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We examined phylogeographic structure in gray fox (Urocyon cinereoargenteus) across the United States to identify the location of secondary contact zone(s) between eastern and western lineages and investigate the possibility of additional cryptic intraspecific divergences. We generated and analyzed complete mitochondrial genome sequence data from 75 samples and partial control region mitochondrial DNA sequences from 378 samples to investigate levels of genetic diversity and structure through population- and individual-based analyses including estimates of divergence (FST and SAMOVA), median joining networks, and phylogenies. We used complete mitochondrial genomes to infer phylogenetic relationships and date divergence times of major lineages of Urocyon in the United States. Despite broad-scale sampling, we did not recover additional major lineages of Urocyon within the United States, but identified a deep east-west split (∼0.8 million years) with secondary contact at the Great Plains Suture Zone and confirmed the Channel Island fox (Urocyon littoralis) is nested within U. cinereoargenteus. Genetic diversity declined at northern latitudes in the eastern United States, a pattern concordant with post-glacial recolonization and range expansion. Beyond the east-west divergence, morphologically-based subspecies did not form monophyletic groups, though unique haplotypes were often geographically limited. Gray foxes in the United States displayed a deep, cryptic divergence suggesting taxonomic revision is needed. Secondary contact at a common phylogeographic break, the Great Plains Suture Zone, where environmental variables show a sharp cline, suggests ongoing evolutionary processes may reinforce this divergence. Follow-up study with nuclear markers should investigate whether hybridization is occurring along the suture zone and characterize contemporary population structure to help identify conservation units. Comparative work on other wide-ranging carnivores in the region should test whether similar evolutionary patterns and processes are occurring.

Position sensing and high bandwidth data reception are functions typically performed by two separate detectors in conventional free-space optical communication systems. In this letter, we report low excess noise, impact ionization engineered InAlAs/InGaAs avalanche photodiode arrays that can perform both functions simultaneously.

Continuous renal replacement therapy (CRRT) is an extracorporeal blood purification therapy that aims to support kidney function over an extended period of time. One of the main objectives of CRRT is the removal of excess fluid and solutes retained as a consequence of acute kidney injury. Because prescription of CRRT requires goals to be set with regard to the rate and extent of solute and fluid removal, a comprehensive understanding of the mechanism by which solute and fluid removal occurs during CRRT is essential. Basic mechanisms of fluid transport and solute removal (ultrafiltration, diffusion, convection, and adsorption) and the factors influencing these processes in CRRT are described. From the combination of the different transport mechanisms, a number of CRRT modalities are identified and described. Finally, these principles are applied to provide a brief overview of the concept of effluent-based CRRT dose.

Despite evidence to the effect that there is low parental adoption of tick-bite personal protective behavior (PPB) for their children - a population at high risk for tick exposure, very limited information is available on factors associated with parental adoption of PPB. The objective of this study was to identify the most significant factors associated with parental adoption of tick-bite PPB on behalf of a child or children at risk of tick encounters. A cross-section of parents in Indiana, USA whose child had spent time outdoors in tick habitat during the summer were recruited from representative online panels maintained by Qualtrics. Binary logistic regression was used to model determinants of five tick-bite PPBs. Our results revealed that the application of tick repellent (89 %, n = 718) followed by conducting a tick check of the child's body soon after returning from the outdoors (84 %, n = 676) were the PPBs most frequently adopted by parents. Conversely, tucking one's shirt into pants and pants into socks was the least frequently adopted PPB (48 %, n = 386). Compared to other factors evaluated in logistic regression models, parents who reported implementing one or more residential tick control practices were significantly more likely to adopt nearly all five tick-bite PPBs for their children. Additionally, parents who were more worried about their health due to ticks and reported being more likely to avoid the outdoors because of ticks were more likely to adopt at least three PPBs on behalf of their children. To ensure children can most safely engage in outdoor activity, identifying the factors associated with parental adoption of tick-bite preventive behaviors represents an important mechanism in the prevention of tick-borne diseases.

OBJECTIVES Renal replacement therapy may be required for acute kidney injury treatment in neonates with complex cardiac conditions. Continuous veno-venous hemofiltration is applied safely in this population but no published recommendations for dose prescription in neonates currently exist. The aim of our study was to evaluate the effects of a relatively small dialysis dose on critically ill neonates. DESIGN Retrospective analysis of clinical charts. SETTING Pediatric Cardiac ICU. PATIENTS Ten critically ill neonates with severe acute kidney injury were analyzed. The primary indication for continuous veno-venous hemofiltration initiation was severe fluid overload with oligoanuria. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The median (range) age and weight were 3 days (1-12 d) and 2.6 kg (2.1-4.2 kg), respectively, whereas the median continuous veno-venous hemofiltration duration was 17 days (3-63 d). Median prescribed blood flow rate, replacement fluid rate, and net ultrafiltration rate were 12 mL/min (9-50 mL/min), 100 mL/hr (40-200 mL/hr), and 20 mL/hr (5-45 mL/hr), respectively. The median effluent-based continuous veno-venous hemofiltration dose was 35 mL/kg/hr (11-66 mL/kg/hr), whereas the median delivered daily Kt/V per session (24 hr) was 0.5 (0.01-1.8). However, for treatment sessions lasting less than or equal to 12 versus greater than or equal to 12 hours per session, the median prescribed effluent dose was 41 (11-66) and 32 (17-60) mL/kg/hr, respectively (p = 0.06), whereas the delivered creatinine daily Kt/V values were 0.3 (0.01-0.9) and 0.9 (0.5-1.8), respectively (p < 0.0001). An inverse correlation was found between delivered daily Kt/V and the blood concentration differences of both creatinine (r = -0.3; p = 0.0093) and urea (r = -0.3; p = 0.0028) measured at the end and the beginning of a 24-hour treatment. The decrease of creatinine concentration was significantly greater during 24-hour treatment sessions with a delivered daily Kt/V greater than 0.9 than during those with daily Kt/V less than 0.9. CONCLUSIONS Based on these findings, we propose on a provisional basis the use of daily Kt/V as a measure of continuous renal replacement therapy adequacy for critically ill neonates.

Background/Aims: Delivered dialysis therapy is routinely measured in the management of patients with end-stage renal disease; yet, the quantification of renal replacement prescription and delivery in acute kidney injury (AKI) is less established. While continuous renal replacement therapy (CRRT) is widely understood to have greater solute clearance capabilities relative to intermittent therapies, neither urea nor any other solute is specifically employed for CRRT dose assessments in clinical practice at present. Instead, the normalized effluent rate is the gold standard for CRRT dosing, although this parameter does not provide an accurate estimation of actual solute clearance for different modalities. Methods: Because this situation has created confusion among clinicians, we reappraise dose prescription and delivery for CRRT. Results: A critical review of RRT quantification in AKI is provided. Conclusion: We propose an adaptation of a maintenance dialysis parameter (standard Kt/V) as a benchmark to supplement effluent-based dosing of CRRT. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=475457

Continuous renal replacement therapy (CRRT) originally was applied with technology adapted from maintenance hemodialysis. Over the past four decades, CRRT machines have evolved into devices specifically designed for critically ill patients. In this chapter, a brief history of this evolution is provided first, with emphasis on the manner in which changes have been made to address the specific needs of the patient and the users of these devices. Subsequently, specific aspects of modern CRRT machines are discussed, including the user interface, pumps, pressure monitoring, safety features, and anticoagulation capabilities. The basic principles of CRRT membranes and filters also are highlighted, especially with regard to the influence of modality, membrane characteristics, and blood/fluid flows on solute transport. Finally, recent CRRT membrane developments designed to broaden the spectrum of solute removal are addressed.

The concept of clearance was established more than 30 years ago as a useful tool to estimate prescribed and delivered dialysis dose in end-stage renal disease. There has been interest in applying these quantification principles for critically ill patients with acute kidney injury (AKI) also. Although continuous renal replacement therapy (CRRT) is understood to have greater solute clearance capabilities relative to intermittent therapies, neither urea nor any other solute is employed specifically for CRRT dose assessments in clinical practice. Instead, the normalized effluent rate is the gold standard for CRRT dosing, although this parameter does not provide an accurate estimation of actual solute clearance for different modalities. This chapter provides a comprehensive review of studies assessing dose prescription and delivery for CRRT. A critical review of renal replacement therapy quantification in AKI is provided, with emphasis on areas in which additional information may be useful for clinicians. An adaptation of a chronic dialysis parameter (standard Kt/V) as a benchmark to supplement effluent-based dosing is proposed to assist clinicians in the prescription and delivery of CRRT.

Conventional hemodialysis remains an important renal replacement modality for critically ill patients with acute kidney injury. Because prescription of hemodialysis requires goals with regard to the rate and extent of solute and fluid removal, an understanding of the mechanisms by which solutes and fluid are removed during hemodialysis is necessary. This chapter provides an overview of basic mechanisms of solute and fluid transfer during conventional hemodialysis. The major characteristics of hollow fiber membranes influencing solute and water removal are discussed subsequently. Within this section, the chemical composition and physical characteristics of commonly used dialysis membranes and the features determining their solute and water permeability properties are reviewed. Flow distribution inside the dialyzer, internal filtration, and backfiltration phenomena are discussed in the last section of the chapter.

Haemodialysis is an extracorporeal process in which the blood is cleansed via removal of uraemic retention products by a semipermeable membrane. Traditionally, dialysis membranes have been broadly classified on the basis of their composition (cellulosic or noncellulosic) and water permeability (low flux or high flux). However, advances in materials technology and polymer chemistry have led to the development of membranes with specific characteristics and refined properties that mandate a reconsideration of traditional membrane classification systems. For adequate characterization of these newer types of membranes, additional parameters are now relevant, including new permeability indices, the hydrophilic or hydrophobic nature of membranes, adsorption capacity and electrical potential. In this Review, we provide clinicians with an updated analysis of dialysis membranes and dialysers. We discuss the basic mechanisms that underlie solute and water removal in dialysis (that is, diffusion, convection, adsorption and ultrafiltration) in the context of treatments that use highly permeable membranes. Specifically, we highlight online haemodiafiltration and new therapies (for example, expanded haemodialysis) that utilize membranes designed to produce a high degree of internal filtration. Finally, we discuss the considerations that govern the clinically acceptable balance between large-solute clearance and albumin loss for extracorporeal therapies.

For continuous renal replacement therapy (CRRT), the extracorporeal filter provides solute depuration, fluid removal, and control of electrolyte and acid-base balance in critically ill patients with acute kidney injury (AKI). The membranes comprising CRRT filters are almost exclusively based on hollow fiber designs and, while adapted from the chronic hemodialysis field, have features that are specific to the requirements of CRRT nevertheless. In addition, these devices have evolved through the 40 years of CRRT in response to changes in clinical practice and the desire to extend the solute removal spectrum. For some critically ill patients, more targeted removal of specific compounds poorly cleared by standard CRRT can be attempted with techniques based on adsorption. Sorbent hemoperfusion is now being applied more broadly in critically ill patients, especially in those with sepsis and systemic inflammation. In this review, the manner in which CRRT membranes and extracorporeal sorbents have evolved over the past 40 years for the treatment of critically ill patients with AKI and other disorders is described.

Continuous renal replacement therapy (CRRT) machines have evolved into devices specifically designed for critically ill over the past 40 years. In this chapter, a brief history of this evolution is first provided, with emphasis on the manner in which changes have been made to address the specific needs of the critically ill patient with acute kidney injury. Subsequently, specific examples of technology developments for CRRT machines are discussed, including the user interface, pumps, pressure monitoring, safety features, and anticoagulation capabilities.

For terrestrial free space optical (FSO) communication applications, large area photodetectors not only allow for more efficient power coupling but also ease the effects of atmospheric turbulence. When fabricated in array form, these devices have the added capability of operating as both data reception sensors and position sensitive detectors (PSD). Concentric five element impact ionization engineered (I2E) avalanche photodetector (APD) arrays have been developed to operate as combinational sensors at gigabit data rates. While the excellent sensitivity performance of these detectors allows for enhanced link range in calm atmospheric conditions, link availability with a high quality of service for an FSO system is strongly impacted by its ability to dynamically counter-act atmospheric fading with varying temporal scale. In this paper we present initial results using a combinational sensor in tandem with an advanced FSO modem which utilizes low-density parity check coding (LDPC) in an incremental redundancy (IR) hybrid automatic repeat request (HARQ) protocol. System performance enhancements as function of varying atmospheric scintillation will be discussed.

For continuous renal replacement therapy (CRRT), the extracorporeal filter provides solute depuration, fluid removal, and control of electrolyte and acid-base balance in critically ill patients with acute kidney injury (AKI). The membranes comprising CRRT filters are almost exclusively based on hollow fiber designs and, while adapted from the chronic hemodialysis field, have features that are specific to the requirements of CRRT nevertheless. In addition, these devices have evolved through the 40 years of CRRT in response to changes in clinical practice and the desire to extend the solute removal spectrum. For some critically ill patients, more targeted removal of specific compounds poorly cleared by standard CRRT can be attempted with techniques based on adsorption. Sorbent hemoperfusion is now being applied more broadly in critically ill patients, especially in those with sepsis and systemic inflammation. In this review, the manner in which CRRT membranes and extracorporeal sorbents have evolved over the past 40 years for the treatment of critically ill patients with AKI and other disorders is described.

Continuous renal replacement therapy (CRRT) machines have evolved into devices specifically designed for critically ill over the past 40 years. In this chapter, a brief history of this evolution is first provided, with emphasis on the manner in which changes have been made to address the specific needs of the critically ill patient with acute kidney injury. Subsequently, specific examples of technology developments for CRRT machines are discussed, including the user interface, pumps, pressure monitoring, safety features, and anticoagulation capabilities.

Over the past several decades, the clinical aspects of acute kidney injury (AKI) and its management with renal replacement therapy (RRT) have evolved substantially in both the pediatric and adult patient populations. The development of AKI in children is now recognized to be a common occurrence, especially among critically ill neonates and infants, and is associated with substantial morbidity and mortality. With respect to dialytic management, continuous RRT (CRRT) has supplanted peritoneal dialysis as the preferred dialytic modality for critically ill pediatric AKI patients in many parts of the world, especially the United States. Although initial CRRT devices for both adults and children involved technology adapted from chronic hemodialysis, dedicated CRRT devices specifically designed for critically ill adult patients have been widely available for more than two decades now. However, these devices generally have not had specific indications for pediatric use due to limitations related to fluid accuracy and extracorporeal circuit volumes. The recent introduction of pediatric-specific machines obviates the need to provide CRRT “off-label” with adult-based CRRT devices to small pediatric patients. In this chapter, some of the clinical challenges associated with treating the complex critically ill AKI patient population are discussed and several important questions for the future are addressed. In addition to CRRT technology, the topics of therapy dosing, timing of initiation and termination, fluid management, drug dosing, and data analytics are discussed, with emphasis on anticipated developments over the next decade.

Background: Docetaxel–prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naive mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone

A method to precisely determine the quantum efficiency and primary photocurrent in avalanche photodiodes (APDs) is presented based on a linear relationship between excess noise factor F and gain, M. The new method is used to accurately compare performance of modern APD designs when nonlocal impact ionization effects govern the relationship between noise and gain.

Extracorporeal therapy for end-stage renal disease is now provided to more than three million patients globally. Nearly all treatments are performed with filters containing hollow fiber membranes, removing solutes and water by diffusion, convection, and ultrafiltration. In this review, we will provide a detailed quantitative analysis of the transport processes involved in different hemodialysis (HD) therapies. We will also report some technical aspects of hollow fiber membranes and filters composed of them along with the mechanisms of solute and water removal for such devices. Diffusive mass transfer will be assessed according to the three major aspects of a hollow fiber filter (blood compartment, membrane, and dialysate compartment). With regard to convective transport, the importance of internal filtration as a solute removal mechanism in high-flux HD will be highlighted, along with the critical role that blood/membrane interactions assume in filtration-based therapies.

Hemodialysis is a process of mass separation by a semipermeable membrane, utilized to cleanse blood from waste products retained in case of kidney failure. Traditionally, dialysis membranes have been classified based on composition and hydraulic conductance, creating the net differentiation between cellulosic versus non-cellulosic on one hand and low-flux versus high-flux on the other. With the evolution of biomaterials and improved spinning technology, new membranes have been introduced in the market with specific characteristics and refined individual properties. Therefore, we should consider new parameters to classify dialysis membranes including polymer blending, surface functionalization, molecular weight cut-off (MWCO), hydrophilic/hydrophobic properties, thickness and architecture, adsorption capacity, and electric potential. All these parameters may be utilized to characterize a membrane alone or in combination. Recently, a new parameter has been identified as an important element to characterize a new class of membranes. Beyond the classic MWCO describing the molecular weight at which the sieving value in pure convection = 0.1, the molecular weight retention onset (MWRO) is a new parameter that defines membrane sieving properties. The retention onset value is the molecular weight at which the sieving value = 0.9. The relationship between MWCO and MWRO describes the steepness of the sieving curve and the membrane pore size distribution with important consequences on the final mass separation process and solute removal.

Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious clinical disorder in the intensive care unit (ICU), occurring in a significant proportion of critically ill patients. However, many questions remain about the optimal administration of RRT with regard to several important considerations, including treatment dose, timing of treatment initiation and cessation, therapy mode, type of anticoagulation, and management of fluid overload. While Level 1 evidence exists for RRT dosing in AKI, all the studies contributing to this evidence base employed fixed-dose regimens throughout a patient's continuous RRT (CRRT) course, without regard for the possibility of individualizing treatment dose according to the clinical status of a given patient at a specific time. As opposed to CRRT dose, no consensus about the timing of RRT in critically ill AKI patients exists currently. While numerous clinical trials over the past 40 years have attempted to assess "early" versus "late" initiation of RRT, they have been plagued by a myriad of methodological problems, including their largely observational nature and the widely varying definitions of early and late initiation. Although questions about the appropriate timing of CRRT discontinuation arise very frequently in clinical practice, even less information is available in the literature to guide this important decision. The aim of this review is to provide a comprehensive update on RRT delivery to critically ill AKI patients, with specific attention paid to treatment dose and timing and emphasis on addressing the practical questions that arise in daily clinical practice.

As is the case in end-stage renal disease (ESRD), both intermittent and continuous renal replacement therapies (RRTs) are employed in acute renal failure (ARF). In fact, a continuum of treatment options is available in ARF. At one end of the ARF RRT spectrum is conventional intermittent hemodialysis (IHD), in which relatively high blood and dialysate flow rates are used (typically ≥250 and 500 mL/min, respectively). Continuous renal replacement therapies (CRRTs), which employ much lower flow rates, comprise the other end of the spectrum. Finally, hybrid therapies, which combine characteristics of both IHD and CRRT, have recently been described. These therapies' removal mechanisms for solutes over a broad molecular weight range are discussed. An understanding of these mechanisms is important when determining the amount of therapy that can be provided by any RRTs. Additional studies are required to improve the understanding of solute removal by the various RRT used in ARF.

Quantification of the prescribed and delivered doses of renal replacement therapy (RRT) in end-stage renal disease (ESRD) is now commonly performed, since recent data demonstrate a clear relationship between dialysis dose and outcome. In recent years, some of the quantification techniques developed for ESRD patients have been extended to the acute renal failure (ARF) setting. This extension has allowed the assessment of the specific effect of the frequency of intermittent hemodialysis (IHD) on delivered dialysis dose and metabolic control. In this review, after a discussion of the manner in which therapy prescription factors differ in the ARF and ESRD settings, the issue of the frequency of IHD in the ARF setting is explored.

Since its inception four decades ago, both the clinical and technologic aspects of continuous renal replacement therapy (CRRT) have evolved substantially. Devices now specifically designed for critically ill patients with acute kidney injury are widely available and the clinical challenges associated with treating this complex patient population continue to be addressed. However, several important questions remain unanswered, leaving doubts in the minds of many clinicians about therapy prescription/delivery and patient management. Specifically, questions surrounding therapy dosing, timing of initiation and termination, fluid management, anticoagulation, drug dosing, and data analytics may lead to inconsistent delivery of CRRT and even reluctance to prescribe it. In this review, we discuss current limitations of CRRT and potential solutions over the next decade from both a patient management and a technology perspective. We also address the issue of sustainability for CRRT and related therapies beyond 2027 and raise several points for consideration.

Photodetectors in free space optical communication systems perform two functions: reception of data communication signals and position sensing for pointing, tracking, and stabilization. Traditionally, the optical receive path in an FSO system is split into separate paths for data detection and position sensing. The need for separate paths is a consequence of conflicting performance criteria between position sensitive detectors (PSD) and data detectors. Combining the functionality of both detector types requires that the combinational sensor not only have the bandwidth to support high data rate communication but the active area and spatial discrimination to accommodate position sensing. In this paper we present a large area, concentric five element impact ionization engineered avalanche photodiode array rated for bandwidths beyond 1GHz with a measured carrier ionization ratio of less than 0.1 at moderate APD gains. The integration of this array as a combinational sensor in an FSO system is discussed along with the development of a pointing and stabilization algorithm.

Limitations imposed by the characteristics of some solutes and the structure of dialysis membranes have spurred new interest in the use of mechanisms beyond diffusion and convection for extracorporeal solute removal. Sorbents have been utilized for more than 50 years in extracorporeal blood treatments for specific purposes, and better understanding of their basic aspects may further expand the potential for their clinical application. In this chapter, the basic principles applying to sorbents are discussed, including composition and structure, along with the fundamental mechanisms of solute removal. The critical importance of sorbent biocompatibility is also highlighted. With these basic principles in mind, the clinical application of sorbents is discussed, with an emphasis on the use of hemoperfusion and coupled plasma filtration-adsorption for sepsis-related disorders. Finally, new sorbent-based clinical approaches for acute conditions and end-stage renal disease are presented, emphasizing that sorbent technologies may assume a larger role for a variety of clinical disorders in the future.

Hemodialysis is a process of mass separation by a semipermeable membrane, utilized to cleanse blood from waste products retained in case of kidney failure. Traditionally, dialysis membranes have been classified based on composition and hydraulic conductance, creating the net differentiation between cellulosic versus non-cellulosic on one hand and low-flux versus high-flux on the other. With the evolution of biomaterials and improved spinning technology, new membranes have been introduced in the market with specific characteristics and refined individual properties. Therefore, we should consider new parameters to classify dialysis membranes including polymer blending, surface functionalization, molecular weight cut-off (MWCO), hydrophilic/hydrophobic properties, thickness and architecture, adsorption capacity, and electric potential. All these parameters may be utilized to characterize a membrane alone or in combination. Recently, a new parameter has been identified as an important element to characterize a new class of membranes. Beyond the classic MWCO describing the molecular weight at which the sieving value in pure convection = 0.1, the molecular weight retention onset (MWRO) is a new parameter that defines membrane sieving properties. The retention onset value is the molecular weight at which the sieving value = 0.9. The relationship between MWCO and MWRO describes the steepness of the sieving curve and the membrane pore size distribution with important consequences on the final mass separation process and solute removal.

High retention onset (HRO) is the designation for a new class of hemodialysis membranes. A unique characteristic of this class is the highly selective and controlled porosity resulting in sieving properties that provide a clinically desirable balance between middle/large molecular weight solute removal and albumin loss. Another defining feature of this membrane class is the relatively small fiber diameter, which produces high convective volumes in the form of internal filtration. The aim of the present study was to estimate, by semi-empirical methods, convective volumes for 2 new HRO dialyzers: Theranova 400 and Theranova 500 (Baxter International Inc., Deerfield, IL, USA). Axial blood and dialysate compartment pressure drop along with transmembrane pressure, measured in vitro with blood (Qb = 300 or 400 mL/min; Qd = 500 mL/min; net ultrafiltration rate = 0), served as input parameters for 3 different models: linear, geometric, and (non-linear) mathematical. Based on the most rigorous mathematical model, the estimated convective volumes were 1,661 mL/h (Qb = 300 mL/min) and 1,911 mL/h (Qb = 400 mL/min) for Theranova 400 and 1,864 mL/h (Qb = 300 mL/min) and 1,978 mL/h (Qb = 400 mL/min) for Theranova 500. These results suggest that the unique fiber characteristics of this new class of membranes provide substantial convective volumes without the need for exogenous substitution fluid. As such, HRO membranes are a major end-stage renal disease treatment advance in the quest to enhance the removal of larger-sized uremic toxins.

Extracorporeal therapy for end-stage renal disease is now provided to more than three million patients globally. Nearly all treatments are performed with filters containing hollow fiber membranes, removing solutes and water by diffusion, convection, and ultrafiltration. In this review, we will provide a detailed quantitative analysis of the transport processes involved in different hemodialysis (HD) therapies. We will also report some technical aspects of hollow fiber membranes and filters composed of them along with the mechanisms of solute and water removal for such devices. Diffusive mass transfer will be assessed according to the three major aspects of a hollow fiber filter (blood compartment, membrane, and dialysate compartment). With regard to convective transport, the importance of internal filtration as a solute removal mechanism in high-flux HD will be highlighted, along with the critical role that blood/membrane interactions assume in filtration-based therapies.

Sex and age data are fundamental vital statistics used to characterize wildlife populations, often integral to models used to assess population responses to harvest or make other management decisions. Misidentification errors could ultimately result in poor management decisions by misrepresenting harvest or population structure. We compared field examination and genetic identification of sex of bobcats (Lynx rufus; n = 248) collected during the 2009–2010 harvest season in Oregon, USA. Furtaker-reported sex assignment and genetics analysis mismatched for 51 (20.6%) cases. In 31 (12.5%) cases, bobcats reported as females were classified as males by genetic analysis, and vice versa for the remaining 20 individuals. Quantification of errors in sex assignment allows for acknowledgment of technique and data limitations and may allow for adjustments to be considered during decision-making processes. State agencies may consider providing formal training in field identification techniques and subsampling harvested bobcats for genetic sex assignment in an effort to more accurately reflect sex ratios in the harvest. © 2014 The Wildlife Society.

Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT094.

In Oregon, USA, bobcats on either side of the Cascade Mountain Range are recognized as distinct subspecies, with Lynx rufus fasciatus west and Lynx rufus pallescens east of the Cascades. These subspecies are currently managed for harvest as separate populations primarily because of substantial differences in regional pelt values. We used genetic data to determine whether bobcats in Oregon are subdivided into genetically discernible populations that support current regional management regulations. We collected 250 tissue samples from 12 a priori sampling districts, and generated data from 15 microsatellite markers and approximately 1 kB of mtDNA sequence. Results of clustering analyses based on the microsatellite data indicated strong support for the presence of 2 genetic populations, generally corresponding to the 2 subspecies. Analysis of molecular variance (AMOVA) indicated significant structure between the east and west regions, which accounted for 1.7% of the total variation in microsatellites. AMOVA based on the mtDNA sequences indicated significant structure between regions, accounting for 12.8% of the mtDNA variation. With both microsatellite and mtDNA data, we observed a significant pattern of isolation-by-distance, whereby geographically proximate sampling districts were more genetically similar than were more distant districts. We identified 21 putative migrants, individuals with genotypes more likely to have originated from the opposite region, showing that the Cascade Mountain Range apparently is not an absolute barrier to gene flow. Given the potential for differential harvest effort by region based on differences in pelt values and bobcat densities, and the vulnerability of bobcats to harvest, our results support the current management framework. © 2013 The Wildlife Society.

Spatial heterogeneity can constrain the movement of individuals and consequently genes across a landscape, influencing demographic and genetic processes. In this study, we linked information on landscape composition, movement behavior, and genetic differentiation to gain a mechanistic understanding of how spatial heterogeneity may influence movement and gene flow of bobcats in the agricultural landscape of Iowa (USA). We analyzed movement paths of 23 animals to parameterize landscape resistance surfaces, applied least cost path analysis to generate measures of effective geographic distance between DNA collection locations of 625 bobcats, and tested the correlation between genetic distance and the different models of geographic distance. We found that bobcats showed a strong preference for forest over any other habitat type, and that incorporating information on habitat composition both along the path and in the surrounding landscape provided the best model of movement. Measures of effective geographic distance were significantly correlated with genetic distance, but not once the effects of Euclidean distance were accounted for. Thus, despite the impact of habitat composition on movement behavior, we did not detect a signature of a landscape effect in genetic structure. Our results are consistent with the issue of limiting factors: the high uniformity of forest fragmentation across southern Iowa, the primary study area, results in a landscape resistance pattern virtually indistinguishable from the isolation-by-distance pattern. The northern portion of the state, however, is predicted to pose a high level of resistance to bobcat movement, which may impede the regional genetic connectivity of populations across the Midwest.

QuickBird satellite imagery and object-based classification were used to map emergent macrophyte response in wetlands that were partially drawn down during a three-year period (2007–2010) in the Saskatchewan River Delta, Manitoba, Canada. Generalized logistic models were used to classify vegetation genera in three drawdown and three high-water (control) wetlands. User accuracy of models averaged 74 %, and was lower in partial drawdown wetlands (72 %) than in high-water wetlands (77 %). In partial drawdown wetlands, emergent macrophytes (especially Typha spp. and Carex spp.) senesced significantly after the first year of lowered water levels but senescent areas decreased over following years. Plants were not completely dead in dewatered areas and emergent stands recovered by the third year after drawdown. Open water area in the partial drawdown wetlands gradually decreased due to clonal expansion of Sparganium spp. Vegetation areas in high-water wetlands remained unchanged throughout the study period. Although partial water-level drawdowns temporarily influenced the growth of emergent macrophytes they did not expose the seed bank and did not result in substantial, prolonged changes in spatial arrangement of vegetation areas. The combination of high-resolution satellite imagery, object-based classification and logistic modeling was useful for documenting vegetation response to management in these remote, boreal wetland systems.

Purpose Dialysis is a highly quantitative therapy involving large volumes of both clinical and technical data. While automated data collection has been implemented for chronic dialysis, this has not been done for acute kidney injury patients treated with continuous renal replacement therapy (CRRT). Methods After a brief review of the fundamental aspects of electronic medical records (EMRs), a new tool designed to provide clinicians with individualized CRRT treatment data is analyzed, with emphasis on its quality assurance capabilities. Results The first platform addressing the problem of data collection and management with current CRRT machines (Sharesource system; Baxter Healthcare) is described. The system provides connectivity for the Prismaflex CRRT machine and enables both EMR connectivity and therapy analytics with 2 basic components: the connect module and the report module. Conclusions The enormous amount of data in CRRT should be collected and analyzed to enable adequate clinical decisions. Current CRRT technology presents significant limitations with consequent lack of rigorous analysis of technical data and relevant feedback. From a quality assurance perspective, these limitations preclude any systematic assessment of prescription and delivery trends that may be adversely affecting clinical outcomes. A detailed assessment of current practice limitations is provided together with several possible ways to address such limitations by a new technical tool.

High sensitivity photodetectors serve two purposes in free space optical communication: data reception and position sensing for pointing, tracking, and stabilization. Because of conflicting performance criteria, two separate detectors are traditionally utilized to perform these tasks but recent advances in the fabrication and development of large area, low noise avalanche photodiode (APD) arrays have enabled these devices to be used both as position sensitive detectors (PSD) and as communications receivers. Combining these functionalities allows for more flexibility and simplicity in optical assembly design without sacrificing the sensitivity and bandwidth performance of smaller, single element data receivers. Beyond eliminating the need to separate the return beam into two separate paths, these devices enable implementation of adaptive approaches to compensate for focal plane beam wander and breakup often seen in highly scintillated terrestrial and maritime optical links. While the Naval Research Laboratory (NRL) and Optogration Inc, have recently demonstrated the performance of single period, InAlAs/InGaAs APD arrays as combined data reception and tracking sensors, an impact ionization engineered (I2E) epilayer design achieves even lower carrier ionization ratios by incorporating multiple multiplication periods engineered to suppress lower ionization rate carriers while enhancing the higher ionization rate carriers of interest. This work presents a three period I2E concentric, five element avalanche photodiode array rated for bandwidths beyond 1GHz with measured carrier ionization ratios of 0.05-0.1 at moderate APD gains. The epilayer design of the device will be discussed along with initial device characterization and high speed performance measurements.

The potential for widespread, mobile species to exhibit genetic structure without clear geographic barriers is a topic of growing interest. Yet the patterns and mechanisms of structure—particularly over broad spatial scales—remain largely unexplored for these species. Bobcats occur across North America and possess many characteristics expected to promote gene flow. To test whether historical, topographic or ecological factors have influenced genetic differentiation in this species, we analysed 1 kb mtDNA sequence and 15 microsatellite loci from over 1700 samples collected across its range. The primary signature in both marker types involved a longitudinal cline with a sharp transition, or suture zone, occurring along the Great Plains. Thus, the data distinguished bobcats in the eastern USA from those in the western half, with no obvious physical barrier to gene flow. Demographic analyses supported a scenario of expansion from separate Pleistocene refugia, with the Great Plains representing a zone of secondary contact. Substructure within the two main lineages likely reflected founder effects, ecological factors, anthropogenic/topographic effects or a combination of these forces. Two prominent topographic features, the Mississippi River and Rocky Mountains, were not supported as significant genetic barriers. Ecological regions and environmental correlates explained a small but significant proportion of genetic variation. Overall, results implicate historical processes as the primary cause of broad-scale genetic differentiation, but contemporary forces seem to also play a role in promoting and maintaining structure. Despite the bobcat’s mobility and broad niche, large-scale landscape changes have contributed to significant and complex patterns of genetic structure.

In free space optical communication, photodetectors serve not only as communications receivers but also as position sensitive detectors (PSDs) for pointing, tracking, and stabilization. Typically, two separate detectors are utilized to perform these tasks, but recent advances in the fabrication and development of large-area, low-noise avalanche photodiode (APD) arrays have enabled these devices to be used both as PSDs and as communications receivers. This combined functionality allows for more flexibility and simplicity in optical system design without sacrificing the sensitivity and bandwidth performance of smaller, single-element data receivers. This work presents the development of APD arrays rated for bandwidths beyond 1 GHz with measured carrier ionization ratios of approximately 0.2 at moderate APD gains. We discuss the fabrication and characterization of three types of APD arrays along with their performance as high-speed photodetectors.

End-stage renal disease (ESRD) is common clinical condition for which life-sustaining therapies fortunately exist. On a global basis, more than 2 million patients now receive chronic haemodialysis (HD) for treatment of ESRD. For the vast majority of these patients, treatment is provided in a dialysis unit on a thrice-weekly basis, although there is growing interest in alternative therapies which vary with respect to location or frequency. Based on the number of patients requiring chronic HD now and in the foreseeable future, it is imperative that nephrologists understand the basic principles underlying this treatment. The factors affecting the delivery of therapy in HD can substantially be divided into two groups: (a) factors affecting the performance of the dialytic technique, which are primarily related to the characteristics of the parameters involved in the dialytic technique; and (b) factors affecting the clinical results of a given technique, which are primarily related to the interaction between the water and solute removal capacity of the technique and the kinetics of water and solutes within the human body. In this group, factors including staff compliance with the orders, patient compliance with prescribed time, and the patient’s physical condition are also important.The focus of this chapter is the technical aspects of chronic HD prescription and delivery. After a brief review of the major components of the HD system (machine and extracorporeal circuit), the principles underlying solute and water removal are reviewed. The concept of clearance is then assessed, with particular emphasis on the determinants of small solute clearance with respect both to the dialyser and the patient.

In extracorporeal renal replacement therapies, the dialyzer is not only the site at which solute removal occurs but also the extracorporeal circuit component having the largest surface area exposed to blood. Therefore, it is not surprising that interactions between blood components and the dialyzer membrane influence the dialysis procedure in several ways. Based on engineering principles, fluid flow along a surface such as membrane results in the development of a boundary layer which can influence solute removal. Furthermore, the exposure of blood to any extracorporeal artificial surface results in the activation of several pathways within the body, including those involving coagulation and complement activation. One of the byproducts of this generalized activation process is protein adsorption to the membrane surface, another phenomenon which can have a significant impact on solute removal. In this article, a detailed review of the ways in which blood-membrane interactions influence solute removal during hemodialysis and related therapies is provided. The influences of secondary membrane formation and boundary layer/concentration polarization effects on solute removal are specifically discussed. Furthermore, the importance of adsorption as a specific removal mechanism for low-molecular weight proteins by highly permeable synthetic membranes is highlighted.