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Highlights • Our study investigated the safety and tolerability of palliative radiation therapy (RT) with concurrent Dabrafenib and Trametinib in patients with metastatic BRAF mutant melanoma, and we found that none of the patients enrolled in this study experienced grade 3 or 4 RT related toxicities. • We suggest that Dabrafenib and Trametinib may be safely used concurrently with common palliative RT doses to extracranial sites., Background Concurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma. Materials and methods Patients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT. Results Between June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation. Conclusions The lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.

Highlights • Targeted anti-cytokine agents, tocilizumab and anakinra, used to treat COVID-19 related cytokine storm yield mixed results. • Early identification of cytokine storm using laboratory abnormalities can detect patients prior to mechanical ventilation. • Early identification and treatment of cytokine storm with anakinra and corticosteroids led to improved outcomes compared to initiating tocilizumab shortly after mechanical ventilation. • Early identification and treatment of cytokine storm may be more important than which anti-inflammatory treatment is chosen. • Our results provide additional support for the use of corticosteroid treatment of COVID19 cytokine storm., Objective To examine outcomes among patients who were treated with the targeted anti-cytokine agents, anakinra or tocilizumab, for COVID-19 -related cytokine storm (COVID19-CS). Methods We conducted a retrospective cohort study of all SARS-coV2-RNA-positive patients treated with tocilizumab or anakinra in Kaiser Permanente Southern California. Local experts developed and implemented criteria to define COVID19-CS. All variables were extracted from the electronic health record. Results At tocilizumab initiation (n = 52), 50 (96.2%) were intubated, and only 7 (13.5%) received concomitant corticosteroids. At anakinra initiation (n = 41), 23 (56.1%) were intubated, and all received concomitant corticosteroids. Fewer anakinra-treated patients died (n = 9, 22%) and more were extubated/never intubated (n = 26, 63.4%) compared to tocilizumab-treated patients (n = 24, 46.2% dead, n = 22, 42.3% extubated/never intubated). Patients who died had more severe sepsis and respiratory failure and met COVID-CS laboratory criteria longer (median = 3 days) compared to those extubated/never intubated (median = 1 day). After accounting for differences in disease severity at treatment initiation, this apparent superiority of anakinra over tocilizumab was no longer statistically significant (propensity score-adjusted hazards ratio 0.46, 95% confidence interval 0.18–1.20). Conclusions Prompt identification and treatment of COVID19-CS prior to intubation may be more important than the specific type of anti-inflammatory treatment. Randomized controlled trials of targeted anti-cytokine treatments and corticosteroids should report duration of cytokine storm in addition to clinical severity at randomization.

In this paper, we focus on students’ symbolizing activity and mathematization relating to linear combination and span in the context of a task sequence designed with digital tools. Considering tools and functions of a digital environment (specifically of GeoGebra) with design heuristics of Realistic Mathematics Education, we introduce four tasks (in R2 and R3) and results of pilot studies. Data sources come from six individual task-based interviews with two linear algebra students. We analyzed these with a lens of mathematization, with a particular focus on tool use. We found students’ use of sliders supported their reasoning about individual linear combinations; the trace function and slider animation supported their intuition for all possible linear combinations of vectors. After shifting from two to three dimensions, students symbolized all possible linear combinations with a parametric vector equation and reasoned about how this could represent particular points on the corresponding lines or planes.

Microbially catalyzed corrosion of metals is a substantial economic concern. Aerobic microbes primarily enhance Fe0 oxidation through indirect mechanisms and their impact appears to be limited compared to anaerobic microbes. Several anaerobic mechanisms are known to accelerate Fe0 oxidation. Microbes can consume H2 abiotically generated from the oxidation of Fe0. Microbial H2 removal makes continued Fe0 oxidation more thermodynamically favorable. Extracellular hydrogenases further accelerate Fe0 oxidation. Organic electron shuttles such as flavins, phenazines, and possibly humic substances may replace H2 as the electron carrier between Fe0 and cells. Direct Fe0-to-microbe electron transfer is also possible. Which of these anaerobic mechanisms predominates in model pure culture isolates is typically poorly documented because of a lack of functional genetic studies. Microbial mechanisms for Fe0 oxidation may also apply to some other metals. An ultimate goal of microbial metal corrosion research is to develop molecular tools to diagnose the occurrence, mechanisms, and rates of metal corrosion to guide the implementation of the most effective mitigation strategies. A systems biology approach that includes innovative isolation and characterization methods, as well as functional genomic investigations, will be required in order to identify the diagnostic features to be gleaned from meta-omic analysis of corroding materials. A better understanding of microbial metal corrosion mechanisms is expected to lead to new corrosion mitigation strategies. The understanding of the corrosion microbiome is clearly in its infancy, but interdisciplinary electrochemical, microbiological, and molecular tools are available to make rapid progress in this field.

Many wastewater treatment plants in the world do not remove reactive nitrogen from wastewater prior to release into the environment. Excess reactive nitrogen not only has a negative impact on human health, it also contributes to air and water pollution, and can cause complex ecosystems to collapse. In order to avoid the deleterious effects of excess reactive nitrogen in the environment, tertiary wastewater treatment practices that ensure the removal of reactive nitrogen species need to be implemented. Many wastewater treatment facilities rely on chemicals for tertiary treatment, however, biological nitrogen removal practices are much more environmentally friendly and cost effective. Therefore, interest in biological treatment is increasing. Biological approaches take advantage of specific groups of microorganisms involved in nitrogen cycling to remove reactive nitrogen from reactor systems by converting ammonia to nitrogen gas. Organisms known to be involved in this process include autotrophic ammonia-oxidizing bacteria, heterotrophic ammonia-oxidizing bacteria, ammonia-oxidizing archaea, anaerobic ammonia oxidizing bacteria (anammox), nitrite-oxidizing bacteria, complete ammonia oxidizers, and dissimilatory nitrate reducing microorganisms. For example, in nitrifying-denitrifying reactors, ammonia- and nitrite-oxidizing bacteria convert ammonia to nitrate and then denitrifying microorganisms reduce nitrate to nonreactive dinitrogen gas. Other nitrogen removal systems (anammox reactors) take advantage of anammox bacteria to convert ammonia to nitrogen gas using NO as an oxidant. A number of promising new biological treatment technologies are emerging and it is hoped that as the cost of these practices goes down more wastewater treatment plants will start to include a tertiary treatment step.

Methanogens are a unique group of strictly anaerobic archaea that are more metabolically diverse than previously thought. Traditionally, it was thought that methanogens could only generate methane by coupling the oxidation of products formed by fermentative bacteria with the reduction of CO2. However, it has recently been observed that many methanogens can also use electrons extruded from metal-respiring bacteria, biocathodes, or insoluble electron shuttles as energy sources. Methanogens are found in both human-made and natural environments and are responsible for the production of ∼71% of the global atmospheric methane. Their habitats range from the human digestive tract to hydrothermal vents. Although biologically produced methane can negatively impact the environment if released into the atmosphere, when captured, it can serve as a potent fuel source. The anaerobic digestion of wastes such as animal manure, human sewage, or food waste produces biogas which is composed of ∼60% methane. Methane from biogas can be cleaned to yield purified methane (biomethane) that can be readily incorporated into natural gas pipelines making it a promising renewable energy source. Conventional anaerobic digestion is limited by long retention times, low organics removal efficiencies, and low biogas production rates. Therefore, many studies are being conducted to improve the anaerobic digestion process. Researchers have found that addition of conductive materials and/or electrically active cathodes to anaerobic digesters can stimulate the digestion process and increase methane content of biogas. It is hoped that optimization of anaerobic digesters will make biogas more readily accessible to the average person.

Caffeine is widely consumed and has widespread physiological effects. We review evidence that the acute alerting and associated psychomotor performance effects of caffeine experienced by frequent caffeine consumers represent withdrawal reversal rather than a net benefit for functioning, and that avoidance of withdrawal is an important motive for caffeine consumption. On the other hand, tolerance develops to the anxiogenic effect of caffeine even in susceptible individuals, and while caffeine raises blood pressure, tea and coffee consumption are not associated with increased risk of vascular disease. Indeed, consumption of these drinks appears to reduce risk of cognitive decline in older age, possibly because of beneficial actions of other compounds present in tea and coffee, and the sensitization of the neuroprotective action of adenosine resulting from caffeine intake. The example of caffeine demonstrates the challenge of finding ingredients for foods or drinks that could be used effectively to acutely enhance mood, alertness and/or cognitive function.

Publisher Summary This chapter elaborates the role of digital forensic examiners throughout these phases of e-discovery, particularly in large-scale cases involving disputes between organizations. It addresses the legal framework for e-discovery as well as unique forensic questions that arise around case management, identification and collection of ESI, and culling and production of data. This chapter also describes common pitfalls in the complex, high-stakes field of e-discovery, with the goal of helping both new and experienced forensic examiners safely navigate this potential minefield. Electronic discovery or “e-discovery” is the exchange of data between parties in civil or criminal litigation. The process is largely controlled by attorneys who determine what data should be produced based on relevance or withheld based on claims of privilege. Forensic examiners play crucial roles as technical advisors, hands-on collectors, and analysts. The e-discovery field is complex, and the technical and logistical challenges routinely found in large e-discovery projects can test even the most experienced digital forensic examiner. The high stakes nature of most e-discovery projects leave little room for error at any stage of the process—from initial identification and preservation of evidence sources to the final production and presentation of results—and to be successful an examiner must understand and be familiar with their role at each stage. The size and scope of e-discovery projects require effective case management, and essential to effective case management is establishing a strategic plan at the outset, and diligently implementing constructive and documented quality assurance measures throughout each step of the process.

The continuing need for sensitive and specific analytical methods for the detection and quantitation of cocaine is reflected by the number of publications that continue to be devoted to this topic. This review focuses on immunoassay-screening methods as well as chromatographic methods that were reported over approximately the last two decades for the determination of cocaine analytes in various biological specimens. Illicit cocaine analysis is addressed briefly in the introduction. The reviewed methods are summarized in tables to provide additional information on each assay. Solid-phase extraction was the most frequently applied technique to isolate cocaine analytes from biological matrices. Also, it was no surprise that gas chromatography-mass spectrometry operated in the positive ion–electron impact ionization mode was the most widely reported instrument used for the detection of cocaine analytes. However, other analytical methodologies, such as liquid chromatography-mass spectrometry, are becoming more important for the analysis of cocaine with the growing interest in identifying and quantitating multiple cocaine analytes with varying physiochemical properties.