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Background While convalescent plasma (CP) may benefit patients with COVID‐19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG‐specific anti‐SARS‐CoV‐2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. Study design and methods Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti‐SARS‐CoV‐2 antibody titers against the receptor‐binding domain responsible for viral entry. Symptom onset was obtained by chart review. Results Increased IgA anti‐SARS‐CoV‐2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID‐19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. Conclusions IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID‐19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.

The near-bed section of submarine gravity flows travels at the highest and most destructive speeds making direct measurements of this region of the flow difficult. Here results are presented from “boulder-like” Benthic Event Detectors (BEDs) that measured their own rotation, depth and temperature while carried within the near-bed region of gravity flows. BEDs were deployed in Monterey Canyon from 200 to 500 m water depth for 18 months (2016–2017) during the Coordinated Canyon Experiment. BEDs moved in 10 out of 14 gravity flows that transited the upper canyon. BEDs moved within the body of the flow because the initial velocities of the BEDs were 66 ± 16% (1 SD) of the flow transit velocities. BEDs rotated freely during most of their first moves and gained depth faster than in later moves, when their motion was more random and wobblier. The differences in BED motions between first and later moves suggest BEDs moved at different depths within the flow. The inferred near-bed flow structure is strongly stratified with a fast, less-dense layer moving above a slower and denser layer. Coherent changes between pressure and acceleration indicate that BEDs rode a crescent shaped bedform (CSB) morphology that persisted throughout flow events. The variability in BED speeds while riding the CSB morphology indicates a fluid-like nature of the near-bed layer. BED motions ended after being caught in the trough of a CSB. Based on recorded temperature decay rates after flow events, the thickness of redeposited sediment is 2–3 m.

Background Delayed hemolytic transfusion reactions (DHTRs) are serious complications of RBC transfusion that can occur in previously alloimmunized patients. Patients who require episodic transfusions during heightened inflammatory states, such as patients with sickle cell disease (SCD), are particularly prone to alloimmunization and developing DHTRs with hyperhemolysis. While efforts to mitigate these hemolytic episodes via immunosuppressive drugs can be employed, the relative efficacy of various treatment options remains incompletely understood. Case reports In this study, we explored five patients with SCD and multiple RBC alloantibodies who received various forms of immunosuppressive therapy in an attempt to prevent or treat severe DHTRs. Results The clinical course for these five patients provides insight into the difficulty of effectively treating and preventing DHTRs in patients with SCD with currently available immunosuppressive therapies. Conclusion Based on our experience, and the current literature, it is difficult to predict the potential impact of various immunosuppressive therapies when seeking to prevent or treat DHTRs. Future mechanistic studies are needed to identify the optimal treatment options for DHTRs in the presence or absence of distinct alloantibodies in patients with SCD.

Background Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID‐19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID‐19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID‐19‐associated hyperviscosity. Study Design and Methods Six critically ill COVID‐19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4‐1.8 cP) underwent daily TPE for 2‐3 treatments. Results TPE decreased plasma viscosity in all six patients (Pre‐TPE median 3.75 cP, range 2.6‐4.2 cP; Post‐TPE median 1.6 cP, range 1.5‐1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre‐TPE median 739 mg/dL, range 601‐1188 mg/dL; Post‐TPE median 359 mg/dL, range 235‐461 mg/dL); D‐dimer levels in all six patients (Pre‐TPE median 5921 ng/mL, range 1134‐60 000 ng/mL; Post‐TPE median 4893 ng/mL, range 620‐7518 ng/mL); and CRP levels in five of six patients (Pre‐TPE median 292 mg/L, range 136‐329 mg/L; Post‐TPE median 84 mg/L, range 31‐211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. Conclusions This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID‐19‐associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID‐19.

Background Fever accompanying vaso-occlusive crisis is a common presentation in patients with sickle cell disease (SCD) and carries a broad differential diagnosis. Here, we report a case of transfusion-transmitted malaria in a patient with SCD presenting with acute vaso-occlusive crisis and rapidly decompensating to multisystem organ failure (MSOF). Case report An 18-year-old African American male with SCD was admitted after multiple days of fever and severe generalized body pain. He received monthly blood transfusions as stroke prophylaxis. A source of infection was not readily identified, but treatment was initiated with continuous intravenous fluids and empiric antibiotics. The patient developed acute renal failure, acute hypoxic respiratory failure, and shock. He underwent red blood cell (RBC) exchange transfusion followed by therapeutic plasma exchange and continuous veno-venous hemodialysis. A manual peripheral blood smear revealed intraerythrocytic inclusions suggestive of Plasmodium, and molecular studies confirmed Plasmodium falciparum infection. Intravenous artesunate was given daily for 1 week. A look-back investigation involving two hospitals, multiple blood suppliers, and state and federal public health departments identified the source of malaria as a unit of RBCs transfused 2 weeks prior to admission. Conclusions Clinical suspicion for transfusion-related adverse events, including hemolytic transfusion reactions and transfusion-transmitted infections, should be high in typically and atypically immunocompromised patient populations (like SCD), especially those on chronic transfusion protocols. Manual blood smear review aids in the evaluation of patients with SCD presenting with severe vaso-occlusive crisis and MSOF and can alert clinicians to the need for initiating aggressive therapy like RBC exchange and artesunate therapy.

To evaluate the ethanol production performance of waxy sorghum hybrids and the effects of location and harvest year on ethanol yield, samples of four waxy sorghum hybrids collected from two Nebraska locations (Mead and Lincoln) in both 2009 and 2010 were tested for ethanol production in a dry-grind process. No significant difference (P = 0.216) in starch contents was observed among the four hybrids, but starch contents of the hybrids were significantly affected by growth location (P = 0.0001) and harvest year (P = 0.0258). Location, hybrid, and harvest year all had significant effects on ethanol fermentation efficiency in the dry-grind process. Lincoln sorghum samples showed higher (P = 0.022) ethanol fermentation efficiency (90.4%) than did Mead sorghum samples (90.0%). Sorghums harvested in 2010 had higher (P < 0.001) ethanol fermentation efficiency (91.1%) than those harvested in 2009 (89.3%). The 2009 sorghum flours had more amylose-lipid complexes than the 2010 samples did, and amylose-lipid...

The Lucia Chica channel system is an avulsion belt with four adjacent channels that progressively avulsed to the north-east from a single, upslope feeder channel. Avulsion occurred from underfilled channels, leaving open channels that were reactivated by flows stripped from younger, adjacent channels. Differences in relief (height from channel thalweg to levee crest), sinuosity and levee stratigraphy between adjacent channels correspond to relative channel age, and indicate a change in channel morphology and architecture with time. Potential triggers for the change over time include differences in gradient, flow behaviour and characteristics, and channel evolution. Gradient does not appear to be a major control on channel formation and avulsion because adjacent channels formed on the same gradient. Based on available ultra-high-resolution remote imaging obtained with an Autonomous Underwater Vehicle, differences in adjacent channel morphology are interpreted to be primarily a result of differences in channel maturity. The interpreted sequence of channel maturity involves erosional channel inception through scouring and incipient channels (defined by linear trains of scours) prior to development of continuous thalwegs. Channel narrowing, formation and growth of levees, increasing channel relief and development of sinuosity occurred as channels evolved. The evolutionary sequence interpreted from the high-resolution Lucia Chica dataset provides a unique perspective on intrinsic controls of architecture for single channel elements. In addition to helping bridge the gap between outcrop and industry-standard reflection-seismic data resolutions and scopes, interpretations in this study also expose potential problems with hierarchical classifications in three-dimensional imaging of distributary systems, and provide potentially important analogues for evolutionary morphologies not resolved in other deep-water channel systems.

Neuronal nicotinic acetylcholine receptor (nAChR) agonists active at the alpha-7 (α-7) receptor subtype are potential therapeutics for cognitive deficits in schizophrenia, Alzheimer's disease, and other mental disorders. SSR180711, an α-7 selective partial agonist, has been shown to improve preclinical cognition. A novel positron emission tomography (PET) radioligand, ¹¹C-Chiba1001, is a close analog of SSR180711. We labeled Chiba-1001 with tritium in order to evaluate its utility as a preclinical radioligand tool. In vitro, the binding affinity of [³H]Chiba-1001 at the α-7 receptor was low (K(d) = 120-180 nM) in both HEK239 cell membranes expressing human α-7 receptor and in native rat hippocampus membranes. The α-7 selective ligands AZD0328, ARR17779, and MLA did not inhibit [³H]Chiba-1001 binding (K(i) > 10,000 nM). In rat hippocampal membranes, Chiba-1001 and SSR180711 inhibited [³H]Chiba-1001 binding (K(i) = 220 and 230 nM, respectively), consistent with the literature reports. The in vivo binding profile of the radioligand was examined in normal rat, wild type mouse, and α-7 knockout mouse brain. We found that [³H]Chiba-1001 lacks adequate and specific brain regional uptake in rat and mouse brain. No significant inhibition of the radioligand binding was obtained following pretreatment of the animal with AZ11637326, AZD0328, or MLA. Our results indicate that [³H]Chiba-1001 has low affinity for α-7 nAChRs in vitro and poor α-7 regional and pharmacological selectivity in the rodent brain.

Positron emission tomography (PET) antagonist ligands such as [(11)C]-raclopride are commonly used to study dopamine D2 receptor (D2) binding of antipsychotics. It has been suggested that agonist radioligands bind preferentially to the high-affinity state of D2 receptor and may provide a more relevant means of assessing D2 occupancy. The main objective of this study was to determine if D2 receptor occupancy (RO) could be differentiated with agonist and antagonist radioligands in vivo. Agonist radioligands [(3)H]-MNPA and [(3)H]-(+)-PHNO were synthesized and compared to antagonist [(3)H]-raclopride in the in vitro binding and in vivo occupancy studies. In vivo, unanesthetized rats were pretreated with quinpirole (full agonist), aripiprazole (partial agonist), or haloperidol (antagonist) prior to administration of the agonist or antagonist radioligand. All three pretreatment compounds showed equivalent dose-dependent D2 receptor occupancy in the rat striatum with each radioligand. The in vivo receptor occupancy results suggested that the binding of quinpirole, aripiprazole, and haloperidol to the high or low affinity state of the D2 receptor could not be differentiated using radiolabeled agonists or antagonists, presumably due to a predominance of high affinity states of the D2 receptor in vivo. This hypothesis was supported in part by the in vitro binding results. Our in vitro results show that [(3)H]-MNPA binds to D2S transfected CHO cell membranes at a single high affinity site. Displacement of [(3)H]-(+)-PHNO binding by quinpirole and elimination of most [(3)H]-(+)-PHNO binding by the guanine nucleotide GppNHp in striatal membranes suggest that the majority of D2 in striatal tissue is G-protein coupled. Together, these findings suggest that D2 agonist radioligands produce in vivo receptor occupancy comparable to [(3)H]-raclopride.

Deuterium and tritium labeling of carbohydrates and glycoconjugates has very wide applicability in the biochemical and biophysical fields. Carbohydrates function as receptors for a variety of hormones and play critical roles in cell recognition and differentiation. Deuterium labeled compounds are frequently utilized in the conformational analysis of oligosaccharides, as well as other glycoconjugates, to alleviate resonance overcrowding in 1 H NMR spectroscopy. Raney® nickel catalyzed 1 H→ 2 H ( 3 H) isotopic exchange is conducted under mild conditions using Ni catalysts, singular metal catalysts, or multi-phasic catalysts were ineffective or caused substrate decomposition. We have explored new digestion conditions for the preparation of highly active Raney nickel catalysts and have developed new protocols for the stereospecific incorporation of 2 H ( 3 H) in a wide variety of glycoconjugates using our facile C-H→C-D (C-T) exchange reactions. The regioselectivity of isotope incorporation is controlled by the judicious use of modified catalysts, co-solvents, and the isotopic source. formula. chem. either ultrasonic or microwave irradiation. The initial and overall rates of isotopic exchange are modulated by the presence of transition metals. Only the Raney-nickel® type alloys afforded stereospecific C- 1 H → C- 2 H isotopic exchange in an ultrasonic or microwave field. Typical supported precious metal catalysts, supported Reactions are easily performed using either a dedicated ultrasound probe, a slightly modified commercial microwave oven, or a dedicated commercial microwave synthesis unit. Research over the past several years is the subject of this attenuated review.

Objective To evaluate the safety and efficacy of etanercept in the treatment of adult patients with Still's disease. Methods Twelve adult patients who met criteria for Still's disease and had active arthritis were enrolled in a 6-month open-label trial of etanercept given in biweekly doses of 25 mg. The mean disease duration at study entry was 10.7 years. All patients had been treated unsuccessfully with other disease-modifying antirheumatic drugs. Efficacy was evaluated according to American College of Rheumatology (ACR) improvement criteria, and adverse events were recorded. Results Ten patients successfully completed the study; 2 withdrew due to disease flare. In 4 patients, the dosage of etanercept was increased from 25 mg biweekly to 25 mg 3 times per week. Seven patients met ACR 20% response criteria. Of these 7 responders, 4 met ACR 50% response criteria and 2 met ACR 70% response criteria. Among the 3 patients with systemic features of Still's disease (fever and rash), improvement in these features was seen in 1; the arthritis did not improve in any of these 3 patients. Except in the 2 patients who withdrew due to disease flare (rash, fever, and arthritis), no other significant adverse events occurred. Conclusion In this initial study of etanercept therapy for Still's disease in the adult, this treatment resulted in improvement in the arthritis and was well tolerated. Additional trials should be performed to elucidate the effects of tumor necrosis factor inhibitors in Still's disease.

Objective To examine the safety and pharmacokinetics of and clinical response to leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to patients with active rheumatoid arthritis (RA) who have been receiving long-term methotrexate therapy. Methods This was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17 ± 4 mg/week (mean ± SD) for ≥6 months were given leflunomide, 10–20 mg/day. Patients were assessed for adverse effects, pharmacokinetic measurements of leflunomide and methotrexate, and clinical response by American College of Rheumatology (ACR) 20% response criteria. Results Twenty-three patients completed 1 year of treatment. No significant pharmacokinetic interactions between leflunomide and methotrexate were noted. This combination therapy was generally well tolerated clinically, with the exception of elevations of liver enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals were voluntary, 3 were due to persistent elevation of plasma transaminase levels, and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20% response criteria. Two met ACR criteria for remission after 1 year. Conclusion The combination of methotrexate and leflunomide has therapeutic potential in RA.

Objective. To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). Methods. Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. Results. There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. Conclusion. CAMPATH-1H is a lymphocytedepleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Objective. To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. Methods. In this randomized, placebo–controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 μg/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. Results. A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. Conclusion. A renal–protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

Objective Pericytes are critical cellular components of the microvasculature that play a major role in vascular development and pathologies, yet their study has been hindered by lack of a standardized method for their isolation and growth. Here we report a method for culturing human pericytes from a readily available tissue source, placenta, and provide a thorough characterization of resultant cell populations.

Objective. To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA). Methods. Eighty-four—month open prospective trial at a single academic rheumatology center. Results. Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity. Conclusion. The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.

Alterations in renal eicosanoid levels have been postulated as a factor in cyclosporin A (CSA) nephrotoxicity. The effects of CSA on renal eicosanoid excretion in rheumatoid arthritis were studied over a 24-week period, during which treatment with nonsteroidal antiinflammatory drugs was discontinued. The initial dosage of CSA was 4 mg/kg/day; at week 24, the mean dosage of CSA was 3.9 mg/kg/day. At week 24, the mean (+/- SD) serum creatinine level (1.04 +/- 0.24 mg/dl) was 32% above the baseline value; renal blood flow had decreased by 21% (P less than 0.03) and the glomerular filtration rate had decreased by 16%. There was a significant increase (P less than 0.03) in the 2,3-dinor thromboxane B2 level at week 2, but there was no significant change in the levels of the other eicosanoids. This study demonstrates that after CSA treatment, there is a selective increase in a thromboxane metabolite that parallels an increase in renal vascular resistance, even in the absence of nonsteroidal antiinflammatory drugs, and with unimpaired formation of other vasodilator eicosanoids.

Purpose: Development of a photon detection system designed for online range verification of laser-accelerated proton beams via prompt-gamma imaging of nuclear reactions. Methods: We develop a Compton camera for the position-sensitive detection of prompt photons emitted from nuclear reactions between the proton beam and biological samples. The detector is designed to be capable to reconstruct the photon source origin not only from the Compton scattering kinematics of the primary photon, but also to allow for tracking of the Compton-scattered electrons. Results: Simulation studies resulted in the design of the Compton camera based on a LaBr3(Ce) scintillation crystal acting as absorber, preceded by a stacked array of 6 double-sided silicon strip detectors as scatterers. From the design simulations, an angular resolution of ≤ 2° and an image reconstruction efficiency of 10−3 −10−5 (at 2–6 MeV) can be expected. The LaBr3 crystal has been characterized with calibration sources, resulting in a time resolution of 273 ps (FWHM) and an energy resolution of about 3.8% (FWHM). Using a collimated (1 mm diameter) 137Cs calibration source, the light distribution was measured for each of 64 pixels (6×6 mm2). Data were also taken with 0.5 mm collimation and 0.5 mm step size to generate a reference library of light distributions that allows for reconstructing the interaction position of the initial photon using a k-nearest neighbor (k-NN) algorithm developed by the Delft group. Conclusion: The Compton-camera approach for prompt-gamma detection offers promising perspectives for ion beam range verification. A Compton camera prototype is presently being developed and characterized in Garching. Furthermore, an arrangement of, e.g., 4 camera modules could even be used in a ‘gamma-PET’ mode to detect delayed annihilation radiation from positron emitters in the irradiation interrupts (with improved performance in the presence of an additional third (prompt) photon (as in 10C and 14O). This work was supported by the DFG Cluster of Excellence MAP (Munich-Centre for Advanced Photonics)

The management of the rheumatoid patient involves the considered use of pharmacologic agents as therapies to induce symptomatic relief and to reduce disease activity. Aspirin and nonsteroidal antiinflammatory drugs are used initially to lessen the degree of pain and swelling associated with the inflammatory disease process. The aggressive institution of second-line therapy, previously known as disease-modifying antiinflammatory rheumatic drugs, is advocated to modify the disease course itself. These second-line treatments include antimalarials, gold salts, methotrexate, d-penicillamine, and azathioprine. Randomized placebo controlled trials have demonstrated the efficacy of these compounds in this illness. Improvement in standard parameters of disease activity (number of painful and swollen joints, duration of morning stiffness, erythrocyte sedimentation rate) can be related to the therapeutic value of second-line agents. Whether they modify radiographic progression is under rigorous study. Newer therapies under research investigation include sulfasalazine, cyclosporin A, and combination therapy.

Aus Benzonorbornadienol (Ia) entsteht ein Mesylat (Ib), die Hydrierung fuhrt zu (IIa), (IIb).