Abstract Deep brain stimulation (DBS) is an established medical therapy for the treatment of movement disorders and shows great promise for several other neurological disorders. However, after ...decades of clinical utility the underlying therapeutic mechanisms remain undefined. Early attempts to explain the mechanisms of DBS focused on hypotheses that mimicked an ablative lesion to the stimulated brain region. More recent scientific efforts have explored the wide-spread changes in neural activity generated throughout the stimulated brain network. In turn, new theories on the mechanisms of DBS have taken a systems-level approach to begin to decipher the network activity. This review provides an introduction to some of the network based theories on the function and pathophysiology of the cortico-basal-ganglia-thalamo-cortical loops commonly targeted by DBS. We then analyze some recent results on the effects of DBS on these networks, with a focus on subthalamic DBS for the treatment of Parkinson's disease. Finally we attempt to summarize how DBS could be achieving its therapeutic effects by overriding pathological network activity.
A four-cell anaerobic baffled reactor (ABR) was operated for two years treating raw municipal wastewater at ambient water and air temperatures of 12–23 °C and −10 to 35 °C, respectively. The 1000-L ...pilot reactor operated at a 12-h hydraulic residence time and was located in the Headworks building of the Plum Creek Water Reclamation Authority. The average influent was TSS = 510 ± 400 mg/L, BOD5 = 320 ± 80 mg/L and the average removal of TSS and BOD5 was 83 ± 10% and 47 ± 15%, respectively. The TSS and BOD removal exceeded that of conventional primary clarification, with no wasting of the settled solids over the two-years and stoichiometric production of methane. The estimated energy content of the biogas produced per unit volume of wastewater treated averaged 0.45 kWh/m3. The TSS and total COD removal in the first cell averaged 75 ± 15% and 43 ± 14%, respectively, but methane production was only 20% of the total observed for the full ABR. The performance of the ABR relative to the extent of solids hydrolysis and methane production can be varied by the number of cells and hydraulic residence time. The anaerobic baffled reactor is an energy-positive technology that can be used for biologically enhanced primary treatment of raw municipal wastewater in cold climates.
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•A mainstream anaerobic baffled reactor (ABR) was operated for two years at 12–23 °C.•The average removal of TSS and BOD5 was 83 ± 10% and 47 ± 15%, respectively.•Stoichiometric amounts of methane were produced based on ultimate BOD removal.•ABR operation does not require energy, and biogas energy content was 0.45 kWh/m3 flow.•No settled solids were wasted over the two years of operation.
The Fourth Industrial Revolution - also known as Industry 4.0 (i4.0) - comprises the digitalisation of the industrial sector. This paper uses the theoretical lens of supply chain innovation (SCI) to ...investigate the implications of i4.0 on supply chain management. For these purposes, the method of structured content analysis is applied to more than 200 use cases of i4.0-enabled SCI introduced by both established and startup companies. i4.0-enabled SCI manifests along three dimensions: process, technology, and business architecture. The key findings of this study can be summarised as follows: first, i4.0-enabled SCI extends the initial focus on productivity improvements in SC processes towards scalability and flexibility. Second, extant i4.0 solutions rely mostly on analytics and smart things while omitting smart people technology and the human-centric approach associated with the i4.0 paradigm. Third, established companies adopt i4.0 merely to sustain their existing business architectures while startup companies radically change their operating models, relying heavily on data analytics and the platform economy. Consequently, established companies pursue a problem-driven, engineering-based approach to SCI while startup companies follow an 'asset-light', business-driven approach. Lastly, there are two distinct approaches to digitalising operational SC processes: platform-based crowdsourcing of standard processes and on-demand provision of customised services.
Integrated performance and risk management is the key lever to increase shareholder value holistically. In this paper, we develop a corresponding framework for value-based performance and risk ...optimization in supply chains. Economic Value Added (EVA) as a prevalent metric of value-based performance is applied to mid-term sales and operations planning (S&OP). Robust optimization methods are utilized to deal with operational risks in physical and financial supply chain management due to the uncertainty of future events. Multiple aspects of robustness and general implications of the framework are highlighted using a case-oriented numerical analysis.
Summary
What is known and objective
Extracorporeal membrane oxygenation (ECMO) is a life‐saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics ...(PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO.
Methods
A literature search was conducted using the PubMed and EMBASE databases with the following keywords: “extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO” and “PK OR pharmacokinetics OR pharmacokinetic*” and “anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*.”
Results and discussion
Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin‐tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher‐than‐standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO.
What is new and conclusion
The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.
Abstract
It is generally held that >100 TeV emission from astrophysical objects unambiguously demonstrates the presence of PeV protons or nuclei, due to the unavoidable Klein–Nishina suppression of ...inverse Compton emission from electrons. However, in the presence of inverse Compton dominated cooling, hard high-energy electron spectra are possible. We show that the environmental requirements for such spectra can naturally be met in spiral arms, and in particular in regions of enhanced star formation activity, the natural locations for the most promising electron accelerators: powerful young pulsars. Our scenario suggests a population of hard ultra-high energy sources is likely to be revealed in future searches, and may also provide a natural explanation for the 100 TeV sources recently reported by the High-Altitude Water Cherenkov Observatory.
The hippocampus and the medial prefrontal cortex (mPFC) are traditionally associated with regulating memory and executive function, respectively. The contribution of these brain regions to food ...intake control, however, is poorly understood. The present study identifies a novel neural pathway through which monosynaptic glutamatergic ventral hippocampal field CA1 (vCA1) to mPFC connectivity inhibits food-motivated behaviors through vCA1 glucagon-like peptide-1 receptor (GLP-1R). Results demonstrate that vCA1-targeted RNA interference-mediated GLP-1R knockdown increases motivated operant responding for palatable food. Chemogenetic disconnection of monosynaptic glutamatergic vCA1 to mPFC projections using designer receptors exclusively activated by designer drugs (DREADDs)-mediated synaptic silencing ablates the food intake and body weight reduction following vCA1 GLP-1R activation. Neuropharmacological experiments further reveal that vCA1 GLP-1R activation reduces food intake and inhibits impulsive operant responding for palatable food via downstream communication to mPFC NMDA receptors. Overall these findings identify a novel neural pathway regulating higher-order cognitive aspects of feeding behavior.
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