Using the Seraph® 100 Microbind® Affinity blood filter under slow flow conditions through 18 G and 16 G central lines.

INTRODUCTION: The Seraph® 100 Microbind® Affinity blood filter (Seraph® 100) has been in use since 2019 for the treatment of fulminant or difficult to treat blood stream infections as an adjunct to pharmacotherapy. In 2020 the device received emergency use authorization by the US Food and Drug Administration for the treatment of critically ill COVID-19 patients with confirmed or imminent respiratory failure. Results of an international registry showed that the Seraph® 100 was operated under blood flow rates of 100-350 mL/min. As those conditions require a large bore central line, a dialysis catheter is currently considered indispensable to operate the Seraph® 100. The use of smaller catheter lumina has neither been evaluated in vitro nor in vivo. METHODS: In vitro pressure data before and after the Seraph® 100 at various blood pump rates (prepump line 16 G, postpump line 18 G) with saline and human plasma were obtained. Further, anecdotal flow and pressure data of two patients treated with the Seraph® 100 for a COVID-19 infection are reported. RESULTS: At a pump speed of 50 mL/min pre-Seraph® pressure using saline was -70 [-70 to -60] mm Hg. In comparison, using plasma pre-Seraph® pressure was lower at -120 [-120 to -105] mm Hg; p < 0.001 (t-test). The post-Seraph® pressure at 50 mL/min using saline of 120 [110-130] mm Hg was not different from plasma at 130 [120-140] mm Hg, p = 0.152 (t-test). Blood flow rates of 50 mL/min did not lead to preAP levels below -250 mm Hg in the two clinical cases. CONCLUSION: Seraph® 100 blood flow rate of 50 mL/min may be achieved using low flow vascular access, allowing to treat a blood volume 72 L in 24 h.

Determining the performance of lignin-based flocculants in improving biosludge dewaterability.

In the wastewater treatment plant of pulp and paper mills, biosludge dewatering is needed to reduce the sludge handling and disposal costs. It is usually facilitated by means of the addition of synthetic polymers. There is increasing interest in replacing synthetic polymers with biopolymers derived from low value by-products or industrial residuals to improve the environmental footprint of dewatering. In this study, lignin-based flocculants (LBF) were tested for their ability to improve the biosludge dewaterability based on Capillary Suction Time (CST) and dry cake solids achieved with a Crown Press. The results demonstrate that LBFs alone can significantly enhance dewatering with a decrease in CSTs from 72.7 ± 5.1 s (unconditioned biosludge) to 23.3 ± 0.4 s and an increase in dry cake solids after pressing from 7.1 ± 0.5% to 13.9 ± 1.3% with a relatively high dosage of 7.5% w/w. However, with dual conditioning a LBF and 0.1% w/w anionic polyacrylamide (APAM), the required dosage of LBF was reduced to 3% w/w to achieve a dry cake solids content of 13.8 ± 0.4%, the same as that achieved with Zetag8165, a commercial synthetic polymer. LBF addition lowered the particle surface charge, allowing the particles to agglomerate and enhancing for the biosludge dewaterability. The application of LBFs for sludge dewatering offers novel considerable promise for providing more sustainable approaches by optimizing the use of lignin from different extraction processes, applying various types of lignin modifications in combination with anionic polymers, and exploring different methods of disposal or utilization of the dewatered sludge.

More Drug Monitoring and Less CT Scans of the Brain: Gabapentin Overdose in Two Peritoneal Dialysis Patients.

In parallel with the decline of renal excretory function, drug dosing of many drugs becomes more challenging. Finding the right dose is even more difficult if kidney replacement therapy is instituted. This is further aggravated by the fact that even for substances with a narrow therapeutic range, drug monitoring is only rarely offered, let alone advocated. This holds also true for gabapentin, an anticonvulsant drug that is increasingly prescribed for indications such as cancer-related pain, restless legs syndrome, migraine, or uremic pruritus. The drug is excreted unchanged in urine, so plasma clearance of gabapentin is directly proportional to creatinine clearance. Hence, renal impairment reduces gabapentin excretion and increases plasma gabapentin concentrations in a linear fashion. Therefore, the elimination half-life of gabapentin is between 5 and 9 h, in patients with normal renal function but increases to 132 h in patients on dialysis. Epidemiological data from the USRDS underline this problem. About 19% of the 140,899 adult USA patients enrolled in Medicare coverage received gabapentin in 2011. Its use was associated with an increased risk of altered mental status, fall, and fracture. We report 2 patients in which overdose of gabapentin occurred. In 1 patient, severe neurological symptoms prompted an extensive diagnostic work up, while the underlying cause of the clinical presentation was a supra-therapeutic drug level of gabapentin. Consequently, symptoms subsided with the discontinuation of the drug. Indication and drug dose of gabapentin in dialysis patients should be tightly controlled, and drug monitoring used to avoid unintended overdose.

Evaluation of the ideal length of the Seldinger needle for internal jugular vein catheter placement.

Placement of central venous catheters (CVC) into the internal jugular vein represents a routine clinical intervention. The periprocedural complication rate ranges from 5 to 20% and can be reduced by ultrasound guidance, training of residents and other measures. We aimed to proof that the average Seldinger needle is too long, increasing the risk of periprocedural injury, best epitomized in the stellate ganglion injury/irritation. The first part of the study was an online market analysis to investigate the standard needle length currently offered as part of the CVC placement sets. The second part of the study involved 35 hospitalized patients (14 female; median age 74.5 years). In those the distance between the skin and the internal jugular vein as well as the diameter of the internal jugular vein was measured by ultrasound in both, supine position as well as 45° semi-sitting position. In the third part of the study 80 body donors (45 female; median age 83.0 years) preserved by the ethanol/formaldehyde method were studied. In those the distance and angle between the typical landmark for insertion of the Seldinger needle for internal jugular vein catheter placement to the stellate ganglion was measured. The median [interquartile range] Seldinger needle length was 7 [4.0-10.0] cm. In the examined patients the maximum distance between the skin and the internal jugular vein was 1.87 cm. The minimum distance was 0.46 cm and the median distance averaging supine and 45° position was 1.14 [0.94-1.31] cm. Regarding the body donors the median distance from the insertion point of the internal jugular vein to the stellate ganglion was longer in men 5.5 [4.95-6.35] cm than in women 5.2 [4.7-5.9] (p = 0.031 unpaired t-test). With 7 cm average length the Seldinger needle currently sold as part of CVC sets is long enough to physically reach the stellate ganglion, not to mention more proximal structures. A shorter needle length would be sufficient to reach the internal jugular vein even in obese patients and with a small insertion angle while minimizing the possibility to cause severe injury as structures like the pleura and the stellate ganglion could not be reached by shorter needles.

Methane production potential of pulp mill sludges: microbial community and substrate constraints.

Sludges from pulp and paper mills represent a major ecological and environmental cost, and anaerobic digestion represents a method of waste reduction and energy recovery for these mills. This study compared methane production potential and microbial communities across 11 primary- and biosludges from five pulp and paper mills using various mill processes. We measured methane production from sludges in anaerobic batch reactor experiments over 64 days. Sludges were incubated with and without added substrate to test for organic substrate limitation versus inhibition of methanogens. Initial microbial communities and changes to community composition were determined using Illumina MiSeq for metabarcoding of bacterial and archaeal 16S rRNA genes. Mean methane production potential varied greatly between sludges (0.002-79 mL CH4 g-1 TS). Among primary sludges, kraft mill sludge produced more methane than other mill types. For these other mills, biosludge produced more methane than primary sludge, which had evidence of methanogen inhibition. Microbial communities and diversity were influenced by the initial community composition, and high methane production was only seen in sludges with high diversity. A number of sludges innately produced substantial methane and may be targets for further modelling and larger scale testing of anaerobic digestion.

Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials.

OBJECTIVE: Ketamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD. METHODS: In 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis. RESULTS: Ketamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen's d = 0.47-0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not. CONCLUSION: The findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD. SIGNIFICANCE: The predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.

Solid-State Anaerobic Digestion of Mixed Organic Waste: The Synergistic Effect of Food Waste Addition on the Destruction of Paper and Cardboard.

Full-scale anaerobic digestion processes for organic solid waste are common in Europe but are generally unaffordable in Canada and the United States because of inadequate regulations to restrict cheaper forms of disposal, particularly landfill. We investigated the viability of solid-state anaerobic digestion (SS-AD) as an alternative that reduces the costs of waste pretreatment and subsequent wastewater treatment. A laboratory SS-AD digester, comprising six 10 L leach beds and an upflow anaerobic sludge blanket reactor treating the leachate, was operated continuously for 88 weeks, with a mass balance based on chemical oxygen demand (COD) of 100 ± 2% (CODout/CODin). The feed was a mixture of fibers (cardboard, boxboard, newsprint, and fine paper) with varying amounts of food waste added. The process remained stable throughout. The addition of food waste caused a synergistic effect, raising methane production from the fiber mixture from a low of 52.7 L kg-1 COD fibersadded at no food waste, to 152 L kg-1 COD fibersadded at 29% food waste, an increase of 190%. Substrate COD destruction efficiency reached 65%, and the methane yield reached 225 L kg-1 CODadded at 29% food waste on a COD basis, with a solids retention time of 42 days. This performance was similar to that of a completely stirred tank reactor digesting similar wastes, but with much lower energy input. Multiple factors likely contributed to the enhanced fiber destruction, including the action of hydrolytic enzymes derived from fresh food waste and continuous leachate recirculation between leach beds of different ages.

Transient plant production of Salmonella Typhimurium diagnostic antibodies.

Salmonella Typhimurium is one of the most important zoonotic pathogens worldwide and a major cause of economic losses in the pig production chain. The emergence of multi-drug resistant strains over the past years has led to considerations about an enhanced surveillance of bacterial food contamination. Currently, ELISA is the method of choice for high throughput identification of S. Typhimurium. The sensitivity and specificity of this assay might be improved by application of new diagnostic antibodies. We focused on plant-based expression of candidate diagnostic TM43-E10 antibodies discovered using as antigen the S. Typhimurium OmpD protein. The scFv-TM43-E10 and scFv-Fc-TM43-E10 antibody derivatives have been successfully produced in N. benthamiana using a deconstructed movement-deficient PVX vector supplemented with the γb silencing suppressor from Poa semilatent virus. The plant-made antibodies showed the same antigen-binding specificity as that of the microbial/mammalian cell-produced counterparts and could recognize the OmpD antigen in S. Typhimurium infected plant samples.

Evaluating the effect of enzymatic pretreatment on the anaerobic digestibility of pulp and paper biosludge.

Anaerobic digestion of biosludge has not yet been implemented in pulp mills due to low biogas yields. Enzymatic pretreatment of biosludge has shown improvements in biogas yields but results are varied. A key limitation of previous studies is that they fail to consider the COD contribution from the enzyme solutions. The aim of this study was to systematically investigate the potential for enzymatic pretreatment on the anaerobic digestibility of pulp mill biosludge. Out of the six enzymes tested, four enhanced the anaerobic digestibility of biosludge. At the end of the BMP, a maximum improvement of 26% in biogas yield was observed with protease from B. licheniformis. There was no correlation between enzymatic activities on standard substrates and/or on biosludge and the effect of enzymes on biogas yields. Enzymes have potential for improving biosludge anaerobic digestibility but more research on optimal conditions and potential synergies with other pretreatment is needed.

Anaerobic digestion of pulp and paper mill wastewater and sludge.

Pulp and paper mills generate large amounts of waste organic matter that may be converted to renewable energy in form of methane. The anaerobic treatment of mill wastewater is widely accepted however, usually only applied to few selected streams. Chemical oxygen demand (COD) removal rates in full-scale reactors range between 30 and 90%, and methane yields are 0.30-0.40 m(3) kg(-1) COD removed. Highest COD removal rates are achieved with condensate streams from chemical pulping (75-90%) and paper mill effluents (60-80%). Numerous laboratory and pilot-scale studies have shown that, contrary to common perception, most other mill effluents are also to some extent anaerobically treatable. Even for difficult-to-digest streams such as bleaching effluents COD removal rates range between 15 and 90%, depending on the extent of dilution prior to anaerobic treatment, and the applied experimental setting. Co-digestion of different streams containing diverse substrate can level out and diminish toxicity, and may lead to a more robust microbial community. Furthermore, the microbial population has the ability to become acclimated and adapted to adverse conditions. Stress situations such as toxic shock loads or temporary organic overloading may be tolerated by an adapted community, whereas they could lead to process disturbance with an un-adapted community. Therefore, anaerobic treatment of wastewater containing elevated levels of inhibitors or toxicants should be initiated by an acclimation/adaptation period that can last between a few weeks and several months. In order to gain more insight into the underlying processes of microbial acclimation/adaptation and co-digestion, future research should focus on the relationship between wastewater composition, reactor operation and microbial community dynamics. The potential for engineering and managing the microbial resource is still largely untapped. Unlike in wastewater treatment, anaerobic digestion of mill biosludge (waste activated sludge) and primary sludge is still in its infancy. Current research is mainly focused on developing efficient pretreatment methods that enable fast hydrolysis of complex organic matter, shorter sludge residence times and as a consequence, smaller sludge digesters. Previous experimental studies indicate that the anaerobic digestibility of non-pretreated biosludge from pulp and paper mills varies widely, with volatile solids (VS) removal rates of 21-55% and specific methane yields ranging between 40 and 200 mL g(-1) VS fed. Pretreatment can increase the digestibility to some extent, however in almost all reported cases, the specific methane yield of pretreated biosludge did not exceed 200 mL g(-1) VS fed. Increases in specific methane yield mostly range between 0 and 90% compared to non-pretreated biosludge, whereas larger improvements were usually achieved with more difficult-to-digest biosludge. Thermal treatment and microwave treatment are two of the more effective methods. The heat required for the elevated temperatures applied in both methods may be provided from surplus heat that is often available at pulp and paper mills. Given the large variability in specific methane yield of non-pretreated biosludge, future research should focus on the links between anaerobic digestibility and sludge properties. Research should also involve mill-derived primary sludge. Although biosludge has been the main target in previous studies, primary sludge often constitutes the bulk of mill-generated sludge, and co-digestion of a mixture between both types of sludge may become practical. The few laboratory studies that have included mill primary sludge indicate that, similar to biosludge, the digestibility can range widely. Long-term studies should be conducted to explore the potential of microbial adaptation to lignocellulosic material which can constitute more than half of the organic matter in pulp and paper mill sludge.

Oligopeptide m13 phage display in pathogen research.

Phage display has become an established, widely used method for selection of peptides, antibodies or alternative scaffolds. The use of phage display for the selection of antigens from genomic or cDNA libraries of pathogens which is an alternative to the classical way of identifying immunogenic proteins is not well-known. In recent years several new applications for oligopeptide phage display in disease related fields have been developed which has led to the identification of various new antigens. These novel identified immunogenic proteins provide new insights into host pathogen interactions and can be used for the development of new diagnostic tests and vaccines. In this review we focus on the M13 oligopeptide phage display system for pathogen research but will also give examples for lambda phage display and for applications in other disease related fields. In addition, a detailed technical work flow for the identification of immunogenic oligopeptides using the pHORF system is given. The described identification of immunogenic proteins of pathogens using oligopeptide phage display can be linked to antibody phage display resulting in a vaccine pipeline.

Atmospheric deposition of current use pesticides in the Arctic: snow core records from the Devon Island Ice Cap, Nunavut, Canada.

Current use pesticides (CUPs) have been detected in the Arctic, even though there are no direct sources and their long range atmospheric transport potential is generally lower than that of legacy pesticides. Data on the deposition of CUPs in the Arctic are required to assess the impact of their global usage and emission. In this study, selected CUPs were measured in the layers of a snow pit sampled on the Devon Ice Cap, Nunavut, Canada. The oldest sampled layers correspond to deposition from the early 1990s. Dacthal and endosulfan sulfate were most frequently detected, with peak deposition fluxes of 1.0 and 0.4 pg cm(-2) per year. While endosulfan sulfate was more abundant than its parent compounds in most years, endosulfan (sum of α and ß isomers) was predominant in 2003 and 2006, which together with air mass backward trajectories suggests a possible origin from ongoing use in Eurasia. The interannual variation in CUP deposition fluxes could not be explained with annual variations in the extent of air mass origin over agricultural lands, suggesting that other factors, such as the interannual variation in pesticide use, play a role in affecting the long range transport of CUPs to the Arctic. The very high variability in the concentrations of CUPs in the horizontal layers of Arctic ice caps is most plausibly explained by the highly episodic nature of long range atmospheric transport and deposition. While this strong influence of rare events limits the suitability of ice caps as reliable records of historical trends in Arctic contaminant deposition with annual resolution, the presence of concentration peaks in the ice record is proof of the possibility of such transport and deposition.

Identification of a new epitope for HIV-neutralizing antibodies in the gp41 membrane proximal external region by an Env-tailored phage display library.

HIV controllers are a valuable source for the identification of HIV-neutralizing antibodies, as chronic infection over decades allows extensive affinity maturation of antibodies for improved Ag recognition. We analyzed a small cohort of elite controllers (ECs) for HIV-neutralizing antibodies using a panel of standardized HIV-1 pseudovirions on TZM-bl cells. An HIV-1 Env-tailored phage display library was generated to select epitopes targeted by neutralizing antibodies in the EC26 plasma sample showing the broadest neutralizing activity. Selected Env fragments were mostly allocated to the membrane proximal external region of gp41. After preabsorbing the EC26 plasma with the selected phage EC26-2A4, we achieved 50% depletion of its neutralizing activity. Furthermore, antibodies affinity-purified with the EC26-2A4 epitope from EC26 plasma showed neutralizing activity, proving that the selected phage indeed contains an epitope targeted by neutralizing plasma antibodies. Epitope fine mapping of the purified plasma antibodies on peptide arrays identified a new epitope overlapping, but clearly distinct, from the prominent 2F5 epitope. Of note, the purified antibodies did not show autoreactivity with cardiolipin, whereas low reactivity with phosphatidylserine comparable to mAb 2F5 was observed. Thus, this new epitope represents a promising candidate for further analysis in view of HIV vaccine development.

Exploring the role of shelf sediments in the Arctic Ocean in determining the Arctic contamination potential of neutral organic contaminants.

The main objective of this study was to model the contribution of shelf sediments in the Arctic Ocean to the total mass of neutral organic contaminants accumulated in the Arctic environment using a standardized emission scenario for sets of hypothetical chemicals and realistic emission estimates (1930-2100) for polychlorinated biphenyl congener 153 (PCB-153). Shelf sediments in the Arctic Ocean are shown to be important reservoirs for neutral organic chemicals across a wide range of partitioning properties, increasing the total mass in the surface compartments of the Arctic environment by up to 3.5-fold compared to simulations excluding this compartment. The relative change in total mass for hydrophobic organic chemicals with log air-water partition coefficients ≥0 was greater than for chemicals with properties similar to typical POPs. The long-term simulation of PCB-153 generated modeled concentrations in shelf sediments in reasonable agreement with available monitoring data and illustrate that the relative importance of shelf sediments in the Arctic Ocean for influencing surface ocean concentrations (and therefore exposure via the pelagic food web) is most pronounced once primary emissions are exhausted and secondary sources dominate. Additional monitoring and modeling work to better characterize the role of shelf sediments for contaminant fate is recommended.

Production of single chain fragment variable (scFv) antibodies in Escherichia coli using the LEX™ bioreactor.

For proteome research, antibodies against a growing number of antigens must be generated and characterized. The high throughput generation of antibody fragments, using in vitro selection, requires bacterial expression of antibody fragments. This created a need to establish an expression method to improve the parallel production of many antibody fragments. In this study, we describe the development of a high throughput bacterial production method for single chain fragment variables (scFvs) using shaking flasks or the LEX™ bioreactor. We compared the influence of a set of production parameters on Escherichia coli production of four different scFv. The results led to an optimized protocol for the parallel production of multiple antibody fragments.