays . RegardlE ~ 4–5 GPa) when dry due to the reinforcing effects of a percolating CNC network through the material. When swollen with water, the CNC network disengages, thus “turning off” the reinforcing effect. Bulk PVAc-CNC films swell 70% by weight [g) to ~20° C. The CNC disengagement and Tg reduction effects combine to yield a dramatic reduction in modulus to E ~ 10 MPa [The biological mechanism underlying the mechanical stiffness modulation of the sea cucumber dermis inspired the development of a polymer nanocomposite with a modulus that can be controlled by temperature and degree of saturation ,46,47. Ay weight , which iy weight . The wat~ 10 MPa ,50,51. F~ 10 MPa . This ma~ 10 MPa ,26,52.PVAc-CNC has a much wider mechanical range than other mechanically-softening polymers used for neural interface applications ,41,53. IIntracortical interfaces based upon PVAc-CNC require processes for forming a neural probe geometry and functionalizing the material with microelectrodes for recording, as well as a robust packaging system for making connection to external electronics. A complete system must consider the biological system, material properties, and forces to which the system is subjected during and after the insertion procedure. The design and method of packaging microscale neural interfaces are critical, yet often neglected, components of the implant system. For the mechanically-softening PVAc-CNC, the package must include a compatible method for making electrical connection between a rigid commercial connector and the mechanically-softening probe. The electrical interconnections between the probe and the connector must be insulated from the physiological environment and should avoid mechanical failure modalities. The connector itself must be protected to prevent mechanical breakage or removal. Finally, the entire headcap must be anchored securely to the skull for successful chronic studies. We previously reported on the fabrication and benchtop studies of an early-stage PVAc-CNC neural probe ,51,55. TOur goal was to produce a planar microelectrode array with up to 8 recording sites on the PVAc-CNC polymer nanocomposite structural material. Planar microelectrode arrays allow for simultaneously measuring from multiple depths within the cortex . The PVAThe polyvinyl acetate-cellulose nanocrystal polymer nanocomposite serves as the structural material for the neural probe. The methods for synthesizing PVAc-CNC have been described in detail elsewhere ,46,48,582 for 24 h at 37C, 90%RH moisture vapor transmission [® 2 Parylene Deposition System .Parylene C serves as an insulating moisture barrier for the interconnection traces between the recording sites and connection contacts. Parylene is an FDA Class VI material and is a good moisture barrier with a 24-h water absorption of 0.06% and 0.14 g-mil/100 insmission . The ParSputter-deposited, thin-film Au was chosen for the microelectrode recording sites, connector contacts, and interconnecting traces due to its biocompatibility, inertness, and low residual stress. 2 and CF4 through a photoresist mask  designed to interface with a Hirose FH-19 Flexible circuit board connector . Both the flexible circuit connector and an Omnetics Nano Strip connector  were mounted to a printed circuit board a, providThe ribbon cables were fabricated by etching the Pyralux copper cladding with a sodium persulfate solution through a laser-printed toner etch mask. The toner was then removed from the surface of the copper using acetone. The copper traces were insulated with an acrylic spray through a shadow mask, then the ribbon cable was cut out by laser micromachining. Probes were attached to the flexible ribbon cable using a cyanoacrylic adhesive. Electrical connection between the copper ribbon cable pads and the gold probe pads was made with conductive epoxy . To insulate the electrical connections, a 2-part epoxy was applied using a needle to the exposed conductive epoxy and contact pads on both the probe and ribbon cable. The ribbon cables were inserted into the flexible circuit connector on the PCB, then the assembly was pushed into the 3D-printed housing. The PCB slides into one section of the housing, while a separate section holds the ribbon cable to ensure that the probe shank was normal to the housing. The components were secured with insulating epoxy.Fully-packaged PVAc-CNC probes were immersed in phosphate buffered saline in a heated water bath at 37 °C, then the impedance spectra of recording sites were measured over 48 days. An EZStat Pro potentiostat  was used to measure the impedance versus a platinum reference wire between 10 Hz and 10 kHz, with 25 points per decade. The impedance magnitude at a frequency of 1 kHz was used to compare frequency over time.−1 to a final depth of approximately 2 mm. After the PVAc-CNC probe and housing were set in place, silicone elastomer  was applied to seal the craniotomy. The connector housing was secured in place with dental acrylic anchored by the screws. Finally, the skin on the scalp was closed around the housing with 1–2 sutures.Three male Sprague-Dawley rats (225–250 g) were implanted with a single PVAc-CNC neural probe in the primary motor cortex, which was then left in place for 16 weeks. The PVAc-CNC probes were sterilized using ethylene oxide. All procedures and animal care practices were approved by and performed in accordance with the Case Western Reserve University Institutional Animal Care and Use Committee. The surgical procedures followed standard protocols ,61,62. BEleven neural recording sessions took place during the 16-week implant duration. Each recording session lasted for approximately 10 min and involved cleaning and drying the housing and Omnetics connector, connecting a pre-amplifier and cable, then allowing the rat to freely move within a clean cage. Neural potentials were recorded with a 16-channel Tucker David Technologies (TDT) Pentusa Z5 system , using a sampling rate of 24.4 kHz. EIS measurements were made with the rat under isoflurane anesthesia using an amplitude of 10 mV between 1 Hz and 10 kHz with 10 frequencies per decade. Nspikes × 100 timepoints) corresponding to the collection of spike snippet windows to cluster the spikes. Neural units were identified by choosing the clusters with more than 20 spikes in a cluster. A mean spike waveform was created from the spikes in the cluster, and the peak-to-peak voltage of the mean waveform determined the peak-to-peak signal voltage. The peak-to-peak noise voltage of each channel and block was determined by first removing the spike snippets windows from the signal and determining the standard deviation of the remaining signal. The peak-to-peak noise voltage was then defined as 3 times the standard deviation of the remaining noise signal. Data from each trial was processed by a MATLAB  analysis program based on code from the Kipke Lab ,64. SignMulti-electrode arrays with between 4 and 8 individually-addressable microelectrode recording sites were fabricated on the PVAc-CNC polymer nanocomposite, as shown in Device yield was largely dependent upon the elimination of air from between the PVAc-CNC film and the underlying silicon handle wafer. Unlike spin-cast or vapor-deposited polymers, PVAc-CNC begins as a free-standing film. Air trapped between the wafer and PVAc-CNC film can expand during microfabrication steps that occur under vacuum, particularly during sputter deposition when the nanocomposite softens with an increase in temperature. Additionally, the in-line design of the 4-channel design had fewer mechanical failures during release from the wafer than the wide connector contact pad layout with the sharp transition to the shank featured in the 8-contact design.We considered materials and process compatibility, modularity, and robustness when designing and developing a package for the PVAc-CNC probes. In our packaging scheme, the probe, reference, and ground wires were attached to a polyimide-based Pyralux ribbon cable with copper traces running from the probe to an end designed to interface with a flexible circuit connector. Electrical connection between the Au contact pads on the probe and the Cu contact pads on the ribbon cable was made with Ag-based conductive epoxy. The contact resistance between the Au contact pads on the probe and the Cu contact pads on the ribbon cable was less than 5 Ω, which is negligible compared to the overall trace resistance and electrode-electrolyte interface impedance. The ribbon cable provides a modular approach to making electrical connection to the probe, thus allowing for testing before assembling the complete package. Further, electrical connection via a ribbon cable lends itself to design flexibility, as the ribbon cable length can be increased to reduce tethering forces, and the configuration can be modified to enable more bending and stretching without putting undue stress on the ribbon cable traces. In our in vivo studies, the ribbon cable was folded and inserted into the 3D printed housing . The ribThe labor-intensive process required to package the PVAc-CNC probes presents several risks for failure of a mechanically-brittle probe. To reduce these risks and improve yield of packaged probes, PVAc-CNC probes are packaged while the shanks are slightly moist and are therefore less brittle. Future designs will include a monolithically-integrated ribbon cable that will reduce the level of skill required to make a connection between the PVAc-CNC and connectors to external electronics.EIS results for the 50 µm-diameter PVAc-CNC microelectrode sites in PBS indicated impedance magnitude values between 55.1 and 190.7 kΩ at a frequency of 1 kHz. EIS results from a typical recording site are shown in Using the custom, 3D-printed clip to hold the probe housing, the probes were inserted into the cortex cleanly and securely. The insertion needed to be performed within a few seconds due to the rapid softening of the PVAc-CNC material ,49,50. TPVAc-CNC swelling is primarily a concern only during the insertion process because swelling corresponds to a reduction in material stiffness. Further, damage during implantation can be minimized by completing the insertion process before the probe is able to swell appreciably. Though an increase in implant size has generally correlated with an increase in glial scarring and a decrease local neuronal density ,66, a de2 [EIS results, averaged across functional channels, measured across the duration of the implant time period, are shown in 2 . Further2 . OverallNeural activity with a signal-to-noise ratio between 2.6 and 4.3 was recorded using the PVAc-CNC neural probes during the 16-week implant duration B. AveragWe developed a neural probe system based on a mechanically-adaptive polymer nanocomposite using a microfabrication process flow designed for compatibility with the chemical and thermal sensitivities of PVAc-CNC. Importantly, the polymer nanocomposite was designed specifically for biocompatibility and biological integration as an implant material, which contrasts strongly with the focus on processability for silicon- and mechanically-static polymer-based neural implants. PVAc-CNC is a sufficiently rigid material in its dry state to penetrate the cortex before dramatically softening and reducing mechanical mismatch at the interface. To overcome the incompatibility of PVAc-CNC with standard microfabrication processes, the process flow used to develop PVAc-CNC neural probes was reliant upon laser micromachining and the use of a conformal Parylene C coating that protects PVAc-CNC from exposure to wet chemicals during processing and insulates thin-film traces from electrolytic fluid absorbed by PVAc-CNC while implanted. A custom, robust package was also designed to interface the microscale polymer nanocomposite-based probes with external electronics and maintain the ability to connect to external electronics for at least 16 weeks. For the first time, we have demonstrated that the PVAc-CNC probes remain electrically functional and stable for an extended duration and are capable of recording electrical neural activity for at least 16 weeks.


To systematically assess patterns and temporal changes in the measurement and valuation of childhood health utilities and associations between methodological factors.Studies reporting childhood health utilities using direct or indirect valuation methods, published by June 2017, were identified through PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL, Cochrane Library and PEDE. The following were explored: patterns in tariff application; linear trends in numbers of studies/samples and paediatric cost–utility analyses (CUAs) and associations between them; changes in proportions of studies/samples within characteristic-based categories over pre-specified periods; impact of National Institute for Health and Care Excellence (NICE) guidance on primary UK research and associations between valuation method, age and methodological factors.335 studies with 3974 samples covering all ICD-10 chapters, 23 valuation methods, 12 respondent types and 42 countries were identified by systematic review. 34.0% of samples using indirect methods compatible with childhood applied childhood-derived tariffs. There was no association between numbers of studies/samples and numbers of CUAs. Compared to 1990–2008, 2009–June 2017 saw a significant fall in the proportion of studies using case series; significant compositional changes across ICD-10 chapters and significantly higher sample proportions using childhood-specific and adult-specific indirect valuation methods, and based on pre-adolescents, self-assessment, self-administration and experienced health states. NICE guidance was weakly effective in promoting reference methods. Associations between valuation method, age and methodological factors were significant.1990–2017 witnessed significant changes in primary research on childhood health utilities. Health technology assessment agencies should note the equivocal effect of methodological guidance on primary research.The online version of this article (10.1007/s11136-019-02121-z) contains supplementary material, which is available to authorized users. Sustained health budget constraints necessitate the comparison of alternative programmes and interventions in terms of costs and consequences . Cost–utValuation methods for utility assessment can be divided into two broad categories: direct and indirect. Direct methods combine the valuation and measurement process into a single step, and include the standard gamble (SG) technique and the time trade-off (TTO) approach . The visUnique methodological challenges arise when utility assessments are conducted for childhood age < 18 years) health conditions or states , 15. For years heThere has been increasing recognition of these methodological challenges in international health technology assessment (HTA) guidelines. The 2013 National Institute for Health and Care Excellence (NICE) methods guidance recognised that its preferred measure, the EQ-5D, lacked a classification system designed for use in children and recommended use of the EQ-5D-Y for children aged 7–12 years, although no separate tariff set for this measure existed . DespiteIn line with the preference of several HTA agencies, CUA is now the leading analytic approach for economic evaluation of health interventions targeting children, with the number of CUAs overtaking that of cost-effectiveness analyses (CEAs) contained in the Paediatric Economic Database Evaluation (PEDE) in 2009 . Althougn = 73) of these CUAs conducted primary estimation of utility values [Catalogues and reviews of health utility values for childhood populations are available, but have largely focussed on a relatively small number of conditions, such as acute lymphoblastic leukaemia , 28, asty values . FurtherThis paper addresses three aims against a backdrop of rapid development of measurement approaches and methods guidance in this area. First, it systematically describes the patterns of primary studies and samples measuring childhood health utilities, by study design and sample characteristics, as well as patterns in the source of tariffs when MAUIs compatible with or specific to children are used. Second, linear trends in the numbers of studies and samples, their associations with the number of paediatric CUAs and changes in proportions of studies and samples before and after key transition timepoints are explored. Third, associations between valuation methods and sample age and other methodological factors are explored.The systematic review followed PRISMA guidelines  and coveArticles that met the inclusion criteria were English language primary studies reporting health utilities for childhood populations or for childhood conditions or descriptors using direct or indirect valuation methods. Two reviewers (JK and SWK) independently assessed titles and abstracts. Articles with two approvals proceeded to the next stage; those with one were referred to a third reviewer (SP) for arbitration. At the second stage, the same primary reviewers analysed full-text articles with disagreements referred to the third reviewer. Conference abstracts were included if they reported original health utilities. Studies reporting primary VAS values were included despite disagreement about their validity for QALY construction .From each study that met the inclusion criteria, the variables listed in Supplementary Material Table S2 were extracted using a proforma. These included bibliographic details, study design, study setting, valuation method, tariff applied to MAUIs , respondent type, administration mode, sample target age(s), whether the health state was experienced or hypothetical, sample size and geographic setting. An International Classification of Diseases 10th revision (ICD-10) code was allocated to each sample according to the health condition studied.The distribution of mean and median utility and VAS  scores extracted from included samples was calculated. The number of studies and samples by publication year was estimated together with the annual number of CUAs included in the PEDE database. Valuation methods applied to studies within each ICD-10 chapter were described. The numbers of samples by respondent type, administration mode, target age(s) of sample and geographical factors  were esLinear regression tested for linear trends in numbers of PEDE-based CUAs, utility studies and utility samples by year of publication. Controlling for these annual trends, associations between number of PEDE-based CUAs and number of utility studies and samples were also estimated. We tested the hypothesis that there were significant changes to the composition of childhood utility data categorised by study- and sample-level characteristics, including study design, health condition, valuation method, age of target population, respondent type, administration mode and valuation of hypothetical health states. Tests of proportions, at the 95% confidence level, were used to assess whether the proportion in each category of study- and sample-level characteristic changed significantly before and after a pre-specified transition point of 2009, which was when CUAs became the prominent analytic approach for paediatric economic evaluations within the PEDE database . In a seFigure Descriptive statistics for health utilities were extracted from 3974 samples contained within the 335 studies. The majority of studies (306 out of 335) contained two or more samples delineated by health condition/state, sociodemographic factors  or methodological factors. Figure n = 698), followed by general childhood population health (n = 501) and cancer (n = 442). Across all ICD-10 chapters, 180 unique ICD-10 codes were used to label samples.Table n = 232; 5.8%) and stand-alone VAS ; (ii) trade-off-based direct valuation methods—TTO , SG , chained gamble and adjusted SG ; (iii) adult-specific MAUIs—EQ-5D , SF-6D , AQoL-5D  and 15D ; (iv) MAUIs compatible with both childhood and adult populations—QWB , HUI2 , HUI3 , modified HUI  and ABC-UI (Aberrant Behaviour Checklist Utility Index) [n = 1; 0.03%); (v) childhood-specific MAUIs—EQ-5D-Y , CHU9D , 16D , 17D , AQoL-6D , PAHOM  [n = 69; 1.7%) and CH-6D  [n = 3; 0.08%);and (vi) mapping non-preference-based clinical measures to utility indices [n = 15; 0.4%).Twenty-three unique valuation methods were identified. These were grouped into six key categories: (i) VAS—EQ-5D VAS , EQ-5D-Y VAS      used self-assessment by children. A total of 456 samples (11.5%) allowed children to generate responses together with proxies. The remainder of the samples relied on proxy assessment, most commonly by parents . Administration modes fell broadly into two categories: (i) self-administered surveys in school or clinical settings, by mail, online or by Delphi elicitation of clinicians [n = 41) had a minimum age of 18 years even though they specified adolescents as the target group. A significant proportion of samples (14.4%) did not report any information on age. As for geographical setting, the skew towards high-income countries was clear (91.6%). The US produced the highest number of samples  followed by Canada  and the UK .Table inicians ; and (iiTable P < 0.001) for number of utility studies, 12.70  for number of utility samples and 3.63  for number of PEDE CUAs. The number of utility studies increased at a steady rate across the whole review period, while the numbers of utility samples and PEDE CUAs increased markedly in the late 2000s.Figure P value: 0.097). There was similarly no association between number of utility samples and number of CUAs . No associations were similarly found between proportion of paediatric economic evaluations that were CUAs and the number of primary utility studies and samples.Linear regression of the number of utility studies on number of CUAs, controlling for linear time trend, showed no association .Table P < 0.001), general health , mental and behavioural disorders  and injury .In terms of health condition, comparisons between the two periods revealed significant changes in proportion of samples in all ICD-10 chapters except musculoskeletal system disorders. Categories that saw the greatest change were cancer  whilst trade-off-based direct valuation methods saw the greatest decrease . However, there was also a significant increase in the use of adult-specific MAUIs  and VAS approaches . MAUIs compatible with both childhood and adult populations experienced a significant decrease in use . There was a significant shift towards self-assessment of health status by children , and the use of self-administered surveys in school and clinic settings . Similarly, there was a significant increase in the number of samples valuing experienced rather than hypothetical health states . As for age of target population, there was a significant shift in focus to pre-adolescent populations  and a significant fall in the proportion of samples failing to provide information on age .There were equally significant changes for valuation method, respondent type, administration mode and valuation of hypothetical health states. For valuation method, childhood-specific MAUIs saw the greatest increase . Seventy-two samples in 1990–2012 did not report age of target population compared to none in 2013–June 2017. The evidence supporting our hypothesis that publication of the NICE guidance would increase the use of reference instruments in relevant age groups and reduce the use of non-reference instruments was mixed. For samples containing pre-adolescents, the use of EQ-5D-Y increased from 3.9% of samples in 1990–2012 to 16.9% in 2013–June 2017 . Moreover, the use of the non-reference HUI2/3 and trade-off-based instruments fell from 75.4% and 5.8% of samples, respectively, in 1990–2012 to no samples in 2013–June 2017. However, the use of EQ-5D also increased from 11.1 to 32.4% , while the uses of the non-reference CHU9D  and VAS approaches  both increased.Table P values all less than 0.001. Results suggest that VAS approaches are more likely to be used in pre-adolescent samples and to be assessed by children themselves using self-administered surveys. However, VAS approaches are also more likely to be used to assess hypothetical rather than experienced health states. Trade-off-based direct valuation methods are more likely to be used in older adolescent samples and/or involve proxy assessment. They are also more likely to be administered by interview and for assessing hypothetical health states. The associative patterns varied for the three categories of MAUIs. Adult-specific MAUIs were more likely to be used in adolescent samples, while MAUIs compatible with or specific to childhood populations were both more likely to be used in pre-adolescent samples. Adult-specific MAUIs were more likely to involve self-assessment by children, and MAUIs compatible with both populations more likely to involve proxy assessment. All MAUI categories were more likely to be self-administered than interviewer-administered and be used to assess experienced rather than hypothetical health states.Table This study represents the most comprehensive systematic review of primary studies reporting health utilities for childhood conditions, covering all studies published up to 30 June 2017. All ICD-10 chapters relevant to childhood health, 23 valuation methods, all childhood ages, 12 respondent types, 8 administration modes and 42 country settings were observed across 3974 samples from 335 studies. There were strong upward linear trends in numbers of utility studies and samples and PEDE CUAs. There was no statistically significant association between numbers of PEDE CUAs and utility studies and samples after controlling for linear trend. Adopting year 2009  as a kePrevious systematic reviews of primary studies assessing childhood health utilities have largely focused on specific diseases –31 or vaTo our knowledge, this review is the first to summarise the distribution of all mean and median utility scores relevant to childhood health. The results show a clear disparity in distributional features between alternative central statistics of mean and median utilities. The ceiling effect, known to be significant in distributions of individual-level utility data , was visThe review is also the first to categorise all primary samples by ICD-10 chapter and code and document their compositional changes over time. Ascertaining how well the distribution of utility samples by ICD-10 chapter reflects prevalence of health needs in children is of interest. Were and colleagues  noted trAnother contribution of the review is documenting the change in patterns of valuation method over time. A clear pattern was visible in the movement away from trade-off-based direct valuation methods towards MAUIs that require only simple responses on a classification system and separate valuations using tariffs derived from representative populations. The proportion of samples using trade-off-based direct valuation methods fell from 23.7% in 1990–2008 to 8.0% in 2009–June 2017, whereas the proportion of samples using MAUIs of any type increased from 59.9% in 1990–2008 to 67.9% in 2009–June 2017. This perhaps reflects the concern over feasibility of applying cognitively demanding assessments in children , as wellThe above concern over comparability may explain the finding that the publication of HTA guidance by NICE had a mixed effect on primary utility assessments. In the UK samples containing pre-adolescent populations, the proportion using the adult-specific EQ-5D increased by more than the proportion using the childhood-specific EQ-5D-Y after the guidance publication in 2013. Adlard and colleagues , after rThis study also catalogues all tariffs applied to MAUI-based studies, the population from whom they were derived and their valuation method. Around one-quarter (23.7%) of samples using MAUIs provided no information on the tariff applied, and this proportion increased from 19.2% in 1990–2008 to 26.0% in 2009–June 2017. Among samples that used MAUIs compatible with or specific to childhood populations, 60.0% applied adult-derived tariffs, and this proportion increased from 50.3% in 1990–2008 to 64.6% in 2009–June 2017. Only one sample using the EQ-5D-Y applied childhood-derived tariffs, while none was available for the HUI3. However, it is difficult to conclude that application of childhood-derived tariffs is more appropriate than adult-derived tariffs even for MAUIs compatible with or specific to childhood populations. Children are not autonomous legal, social and economic agents and do not bear the burden of financing public healthcare. Hence their preferences, even when conflicting with those of the general adult public, may arguably be of less importance. That said, analysts should recognise that applications of childhood and adult-derived tariffs may produce enough variation in utility values to alter policy decisions . They shOne potential-related research area is assessing the quality of utility research and its improvement over the review period. However, the tests of association between sample-level characteristics showed that choice in one methodological area (e.g. use of proxy assessment) was strongly associated with other methodological choices  and target population age, which makes it challenging to assess quality and its improvement in terms of methodological choices (e.g. the proportion of samples using proxy assessment). This is more so in the absence (to our knowledge) of any validated quality assessment tool for primary utility studies. That said, the increase in the proportion of samples reporting target population age over the review period was an unambiguous improvement, as was the decrease in the proportion of samples valuing hypothetical health states that may result in significant overestimation of disease burden relative to valuation of experienced health states in childhood . There wThere are several limitations to the study. First, some eligible studies may have been missed during the systematic review process, even though the search strategies were extensively piloted to maximise sensitivity. Second, several studies did not report or did not clearly specify important covariates, such as age and comorbidities, which may affect utility values. Third, the broad criteria for selection of valuation methods resulted in inclusion of modified forms of methods  and preference-based disease-specific instruments (e.g. PAHOM and ABC-UI), which complicated between-method comparisons. Fourth, the choice of 2009 as a transition point for all studies and samples was not based on potential causal or associative mechanisms determining the design and volume of primary utility research. Finally, cross-tabulations between methodological factors were limited to two-way Chi-square tests for association, and further research should consider application of multivariate regressions.This systematic review reveals significant growth in both volume and diversity of childhood utility studies over the past three decades. HTA agencies should note the weak adherence to guidance concerning the use of reference case valuation methods by primary studies. There is a need for studies that derive tariffs in settings relevant to primary utility collection. Geographic coverage of utility assessment is heavily skewed to high-income countries, and further research in LMICs is pressing.Below is the link to the electronic supplementary material.ONLINE RESOURCE Excel database containing information on all 3,974 sub-samples of health utilities and descriptors can be found online at http://childhoodutilities.wordpress.com. The website also contains the detailed search strategy and a guidance note for Excel navigation. (DOCX 162 KB)Supplementary material 1


Wireless avionics intra-communication (WAIC) refers to a wireless communication system among electronic components  that are integrated or installed in an aircraft and it is proposed to replace heavy and expensive wired communication cables. Recently, the use of a frequency band (4.2–4.4 GHz) for the WAIC  has been approved by international telecommunication union (ITU). Accordingly, several existing wireless protocols such as IEEE 802.11 and IEEE 802.15 are being considered as candidate techniques for the intra-avionics sensor network. In this paper, we perform a real field experiment to investigate wireless channel characteristics in intra-avionics sensor networks at the WAIC bands by a software-defined radio platform  and self-produced monopole antennas for the WAIC band. Through the experiment, we validated the feasibility of IEEE 802.11 protocol for the intra-avionics sensor network at the WAIC band in real aircraft environments. Furthermore, based on the measurement data, we evaluated the bit error rate (BER) performance of multiple antenna techniques where we considered the maximum ratio combining (MRC) for the multi-antenna receiver and the space-time block coding (STBC) for the multi-antenna transmitter. Wireless avionics intra-communications (WAIC) refers to radio communication systems that interconnect avionics components  installed in an aircraft . WirelesSeveral studies related to WAIC are reported recently. Raharya and Suryanegara investigated the compatibility of WAIC systems with radio altimeters at 4.2–4.4 GHz by simulations , and anahttp://www.koreaaero.com/english/product/fixedwing_kt-1.asp) for our experiment.) Further, reliable transmission techniques  in intra-avionics sensor network environments were evaluated using our measured data.  We believe that our field test shed light on the first step for implementing WAIC systems in practice. The main contributions of this paper are summarized as follows:We used software-defined radio devices and modified the IEEE 802.11 application framework to measure wireless channel for WAIC systems see .Commercial antennas do not support the WAIC bands (4.2–4.4 GHz), and thus we self-produced monopole antennas to transmit and receive wireless signals at the WAIC bands see .We performed point-to-point wireless channel measurements and feasibility test of adopting IEEE 802.11 protocol in a real aircraft (KAI KT-1 Woongbi). (Specific reasons why we chose KAI KT-1 Woongbi as our test aircraft are explained in We simulated the bit error rate (BER) performance using our measurement data when we considered a candidate sensor network scenario and reliable transmission techniques such as a maximum ratio combining (MRC) and space-time block coding (STBC) schemes see .In this study, we performed a real-field experiment to measure channel characteristics of the WAIC bands (4.2–4.4 GHz) and to investigate the feasibility of IEEE 802.11 protocol in real aircraft environments.  based physical layer specification in IEEE 802.11 protocols and its channel estimation principle.IEEE 802.11 is a set of media access control layer and physical layer protocol specifications for implementing wireless local area network (WLAN) in the industrial, scientific and medical (ISM) frequency bands . The original version of the standard was released in 1997 (IEEE 802.11-1997 or legacy) and subsequent amendments  have been done to support various system requirements. In most releases of IEEE 802.11 protocols, OFDM was widely adopted due to its robustness on the multi-path fading and its flexibility on operating bandwidth. Note that high throughput or very high throughput modes with different OFDM configurations are specified and provided in recent releases . However, legacy mode based on L, given by [k indicates subcarrier index, i.e., The long training symbol consists of 53 subcarriers including the zero value at DC, which are modulated by the elements of the sequence given by (1)L−26,kth subcarrier, which is transformed from the received preamble in time domain. Using IFFT (Inverse Fast Fourier Transformation) operation, channel response in time domain  can be obtained as follows:The long training symbol generated based on Equation  is repeaIn this section, we introduce the details of the experimental setup including software, hardware, and measurement environment. An overview of major components (hardware and software) in our experimental setup is described in http://www.ni.com/en-us.html), ① in http://github.com/bastibl/gr-ieee802-11). We used two USRPs: one for transmitter only with transmit antenna and the other for receiver only with receive antenna.We used the software-defined radio device  and the radiation beam pattern to verify the performance of the designed monopole antenna.S-parameters are used to describe the electrical behavior of linear electrical networks [networks . In geneE-plane) and the magnetic field plane (H-plane).The radiation beam pattern indicates the directional (angular) dependence of the strength of the radio waves from the antenna . In geneE-plane and H-plane, respectively. Measurement results agreed well with simulation ones. Additionally, the maximum antenna gain aws E-plane was about 60°. Note that, based on measurements, we verified that the designed monopole antenna was appropriate to transmit and receive signals at WAIC bands.The main objectives of our experiment were to measure wireless channel and to test the feasibility of adopting IEEE 802.11 physical layer specification in the real aircraft. We performed our experiment in a flight test site located in South Korea. The target aircraft was KT-1 Woongbi, shown in poly-fiber [WAIC is designed to reduce the use of cable, eventually resulting in the weight of a big-sized aircraft and saving fuel. However, it is worth noting that the basic cover material for both KT-1 Woongbi and a WAIC-targeted aircraft such as a passenger plane  would be similar, so-called ly-fiber . From thly-fiber .Specifically, we set several measurement points in KT-1 Woongbi for our experiment, as described in single transmitter–receiver link at one time instead of multiple links simultaneously.  Obviously, there was interference when we considered multiple data transmission at the same time . To resolve the interference issue during data transmissions, we used conventional TDMA (time-division multiple access) as in [During our experiment, we measured a s) as in .In this section, we introduce data processing methods for raw data obtained in our experiment, and the measurement results.f, l, and n denote frequency , location index, and sample index, respectively. Location index indicates the different locations in the same measurement point, described in As described in We obtained 100 samples per each measurement and average them to reduce the effect of white noise , given byThe channel impulse response, Equation . Accordi follows :(7)τ¯=∫−To verify the feasibility of adopting IEEE 802.11 physical layer specification in KT-1 Woongbi, we checked block error rate (BLER), constellation, and throughput during packet transmissions. During our experiments, we set a transmit power of USRP as 20 dBm (=100 mW). Note that the transmit power set in our experiment can be a reference value for the minimum required power for the communication in the aircraft since SDR devices  usually have less performance in terms of radio transmission/reception compared to commercial radio devices.  with commercial grade radio devices. However, unfortunately, as mentioned in Remark 1.It is worth noting that we performed our experiment in both LOS and NLOS environments where electronic devices and mechanic components are filled in the measurement points, as shown in We measured path loss in KT-1 Woongbi by considering transmit/receive power, antenna cable loss, and the designed monopole antenna gain. To verify our measurement results, we also considered formally verified radio propagation simulation, carried out by the international aerospace community . The simRemark 2.We obtained at most 1.9 m transmit range under the power constraint  in our test, as shown in We simulated the bit error rate (BER) performance using our measurement data when we considered a candidate sensor network scenario for applying wireless networks in the aircraft such as intra-avionics sensor networks. Note that we utilized channel data samples measured in all measurement points during the experiment for simulations.M antennas, respectively. We considered the TDMA in a sensor node scheduling to avoid interference issue and guarantee the reliability of wireless link. For modulations, we considered quadrature phase-shift keying (QPSK) and 16-level quadrature amplitude modulation (16-QAM). In addition, we set multiple antenna configurations for the AP: For simulations, we considered a sensor network that consists of multiple sensors and a single access point (AP) as described in n time-slot.During uplink transmissions (data transmission from the sensor to the AP), we considered a maximum ratio combining (MRC) scheme to improve receive diversity . Similar and M=4 ,23:(8)Cformance a was cleformance b, only pRemark 3.Note that our observations in In this paper, we present the experimental results on wireless channels of the wireless avionics intra-communications (WAIC) in the real aircraft environment (KT-1 Woongbi). To transmit and receive wireless signals at the WAIC bands (4.2–4.4 GHz), we made monopole antennas. We adopted IEEE 802.11 physical-layer specification as a candidate techniques for high data-rate applications of the WAIC. We performed tests under several measurement points in the real aircraft and obtained channel measurement results. Based on the results, we analyzed power delay profile and the path loss characteristics of the WAIC. Furthermore, we simulated the BER performance using Rayleigh channel coefficients and our measurement data when we considered maximum ratio combining (MRC) and space-time block code (STBC) schemes in uplink and downlink transmissions, respectively. Our results emphasize the crucial importance of studying and applying wireless technologies in LOS dominant environment rather than simply assuming Rayleigh fading channel. In addition, the installation of relay nodes is highly required to guarantee the reliable wireless communication within the aircraft. An additional real-field experiment design using multiple relay nodes to wirelessly cover a big-sized aircraft remains as future work for in-depth WAIC feasibility test. The experimental results in this paper can be applied to design another aircraft.


M age = 63.8; range = 53–83) were administered a verbal n-back paradigm during fMRI. For each participant, the volume of brain response was summarized by left and right frontal regions of interest, and laterality indices  were calculated to assess HAROLD effects. Group level results indicated that age was significantly and negatively correlated with LI  for deactivations, but positively correlated with LI  for activations. The relationship between age and LI for deactivation was significantly moderated by performance level, revealing a stronger relationship between age and LI at higher levels of 2-back performance. Findings suggest that older adults may employ neurocompensatory processes specific to deactivations, and task-independent processes may be particularly sensitive to age-related neurocompensation.The hemispheric asymmetry reduction in older adults (HAROLD) is a neurocompensatory process that has been observed across several cognitive functions but has not yet been examined in relation to task-induced relative deactivations of the default mode network. The present study investigated the presence of HAROLD effects specific to neural activations and deactivations using a functional magnetic resonance imaging (fMRI) n-back paradigm. It was hypothesized that HAROLD effects would be identified in relative activations and deactivations during the paradigm, and that they would be associated with better 2-back performance. Forty-five older adults ( The number of individuals aged 65 or older is projected to exceed 1.5 billion in 2050  and willdedifferentiation , which postulates that under similar circumstances, PFC activation during cognitive processes tends to be less lateralized in OAs than YAs . HAROLD While the HAROLD model has been well-documented, several aspects of this model are not fully delineated. For example, some evidence suggests that HAROLD patterns observed in prefrontal regions may be specific to higher levels of task demand . In addiAnother aspect of the HAROLD model that has not been clarified is the distinction between relative activation and deactivation. Despite substantial evidence for HAROLD effects in task-related activation patterns, neurocompensation relative to task-independent neural processes have been understudied. The default mode network (DMN) has been defined by coactivation within a distributed network of cortical regions, which characterizes the resting state of the human brain . EvidencEvidence suggests that DMN deactivations may be particularly susceptible to aging and a potential contributor to neurocompensatory processes. For example, using fMRI and spatial judgment tasks, Further investigations of task-independent processes are needed to determine how the DMN and task-independent networks may interact with other models of neurocompensation, such as the HAROLD pattern in OAs. Since HAROLD and PASA models do not have direct support from studies of relative deactivation and given a lack of clarity in prior literature whether effects included summation of activation and relative deactivation or only activation effects, we considered examination of activation and relative deactivation separately to have high theoretical and methodological importance. The present study provides the first examination of HAROLD lateralization effects in both brain activations and relative deactivations in healthy OAs. Using fMRI during a WM paradigm, we evaluated the presence of the HAROLD pattern in the task-dependent brain response because neural activation associated with VWM has previously demonstrated sensitivity to age-related neurocompensatory processes, including the HAROLD effects. Second, using a resting fixation baseline to isolate suppression of baseline DMN activity, we evaluated the presence of HAROLD among task-induced deactivations. Moderation analyses were conducted to address whether observed HAROLD effects were associated with cognitive performance . Two homologous frontal lobe regions of interest (ROI) were used to calculate the laterality indices (LI) and examine the expected HAROLD effects. It was hypothesized that (1) OAs would demonstrate HAROLD patterns of task-elicited relative brain activation and deactivations, and (2) effects would be significantly moderated by 2-back performance, as a reflection of successful compensation.M age = 63.78 years, SD = 7.99) who comprised a healthy control group in a larger study of neurocognitive function in cardiovascular disease (SD from 50%), low global cognitive function , or any MRI contraindications . Significant medical , neurological , and psychiatric problems  were exclusion criteria that were assessed by interview, physical examination, review of medical records and self-report questionnaires. Participants were compensated for their participation. The study was approved and monitored by the university and hospital institutional review boards (IRB) where the research took place and conformed to the Helsinki Declaration on human subjects’ protection.Participants included 45 healthy, right handed English-speaking men and women over the age of 50  and above average intellectual functioning  and years of educational attainment . WM performance  was consistent with prior 2-back literature  presented two earlier in the series . Six 0-Back control blocks of nine consonants each were presented with the same duration of letter presentation and ISI. 0-Back blocks preceded each 2-Back block during the first imaging run and followed the 2-Back during the second run. Participants responded yes when a predetermined target consonant (“H” or “h”) appeared and no for other consonants. Consonant blocks of both conditions contained 33 percent “yes” targets in random locations within each series. Capitalization was randomized throughout to encourage verbal encoding. Two 27-s (27000 ms) blocks of resting fixation blocks were presented between the 0-Back/2-Back cycles. 2-back performance was calculated for each participant using the following formula: (number of correct positives + correct negatives)/ total number of letters presented. Two subjects were excluded from behavioral analyses due to near-chance 2-back performance (<60% accuracy). A diagram of the n-back task is presented in se e.g., . During MRI Acquisition. Whole-brain echo-planar fMRI was conducted using a Siemens TIM Trio 3 tesla scanner . This procedure yielded 116 whole-brain volumes for each of the two 288s imaging runs, yielding a spatial resolution of 3 mm3 per voxel. Whole-brain high-resolution T1 images were also acquired in the sagittal plane for anatomical reference . Two conditions of the n-back paradigm  and a resting state “+” were presented using E-prime  and back-projected onto a screen visible to the participant via a mirror mounted to the head coil.MRI analysis. MRI dataset processing and statistical analyses were performed with Analysis of Functional NeuroImages version 18.0.05 software  and corrected for multiple comparisons using AFNI’s false discovery rate  procedure in order to provide a measure of volumetric activity, measured by significantly activated voxels beyond the threshold per ROI, for each participant.Group level processing. For group level-analyses, two frontal ROIs were defined based on left or right hemisphere  which extended to y-plane = 0. LIs, defined as left relative to right (left/right) frontal ROI response to the 2-back were calculated using each individual’s volume of significant response in each ROI . Consistent with prior literature  using one-sample t-tests. These whole-brain analyses were conducted using an FDR-corrected threshold of p = 10-9 (voxels greater than t = 8.42) with and a minimum of 10 contiguous voxels. Clusters of significant n-back response exhibited by our sample was compared to prior n-back literature  and high (+1 SD above the mean) levels of 2-back performance.esiduals . Multicoesiduals . For modesiduals  was applThe 2-back versus baseline contrast revealed widespread activation patterns commonly associated with n-back performance , includiactivation LI yielded left-lateralization of this VWM task  as expected . Descriptive statistics and the computed LI values are presented in Volumetric effects of the 2-back were summarized by the two frontal ROIs for both activations and deactivations. LIs were then calculated from these values and averaged at the group level. The expected . Similarr(42) = 0.34, p = 0.02 (see r(42) = -0.31, p = 0.04 . However, 2-back accuracy , and the age × 2-back accuracy interaction term  were not significantly predictive of LI . Moderation analysis specific to neural deactivations, however, yielded significant effects. Over and above age , 2-back accuracy  was a significant predictor of unique variance in LI  = 5.09, p < 0.001). In addition, the interaction term of 2-back accuracy x age was a significant predictor of unique variance in LI over and above age and 2-back accuracy  = 4.33; b = 0.00; p = 0.04). Results of this moderation effect are presented in For neural activations, age significantly predicted LI  but not significantly related to LI for lower levels . In other words, high 2-back performers exhibited a stronger negative relationship between age and deactivation LI, or HAROLD effects. A plot of the simple slopes analyses is presented in Given evidence of an interaction effect between age and 2-back accuracy on the relative deactivation LI, simple slopes analyses were conducted by estimating the conditional effect of age at specific values of 2-back performance  and tested whether the slopes were statistically significant from zero by a null hypothesis test see . ResultsHemispheric asymmetry reduction in older adults is a well-established neurocompensatory process that has been consistently demonstrated to support healthy OAs maintenance of cognitive function . HoweverThe significant positive correlation between age and activation LI suggests that an age-related increase in left hemispheric brain response may have supported OAs’ maintenance of cognitive functioning. While this finding appears to contradict the HAROLD model, it is consistent with evidence supporting the presence of other neurocognitive compensatory processes in OAs. For example, differences in capacity  has been associated with cognitive maintenance . At the Uncertainty regarding the function of overactivation, however, has led to increased interest in cognitive performance correlates. For example, overactivation among OAs has been linked to both reduced  and mainFindings of the present study support the notion that relative deactivations are sensitive to the aging process, lateralized similarly to task-induced activations, and associated with successful task performance on a measure of VMW. A significant negative correlation between age and the deactivation LI, coupled with maintained 2-back performance  suggests that reduced asymmetry of deactivations supported the OAs’ maintenance of cognitive functioning. Therefore, the current results provide evidence of a novel HAROLD finding, extending previous findings to deactivations, and more specifically, via a within-group fMRI study of community-dwelling OAs. This finding is further strengthened by an observed moderation effect of 2-back accuracy, suggesting that reduced asymmetry of deactivations may support maintenance of baseline cognitive abilities. Results of simple slopes analyses, conducted to elucidate the nature of this effect, revealed that higher performing OAs demonstrated an increased reduction of asymmetry specific to deactivations, while lower performing OAs did not see . This isDue in part to observations of their importance in neurocognitive function, task-induced deactivations of the DMN have become the target of increased investigation . EvidencConsistent with this notion, the PASA model has been used to explain an age-related posterior-anterior shift of task-related DMN deactivations that appear to support cognitive function, such as semantic fluency . Others SD = 7.99), as researchers often sample OA populations from 65 years and beyond. Interpretation of study findings are also limited by a relatively small sample size . The sample was above average in intelligence, well-educated, and predominantly of Caucasian ethnicity (96%), which poses potential problems with generalizability.Few studies have investigated HAROLD effects specific to WM among healthy OAs, and most were older PET studies. Prior literature has also focused almost exclusively on group differences  in HAROLD effects specific to task-dependent activations associated with WM. Interpretation of our findings by comparison to prior studies is therefore limited. A YA comparison group would have aided the interpretation of results. In addition, the sample of the present study was relatively young with respect to the aging literature  where the research took place and conformed to the Helsinki Declaration on human subjects’ protection. All participants underwent standard informed and written consent procedures.BD, MO, EH, and LS contributed to the design and implementation of the research, analysis of the results, and writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients with chronic kidney disease (CKD), a precursor of end stage renal disease (ESRD), face an increasing burden of hospitalizations. Although mortality on dialysis is highest during the first year, the impact of pre-dialysis acute hospitalizations on clinical outcomes in dialysis patients remains unknown.We evaluated 170,897 adult patients who initiated dialysis between 1/1/2010 and 12/31/2014 with linked Medicare claims from the United States Renal Data System. Using logistic regression models, we examined the association of 2-year pre-dialysis hospitalization on the primary outcome of 1-year all-cause mortality. Secondary outcomes included 90-day mortality, type of initial dialysis modality and type of vascular access at hemodialysis initiation.Mean age was 72.7 ± 11.0 years. In the study sample, 76.0% of patients had at least one pre-dialysis hospitalization. Compared to patients with no pre-dialysis hospitalization, the adjusted 1-year mortality was higher with pre-dialysis cardiovascular related hospitalization , infection related hospitalization , both cardiovascular and infection hospitalization , and neither-cardiovascular nor-infection hospitalization . Additionally, the adjusted odds of hemodialysis vs. peritoneal dialysis as the initial dialysis modality were higher, whereas adjusted odds to initiate hemodialysis with an arteriovenous access vs. central venous catheter were lower in patients with any type of hospitalization.Pre-dialysis hospitalization is an independent predictor of 1-year mortality in dialysis patients. Reducing the risk of pre-dialysis hospitalization may provide opportunities to improve quality of care in ESRD. Approximately 30 million adults in the United States have chronic kidney disease (CKD). CKD, which can be a precursor to end stage renal disease (ESRD), is associated with high burdens of mortality and cost of care –4. AdditOne of the major factors affecting morbidity and mortality after dialysis initiation is acute hospitalization. Several studies have examined the trends and causes of hospitalizations in ESRD patients receiving dialysis –9. It isWe hypothesized that the types or frequencies of hospitalizations occurring prior to ESRD would influence dialysis outcomes. We tested this hypothesis by leveraging the unique strengths of the United States Renal Data Systems (USRDS), which is the largest comprehensive registry of ESRD patients, and linked Medicare claims information for two complete years prior to incident ESRD. We examined the primary outcome of all-cause 1-year mortality; and secondary outcomes of mortality at 90-days, choice of initial dialysis modality, and type of vascular access in hemodialysis subjects.Fig 1 shows the derivation of study cohort. The study was reviewed and deemed exempt by the University of Cincinnati institutional review board.We identified all patients with ESRD who initiated dialysis between January 1, 2010 and December 31, 2014 from the “back-casted” database USRDS, with Medicare Part A and Part B or Medicare Primary Other as the primary payer for the entire 2 years prior to dialysis initiation and linked Medicare claims data , and followed them until December 31, 2015. We excluded patients younger than 18 years old, those with history of kidney transplant, those with inconsistent dates/identifiers, those that had started dialysis more than 3 months after or before date of first ESRD service due to discrepant or missing date of first dialysis treatment , and those with missing information on type of dialysis, dialysis access, gender or cause of ESRD . This resulted in 170,897 patients available for analysis in our final study sample. th revision Clinical Modification (ICD-9-CM) codes for discharge diagnoses of hospitalization for an infection or cardiovascular event by using a previously validated method  [The major predictor of interest for all outcomes was the presence or absence of a pre-dialysis acute care hospitalization. We searched the primary Medicare inpatient claims for all study participants during the complete two years preceding ESRD using International Classification of Disease 9 method  . Our stu method  . The pri method  .P values less than 0.05, adjusted for other predictors left in the model. The risk estimates were expressed as odds ratios (ORs), hazard ratios (HRs) and their 95% confidence intervals (95% CIs). Kaplan-Meier methods were used to construct unadjusted survival curves, and the survival rates of different groups were compared using a log-rank test. Data were analyzed using SAS .Distributions of categorical variables are expressed as frequencies or percentages, and continuous variables are described using mean and standard deviation (SD). Bivariate comparisons of subjects who did or did not have a pre-dialysis acute hospitalization were made using t tests, chi-squared tests, and Fisher exact tests for continuous and categorical variables as appropriate. Statistical significance was set at a two-tailed p-value of 0.05, unadjusted for multiple tests. We conducted multivariable regression analyses to examine the effects of pre-dialysis hospitalizations and their causes and frequencies vs. no acute hospitalization, on 1-year mortality, and secondary outcomes. In addition, the primary outcome of 1-year mortality was analyzed using a multivariable Cox proportional analysis censored for 1-year of follow up, loss to follow-up and recovery of renal function. Other covariates included in the regression model specification process were demographic variables, comorbidities, laboratory data, nursing home history, ESRD cause and access to transplant information. Multivariable models were constructed by applying backwards elimination to a set of candidate predictors until all predictors remaining had P < 0.001). AV access was the vascular access used for initiation of hemodialysis in 20.0% of patients. Patients with a pre-dialysis hospitalization had a lower frequency of AV access use for dialysis initiation than without pre-dialysis hospitalization . Rates of no pre-dialysis nephrology care were higher in the group with hospitalization as compared to patients without hospitalization . More patients with pre-dialysis hospitalizations were females and had CHF as comorbidity. Patients with a pre-dialysis hospitalization had higher rate of low albumin < 3.5  and higher rates of low hemoglobin < 11 . Table 1 shows comparison of patient characteristics across those who had pre-dialysis hospitalization vs. those who did not.The sample was 54.4% male and 28.1% octogenarian, with a mean age of 72.7 years . The frequencies of hypertension, congestive heart failure, or diabetes mellitus among the patient population were 87.3%, 41.9%, and 56.8%, respectively. Of the study cohort, 76.0% had at least one pre-dialysis hospitalization. Among the causes of pre-dialysis hospitalization, 28.4% of patients experienced cardiovascular hospitalization, 12.3% had infection hospitalization, 11.3% had both cardiovascular and infection hospitalization and 24.5% had neither cardiovascular nor infection hospitalization. With regards to frequency of pre-dialysis hospitalization, 24.1% experienced 1 hospitalization, 17.2% had 2 hospitalizations, 11.5% had 3 hospitalizations, and 23.7% had ≥ 4 hospitalizations. For those with history of hospitalization during 2-year pre-ESRD period, mean length of stay in the hospital during all hospitalizations was 22.7 days . Hemodialysis was the initial dialysis modality in 94.3% of patients; its frequency was 91.2% in patients who did not have a pre-dialysis hospitalization, compared with 95.3% in those who did have a pre-dialysis hospitalization .Table 2 shows independent predictors of 1-year mortality in ESRD patients from a multivariable regression model. Patients with any hospitalization were at a higher risk of death within 1 year than those who did not have a pre-dialysis hospitalization. Compared with no pre-dialysis hospitalization, patients had a higher odds of dying within 1 year with cardiovascular hospitalization , infection hospitalization , both infection and cardiovascular hospitalization  and neither-cardiovascular nor-infection hospitalization  . Additional factors associated with higher risk of 1-year mortality included presence of specific comorbidities like congestive heart failure and peripheral vascular disease, absence of pre-dialysis nephrology care, presence of nursing home history, male gender, white race, low albumin, and lack of access to transplant information. In a separate regression model, which examined the effect of multiple pre-dialysis hospitalizations, each hospitalization increased the risk of dying, independent of other covariates. Compared with no pre-dialysis hospitalization, patients had higher odds of dying within 1 year with 1 pre-dialysis hospitalization ; 2 pre-dialysis hospitalizations ; 3 pre-dialysis hospitalizations  and ≥ 4 pre-dialysis hospitalizations  . The adjusted odds of 90-day mortality were also higher in patients with any type hospitalization,  or with ≥ 1 hospitalization .Fig 3A represents unadjusted survival curves for patients with and without pre-dialysis acute hospitalization by type, censored on 31 December 2015. Fig 3B represents unadjusted survival curves for patients without pre-dialysis hospitalization and those with multiple episodes of pre-dialysis hospitalization, censored on December 31, 2015.The results of the Cox proportional hazards model for 1-year mortality were aligned with the results from the logistic regression for 1-year mortality. Compared with no pre-dialysis hospitalization, patients had a higher hazards of dying within 1 year with cardiovascular hospitalization , infection hospitalization , both infection and cardiovascular hospitalization  and neither-cardiovascular nor-infection hospitalization . In a separate Cox proportional hazards regression model, which examined the effect of multiple pre-dialysis hospitalizations, each hospitalization increased the hazard of dying, independent of other covariates. Compared with no pre-dialysis hospitalization, patients had higher odds of dying within 1 year with 1 pre-dialysis hospitalization ; 2 pre-dialysis hospitalizations ; 3 pre-dialysis hospitalizations  and ≥ 4 pre-dialysis hospitalizations . In the study cohort, 63.9% of patients with pre-dialysis hospitalization received in-hospital dialysis initiation as compared to 56.9% with no history of pre-dialysis hospitalization. Compared with patients with no pre-dialysis hospitalization, patients had higher odds of in-hospital dialysis initiation with history of pre-dialysis cardiovascular hospitalization , infection hospitalization , and both cardiovascular and infectious hospitalization  .. In a separate model, compared with no pre-dialysis hospitalization, patients had higher odds of using hemodialysis as the initial dialysis modality with 1 hospitalization , 2 hospitalizations , 3 hospitalizations ; and ≥ 4 hospitalizations  .Next, we looked at the secondary outcome of hemodialysis as the initial dialysis modality in patients with ESRD. Cardiovascular, infection, both cardiovascular and infection, and neither cardiovascular nor infection pre-dialysis hospitalization increased the risk of hemodialysis vs. peritoneal dialysis as the initial dialysis modality, as compared to those with no pre-dialysis hospitalization  . In a separate model, compared with no pre-dialysis hospitalization, patients had lower odds of using AV access for hemodialysis initiation with at 1 hospitalization , 2 hospitalizations , 3 hospitalizations ; and ≥ 4 hospitalizations  .Finally, we examined the secondary outcome of use of AV access vs. CVC in ESRD patients with hemodialysis as the initial dialysis modality. Patients had lower adjusted odds of using AV access with pre-dialysis cardiovascular hospitalization , infection hospitalization , both cardiovascular and infection hospitalization , and neither cardiovascular nor infection hospitalization , as compared to those with no pre-dialysis hospitalization The present study represents a large nationwide cohort of incident ESRD patients, with linked Medicare information on each patient for two years prior to initiation of dialysis. The study finds that majority of incident dialysis patients experience frequent hospitalizations prior to ESRD initiation. More importantly, the study indicates that acute care hospitalizations prior to ESRD are not inconsequential, and that they continue to be associated with poor patient survival at one year after dialysis begins. The study also elucidates the effect of both type or frequency of hospitalization on one-year mortality, as well as on secondary outcomes of dialysis modality, and type of hemodialysis access.Acute care hospitalizations are common among dialysis patients, and represents the single largest proportion (~ 40%) of total ESRD expenditures . In an eIn the present study, we found that about three fourths of patients with incident ESRD experienced at least one hospitalization during the 2-year pre-ESRD period, with majority of them involving cardiovascular causes. The data also indicates that more than half of the patients were hospitalized two or more times prior to incident dialysis. This high burden of hospitalizations demonstrates the high resource utilization required in patients with advanced kidney disease before they get initiated on dialysis. Patients experiencing pre-ESRD hospitalizations had poorer indicators of health status at the time of dialysis initiation; for instance, compared to those without hospitalizations, patients with pre-dialysis hospitalization had lower serum albumin and hemoglobin levels at the time of incident dialysis. Surprisingly, hospitalized patients were also less likely to have received pre-ESRD nephrology care prior to incident dialysis. It can be speculated that perhaps hospitalizations prior to ESRD could have higher probability of receiving nephrology care if these patients had either advanced CKD or suffered acute worsening of their renal function. However, studies have shown that trajectories of renal function loss are very variable in the two-year period prior to ESRD . It is aMortality after initiation of ESRD is considered an important metric for comparing quality of care across the dialysis industry and is linked to reimbursements. Typically, the standardized mortality rates for dialysis patients are estimated based on characteristics at the time of dialysis initiation , 26. In This study has several limitations. First, the data were derived from an administrative dialysis dataset, and the pre-dialysis information was made available from Medicare claims files. However, such limitations are inherent in de-identified national cohorts, in the absence of longitudinal datasets with reliable patient level information. Second, the hospitalization information was only analyzed for the period of two calendar years prior to incident ESRD, and for only those patients who were primarily Medicare beneficiaries during that entire time period. This may lead to over representation of older patients in our cohort and may not remain generalizable to broader ESRD population. Medicare claims data, as has been reported in other similar studies, can have low sensitivity, and potentially can lead to misclassification of the types of hospitalization. To mitigate this weakness, we used validated codes for primary admission diagnoses, and we analyzed our data both by cause as well as frequency of hospitalizations. We ascertained the comorbidities from the CMS-2728 form instead of Medicare claims, which remains another limitation of the study. Finally, in the present design, our study could not examine the association of hospitalization with outcomes in advanced CKD, but was able to determine the association of hospitalization with future outcomes among those CKD patients only who survived to initiate dialysis.Despite these limitations, these findings have several important implications for ESRD care. ESRD initiation is a life-changing event for a patient, which is also associated with changes in providers, healthcare systems, and health insurance status. During this transition of care period, it is common to either not have access to or under-recognize important factors during the pre-dialysis period that may impact post-dialysis care. Our observations from a national cohort point out that both the type and frequency of acute care hospitalizations prior to dialysis initiation are of prognostic significance. We found that about 75% of patients had occurrence of pre-dialysis hospitalization. Although these hospitalizations could not necessarily be avoided, as they likely occur for some acute illness, the observation still allows us to speculate about how this information may lead to future improvements. One possibility is that better pre-ESRD care can potentially reduce the risk of pre-ESRD hospitalizations, and this can be associated with improved outcomes. Additionally, the study also shows that pre-ESRD hospitalization may be a lost opportunity to involve nephrology care after discharge, and efforts to enhance longitudinal follow up to nephrology specialty could potentially impact ESRD outcomes. From the standpoint of comparing the quality of dialysis care; efforts should be made to incorporate type or frequency of pre-dialysis hospitalization as an important risk factor of mortality.In conclusion, the majority of the incident ESRD patients experience at least one hospitalization prior to initiating dialysis. Both the cause and frequency of hospitalization during the pre-ESRD period significantly increases one-year dialysis mortality. Additionally, pre-ESRD hospitalization is also associated with greater risk of initiating hemodialysis versus peritoneal dialysis; and among hemodialysis patients, it lowers the odds of presence of AV access at dialysis initiation. The study emphasizes that both healthcare providers and dialysis providers need to consider that pre-dialysis acute care utilization can continue to impact outcomes after initiation of dialysis. Whether this presents an opportunity to either intervene prior to dialysis, or to customize care after dialysis begins requires further investigation.S1 Table(DOCX)Click here for additional data file.