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PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (–3%, −16%, and −27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

This study utilized Harris Hawk optimization to analyze the harmonic distortions of a symmetric capacitor based multilevel converter. The proposed multilevel converter uses identical and symmetric DC sources in its input. The proposed topology for a multilevel converter uses fewer switches than typical cascaded designs. It can output 9-level outputs and can be scaled up to higher levels. The proposed multilevel converter can be improved by implementing a low frequency pulse width modulation technique to reduce the stress on the switches. The optimization of the switching angles using Harris Hawk was able to solve the non-linear aspects of the Selective Harmonic Elimination Pulse Width Modulation. The output voltage's THD was compared with that of other optimization methods, such as ant colony and particle swarm. The comparison shows that the output THD of the Harris Hawk optimizer is lower than that of other methods, which is about 5 %, according to the standards of IEEE-519.

China's water stress and its pressure on food security is a widely recognized crisis. A framework is proposed and applied at the provincial level to evaluate China's water security for food production. It is based on a water stress index that accounts for the deficit between water supply and aggregate demand of 23 major field crops over the study period (1961–2015). The water demand is estimated based on method recommended by the Food and Agriculture Organization of the United Nations. The water supply is composed of rainfall and irrigation. Consequently, the water security of both rainfed and irrigated agriculture is evaluated in our research, and the respective contribution of rainfall and irrigation is distinguished. Suggestions regarding adjustment in irrigation investment and planting area are proposed for practical application. The framework also holds great potential to investigate the impact of climate change and the virtual water flow of crops. With 7% of the world's arable land and 6% of its water resources, China has to feed 20% of the world's population. Consequently, China's water stress and its pressure on food security is a widely recognized crisis. A framework is proposed in our research to evaluate China's water security for food production. It is mainly designed to answer the following three questions critical to China's food security but have not been systematically addressed in the literature. How much water is required under China's current agriculture planting structure? What is the respective role of rainfall and irrigation in meeting this requirement? What is the status of water security for China's rainfed and irrigated agriculture? The above three questions are answered based on a water stress index that accounts for the deficit between water supply and aggregate demand of 23 major field crops over the study period (1961–2015). We have also proposed suggestions regarding water security for food production from the framework. For future use, our proposed framework lays the groundwork to investigate the virtual water flow of crops. Climate change signals can also be incorporated into this framework to inform climate‐driven water risk for agriculture. A new framework is proposed to evaluate water security for food productionRespective contribution of rainfall and irrigation to water security is distinguishedSpatial patterns of China's water security for food production are investigated

A Bayesian model that uses the spatial dependence induced by the river network topology, and the leading principal components of regional tree ring chronologies for paleo‐streamflow reconstruction is presented. In any river basin, a convergent, dendritic network of tributaries come together to form the main stem of a river. Consequently, it is natural to think of a spatial Markov process that recognizes this topological structure to develop a spatially consistent basin‐scale streamflow reconstruction model that uses the information in streamflow and tree ring chronology data to inform the reconstructed flows, while maintaining the space‐time correlation structure of flows that is critical for water resource assessments and management. Given historical data from multiple streamflow gauges along a river, their tributaries in a watershed, and regional tree ring chronologies, the model is fit and used to simultaneously reconstruct the full network of paleo‐streamflow at all gauges in the basin progressing upstream to downstream along the river. Our application to 18 streamflow gauges in the Upper Missouri River Basin shows that the mean adjusted R2for the basin is approximately 0.5 with good overall cross‐validated skill as measured by five different skill metrics. The spatial network structure produced a substantial reduction in the uncertainty associated with paleo‐streamflow as one proceeds downstream in the network aggregating information from upstream gauges and tree ring chronologies. Uncertainty was reduced by more than 50% at six gauges, between 6% and 50% at one gauge, and by less than 5% at the remaining 11 gauges when compared with the traditional principal component regression reconstruction model. A novel Bayesian network model for streamflow reconstructions using the spatial dependence induced by the river network and regional trees is presentedThe spatial network structure allows a substantial reduction in the uncertainty associated with paleo‐streamflowsThe spatial Markov model improves upon traditional streamflow reconstruction methods

Understanding spatially correlated floods and modeling joint hazard associated with threshold exceedances across multiple locations is crucial for accurate estimation of continental‐scale portfolio risk. This work uses a non‐parametric copula‐based spatial simulator to analyze peak floods across the United States to derive the first‐of‐its‐kind continental portfolio risk estimates at the 10‐ and 100‐year return levels. We find significant interdependence in floods across the nation, revealing the recurring pattern of extreme events affecting the Northeast, Central, West, and Northwest United States in the same year. The stochastic simulator effectively manages high‐dimensional data and offers reliable uncertainty estimates for both spatially dependent floods and the aggregated flood losses at the continental level. El Niño‐Southern Oscillation and Atlantic Multidecadal Oscillation are identified as statistically significant tele‐connectors of aggregate loss. This research aims to advance the understanding of compound continental flood hazard and the potential large‐scale climate teleconnections that lead to such compound floods. It is important to know why past floods occurred in different parts of the United States in the same year and how they were connected to each other. This knowledge helps determine how likely it is for major annual floods to occur all across the country in the future. Consequently, an understanding of what drives such total annual flood losses each year and their relation to climate conditions is of strategic importance. Large‐scale climate patterns can influence where, how much, and how often it floods in a given year. The coincidence of many such events in a year across the country is an example of a compound flood hazard, whose aggregate loss is of interest. This study uses a stochastic model for simulating multiple floods across the United States while preserving information as to their co‐occurrence. The model also calculates the likelihood of combined flood losses, along with its uncertainty. The key patterns in the ocean and the atmosphere that lead to these widespread losses are then identified. The broader impact of this study is to establish a foundation that any country or region can use to evaluate potential consequences of compound risk from joint extreme events. A non‐parametric copula‐based stochastic framework is forwarded to assess the risk of multiple peak floods across a regionPeak floods in the US exhibit significant co‐occurrence of extreme events, leading to compound flood hazard with high aggregate lossesThe joint occurrence of extreme flood events across the country is a signature of large‐scale climate teleconnections A non‐parametric copula‐based stochastic framework is forwarded to assess the risk of multiple peak floods across a region Peak floods in the US exhibit significant co‐occurrence of extreme events, leading to compound flood hazard with high aggregate losses The joint occurrence of extreme flood events across the country is a signature of large‐scale climate teleconnections

Down Syndrome related AML is driven by GATA1 alterations in patients with trisomy 21. Using exome or targeted sequencing, prior studies identified GATA1 alterations in ~80-90% of patients. We performed whole genome sequencing coupled with whole transcriptome sequencing on 207 cases to study the genomic basis of Down Syndrome AML. We detected GATA1 alterations in 96.1% of cases, with additional structural rearrangements in GATA1 in 15% of cases that may have been missed in prior studies. For GATA1, although substitutions and small indels occur nearly uniformly across exon 2, we observed that internal tandem duplications (ITDs) are significantly enriched in the second half of exon 2, suggesting a specific mutational mechanism for these cases. We also detected exon 3 (instead of exon 2) deletion in one case, where the resultant truncated GATA1 protein is different from the commonly recognized sGATA1. Our study further revealed that mutations in genes mediating JAK-STAT signaling (JAK1/JAK2/JAK3), RAS pathway (KRAS/NRAS/NF1), Cohesin complex (STAG2/CTCF/RAD21/SMC3), as well as MBNL1, KANSL1, IRX1, and NFIA. By integrating the genome with transcriptome sequencing data, we discovered that GATA1 exon 2 skipping to be a significant event in DS-AML. Although exon 2 is nearly completely skipped in cases with exon 2 deletion or splice site alterations, significant exon 2 skipping is also observed in cases where the alteration is small and is in the middle of exon 2. Further, exon 2 skipping is also observed in cases wither the alteration is a single base substitution that results in stop codon in the middle of exon 2 (therefore splicing is unlikely affected by these alterations in such cases). Based on this observation, we propose a hybrid genetic-epigenetic model on the development of Down Syndrome AML. In DS-AML, GATA1 exon 2 skipping during transcription/splicing might be a developmentally (epigenetically) regulated event in early fetal development that is destined to be silenced in the postnatal period that results in activation of the canonical long GATA1. This epigenetic silencing of sGATA1 is overridden by secondary genetic events, thus maintaining sGATA1 as the predominant GATA1 protein. Notably, the sGATA1 have variable isoforms as a result of exon 2 or exon 3 loss. In summary, our integrated whole genome and transcriptome approach has resulted in discovery of novel and high-prevalence structural alterations in GATA1 and potentially novel genes involved in pathogenesis of DS-AML. Our integrated analysis provided evidence on the epigenetic/developmental regulation of GATA1 exon 2 skipping via alterative splicing in the context of trisomy 21 that warrants further investigation.

Our understanding of the full range of natural variability in streamflow, including how modern flow compares to the past, is poorly understood for the Upper Indus Basin because of short instrumental gauge records. To help address this challenge, we use Hierarchical Bayesian Regression with partial pooling to develop six centuries long (1394–2008 CE) streamflow reconstructions at three Upper Indus Basin gauges (Doyian, Gilgit, and Kachora), concurrently demonstrating that Hierarchical Bayesian Regression can be used to reconstruct short records with interspersed missing data. At one gauge (Partab Bridge), with a longer instrumental record (47 years), we develop reconstructions using both Bayesian regression and the more conventionally used principal components regression. The reconstructions produced by principal components regression and Bayesian regression at Partab Bridge are nearly identical and yield comparable reconstruction skill statistics, highlighting that the resulting tree ring reconstruction of streamflow is not dependent on the choice of statistical method. Reconstructions at all four reconstructions indicate that flow levels in the 1990s were higher than mean flow for the past six centuries. While streamflow appears most sensitive to accumulated winter (January–March) precipitation and summer (May–September) temperature, with warm summers contributing to high flow through increased melt of snow and glaciers, shifts in winter precipitation and summer temperatures cannot explain the anomalously high flow during the 1990s. Regardless, the sensitivity of streamflow to summer temperatures suggests that projected warming may increase streamflow in coming decades, though long‐term water risk will additionally depend on changes in snowfall and glacial mass balance. Tree ring reconstructions of streamflow in the Upper Indus Basin show wetter conditions in the 1990s compared to the last 600 yearsReconstructions are insensitive to the choice of statistical method used (principal components versus Bayesian regression)Streamflow is most sensitive to winter precipitation and summer temperature, but anomalies in these seasons cannot explain recent high flow

Background: Clobazam (CLB) has been used as an anxiolytic, anticonvulsant and antiepileptic drug under the trade names, Frisium, Urbanol, Onfi and Tapclob. Impurity profiling in the pharmaceutical industries is a central task in the manufacturing of drug product. The quantification of impurities in active pharmaceutical ingredients (APIs) is also receiving considerable importance from the regulatory authorities in the point of stringent quality requirement. Thus, the provision of substantial quantity of impurities as standards, which are accomplished either by isolation from crude reaction mass or the synthesis of material with proposed structure using new synthetic route, to analytical method development and validation is a good demand. Therefore, easily accessible synthetic routes to the preparation of impurities with the lowest cost are sought after. To date, no synthetic specifics were found on the synthesis and characterization of CLB Imp-B, -C, -D and -F, and the synthesis of CLB Imp-E. Therefore, the comprehensive study was undertaken on the synthesis and characterization of CLB related impurities and this study might be useful to prepare CLB impurities in the required quantity with purity to use as a reference standard of analytical method development in pharmaceutical industry. Methods: The synthetic routes were developed for the synthesis of CLB impurities such CLB Imp-B to Imp-F and isolated them using purification techniques with purity in the required quantity. The commercially available key starting materials, reagents and solvents were used in the course of synthesis of impurities. The analytical techniques such as NMR, IR and mass were used to characterize the structure of synthesized CLB related impurities. Results: The easy accessible synthetic methods were developed for the synthesis of clobazam related impurities, CLB Imp-B to F in good to excellent yields with purity as well as described the cause to formation of these impurities. The KSM related impurity, 2-chloro-1-nitrobenzene and the active methylene hydrogens in clobazam are caused to the formation of CLB Imp-B and CLB Imp-C&-D, respectively. CLB Imp-E and -F are formed due to the degradation of drug molecule, CLB in the presence of base (NaOH). CLB Imp-B was prepared from 2-chloro-1-nitrobenzene by following similar process of CLB reported in the synthetic specific. CLB Imp-F was prepared from 5-chloro-N1 -phenylbenzene-1,2-diamine by coupling with mono-methyl malonate followed by N-methylation using dimethyl sulfate. The rest of all impurities were planned to prepare by taking CLB as starting material. CLB Imp-C and -D were synthesized by treating CLB with methyl iodide in the presence of inorganic base. The mixture of aqueous NaOH and CLB was agitated vigorously at 75-80°C to obtain CLB Imp-E. All the synthesized compounds were purified using purification techniques such as crystallization and column chromatography, and well characterized by IR, ESI-mass, 1H NMR, 13C NMR and DEPT analyses. Conclusion: The immaculate discussion about synthetic approaches and structural elucidation using analytical applications such as IR, NMR (1H, 13C and DEPT) of CLB Imp-B to F, which are listed in the European pharmacopoeia monograph of clobazam, has been described. All the impurities were obtained with stringent purity (>98%) in the described synthetic routes and the same impurities have been used in analytical method development in our pharmaceutical industry. Also, the plausible mechanistic path ways to the formation of impurities, keeping in view the regulatory importance of clobazam, were discussed in detail.

Background: Cyclooxygenase (COX-2) inhibitors have been developed to provide better anti-inflammatory and analgesic efficacy than those of traditional NSAIDs. Several compounds having selective COX-2 inhibitors such as SC-558, Celecoxib, Rofecoxib, Valdecoxib and Etoricoxib are marketed as new generation NSAIDs and block the production of prostaglandins (PGs) in inflammatory cells. New anti-inflammatory agents with improved potency and safety profile are still needed. Objective: As a part of our continuation research work towards new anti-inflammatory agents, the synthesis of N-substituted aryl/heteroaryl-pyrazole-1yl benzene sulfonamide (Celecoxib) derivatives, their anti-inflammatory activity in both methods in vitro and in vivo and molecular docking study on COX-2 enzyme will be discussed in this study. Methods: A series of N-substituted (aryl/heteroarylpyrazol-1-yl)benzenesulfonamide (Celecoxib) derivatives was synthesized and characterized them using IR, NMR (1H and 13C), mass and elemental analyses. Anti-inflammatory activity of the title compounds was evaluated by in vitro initially using albumin denaturation and membrane stabilization methods, enzymatic activity against COX-2 enzyme using colorimetric assay and then in vivo by carrageenan induced paw oedema and cotton pellet induced granuloma methods. The docking study was performed, to find the binding mode of the title compounds with the binding site of the COX-2 enzyme. Results: The biological activity screening data disclosed that some of the compounds 5b, 5e, 5f and 5i exhibited potent anti-inflammatory activity in both methods, in vitro and in vivo. The enzymatic assay on COX-2 enzyme demonstrated that few compounds potently inhibit COX-2 enzyme activity with IC50 of <0.89 μM. Unexpectedly, compound 5e (IC50, 0.62±0.17 μM) showed more potent COX-2 inhibited activity than that of parent drug, celecoxib (IC50, 0.62±0.25 μM) and the standard, flufenamic acid (IC50, 0.71±0.12 μM). Conclusion: The bio-screening data, in vitro and in vivo anti-inflammatory activity and COX-2 enzymatic assay revealed that few N-substituteed aryl/heteroaryl-pyrazol-1-yl) benzene sulfonamides showed potent activity and compound 5e showed more potent COX-2 inhibit activity than that of parent drug, celecoxib and the standard, flufenamic acid. Moreover, all the newly synthesized title products were bonded well with good binding energies in the sight of COX-2 enzyme. Therefore, the described study might provide sustained information to the development of new series of derivatives with potent drug like activity.

Storage and controlled distribution of water have been key elements of a human strategy to overcome the space and time variability of water, which have been marked by catastrophic droughts and floods throughout the course of civilization. In the United States, the peak of dam building occurred in the mid‐20th century with knowledge limited to the scientific understanding and hydrologic records of the time. Ecological impacts were considered differently than current legislative and regulatory controls would potentially dictate. Additionally, future costs such as maintenance or removal beyond the economic design life were not fully considered. The converging risks associated with aging water storage infrastructure and uncertainty in climate in addition to the continuing need for water storage, flood protection, and hydropower result in a pressing need to address the state of dam infrastructure across the nation. Decisions regarding the future of dams in the United States may, in turn, influence regional water futures through groundwater outcomes, economic productivity, migration, and urban growth. We advocate for a comprehensive national water assessment and a formal analysis of the role dams play in our water future. We emphasize the urgent need for environmentally and economically sound strategies to integrate surface and groundwater storage infrastructure in local, regional, and national water planning considerations. A research agenda is proposed to assess dam failure impacts and the design, operation, and need for dams considering both paleo and future climate, utilization of groundwater resources, and the changing societal values toward the environment. Water storage and control have been key elements of a human strategy to overcome differences between water availability and water needs. The future promises changes to when and where water will be available and many regions in the USA will likely see an increase in the imbalance between existing water storage and evolving demands for water. This indicates the need for more storage or new dams to meet human and ecological needs. The current trend for removal of old, hazardous or unpopular dams now and into the future may impact regional groundwater outcomes, food and energy production, migration, and urban growth. We advocate for a formal analysis of the role dams play in the future of the USA's water landscape. We also stress the need for national water planning considerations to develop environmentally and economically sound strategies to integrate the management of surface and groundwater storage infrastructure in the USA. Climate change projections suggest more hydrologic extremes. Are more dams subsequently needed?Most US dams now exceed their economic design life and represent a need for infrastructure investment and recognition of associated risksA national water assessment is needed to examine dam removal and modified storage provision options considering hydroclimatic risk exposure

The article discusses the opinions and concerns of various medical professionals on the topics of telehealth, 60-day dispensing, burnout, and the Medicare system.

Accurate flood risk assessment requires a comprehensive understanding of flood sensitivity to regional drivers and climate factors. This paper presents the scaling of floods (duration, peak, volume) with geomorphologic characteristics of the basin (i.e., drainage area, slope, elevation) and precipitation patterns (rainfall accumulation, variability). Long‐term daily streamflow observations over the 20th and early 21st centuries from Hydro‐Climatic Data Network streamgages across the conterminous United States are used to create a flood event database based on their flood stage information. Antecedent daily rainfall accumulation and variability corresponding to these floods are computed using Global Historical Climatology Network daily data set. Two Bayesian scaling models are developed, and the spatial organization of scaling exponents is investigated. The baseline model quantifies the scaling of floods to geomorphologic characteristics. The dynamic model quantifies the scaling of floods to antecedent precipitation distribution which is further conditioned on geomorphologic characteristics. Results show that small and low‐elevation basins have a stronger response to antecedent rainfall distribution in amplifying flood peaks, while high‐elevation steeper basins have a lower response for flood duration and volume. The dynamic models demonstrate that there are significant variations in the flood scaling rates, with the largest rates up to 40% and 4.5% for flood duration, 64% and 44% for peak, and 98% and 40% for volume found across the Northeast, Coastal Southeast, and Northwest with intensifying rainfall accumulation and variability, respectively. This study advances flood predictions by better informing the flood attributes in the context of dynamical land‐atmosphere perturbations. The relationships between floods, physical properties of river basins, and the spatio‐temporal distribution of precipitation define the regional flood scaling laws. Improved regional flood scaling models are required for updating flood risk scoring tools to help insurers and decision‐makers in the light of anthropogenic climate changes and natural variability of Earth systems. Two scaling models are developed here to examine how the physical properties of basins and precipitation patterns can inform flood attributes across the conterminous United States (US). Using long records of streamflow and precipitation observations, we identified different scaling relationships between the catchment factors, preceding precipitation, and the duration, peaks, and volume of floods. Larger basins located at higher elevations are found to have lower scaling rates with flood peaks when interacting with the preceding precipitation patterns. Overall, low‐elevation flat basins across the Eastern, Southern, and Northwestern US have a larger positive response to precipitation in amplifying flood attributes. These new scaling laws can help advance our understanding of controlling mechanisms for flash floods and mega‐floods, which is required for a dynamic flood risk assessment in a changing environment. Two Bayesian scaling models are developed to understand the sensitivity of floods to geomorphologic characteristics and catchment rainfallLow‐elevation and flat basins with different sizes have greater scaling to rainfall in amplifying flood duration and volumesLow‐elevation and small basins with different steepness show larger sensitivity to rainfall distribution that enhances flood peaks Two Bayesian scaling models are developed to understand the sensitivity of floods to geomorphologic characteristics and catchment rainfall Low‐elevation and flat basins with different sizes have greater scaling to rainfall in amplifying flood duration and volumes Low‐elevation and small basins with different steepness show larger sensitivity to rainfall distribution that enhances flood peaks

•The motivation behind urban flood research is given, including the health and safety impacts, and the economic consequences.•Commonly attributed factors of urban flood occurrences are described.•Recent trends in urban flood modeling are detailed, particularly highlighting the modern computationally-efficient hydraulic-hydrological models and the increasing use of data-driven models.

Agricultural, industrial, and urban water use in the conterminous United States (CONUS) is highly dependent on groundwater that is largely drawn from nonsurficial wells (>30 m). We use a Demand‐Sensitive Drought Index to examine the impacts of agricultural water needs, driven by low precipitation, high agricultural water demand, or a combination of both, on the temporal variability of depth to groundwater across the CONUS. We characterize the relationship between changes in groundwater levels, agricultural water deficits relative to precipitation during the growing season, and winter precipitation. We find that declines in groundwater levels in the High Plains aquifer and around the Mississippi River Valley are driven by groundwater withdrawals used to supplement agricultural water demands. Reductions in agricultural water demands for crops do not, however, lead to immediate recovery of groundwater levels due to the demand for groundwater in other sectors in regions such as Utah, Maryland, and Texas. Relationship between groundwater levels and a Demand‐Sensitive Drought Index is examinedDepletion of groundwater continues even when agricultural demands are reducedStorage of winter precipitation critical to supplying agricultural water demands

Background: Michaelis-Arbuzov reaction is one of the well studied reaction in phosphorus chemistry and used for the synthesis of phosphonates, phosphinates and phosphine oxides. Phosphonates are not only versatile intermediates in synthetic organic chemistry but also plays a vital role in biological activity. The usage of niobium(V) chloride as a catalyst has attracted the considerable attention due to its low hygroscopic character, high stability, cost effective, low loading and ease of handling. Methods: The present study describes the synthesis of a series of various aryl/heterocyclic substituted phosphonates/ phosphinates of 2-chloroquinoxaline 3(a-e) and 6-iododibenzo[d,f][1,3]dioxepine 5(a-e) using an expeditious catalyst, niobium(V) chloride by Michaelis-Arbuzov reaction and evaluated their antimicrobial and antioxidant activities. Results: A simple, efficient and new synthetic protocol was developed for the synthesis of quinoxalinyl and dibenzodioxepinyl phosphonate/phosphinate derivatives (3a-e/5a-e) in good yields using niobium(V) chloride as a catalyst. Biological data revealed that compound 5c exhibited potent antimicrobial activity and the compounds 3e and 5e good antioxidant activity. Conclusion: From the results it was concluded that niobium(V) chloride was an efficient catalyst for the synthesis of quinoxalinyl and dibenzodioxepinyl phosphonate/phosphinate derivatives and also exhibited good antimicrobial and antioxidant activities.

In this research paper, the effect of abrasive water jet (AWJ) machining process parameters such as jet operating pressure, feed rate, abrasive concentration and standoff distance (SOD) on the surface roughness produced during machining of graphite mixed glass fibre reinforced polymer (GFRP) composite is investigated. Experiments were conducted using Taguchi's L27orthogonal array design and the process parameters were optimised to obtain high surface finish. Experimental data were analysed using analysis of variance (ANOVA) which shows that the surface roughness decreased by 15.90% and increased by 9.22% for the increase in operating pressure and SOD respectively. Also, regression model is developed to predict the surface roughness and found that the predicted values are in close agreement with the experimental values (error 6.57%).

A substantial number of adults suffer young-onset dementia (YOD). The diversity of types and syndromes makes recognition and diagnosis difficult. An algorithmic approach to interpreting clinical data, informed by clinical epidemiology, integrates data pertaining to defining syndromes and their chronology and tempo, family history, and other neuropsychiatric features and neurologic signs, is used to reach a preliminary diagnosis and direct diagnostic tests and their interpretation. Screening for YOD in the psychiatric context is a rational process in which vigilance is combined with careful searches for red flags that signal a neurodegenerative etiology.

A new indicator of drought‐induced water stress is introduced and applied at the county level in the USA. Unlike most existing drought metrics, we directly consider current daily water demands and renewable daily water supply to estimate the potential stress. Water stress indices developed include the Normalized Deficit Cumulated to represent multiyear droughts by computing the maximum cumulative deficit between demand and supply over the study period (1949–2009) and the Normalized Deficit Index representing drought associated with maximum cumulative deficit each year. These water stress indices map directly to storage requirements needed to buffer multiyear and within‐year climate variability and can reveal the dependence on exogenous water transferred by rivers/canals to the area. Future climate change and variability can be also incorporated into this framework to inform climate‐driven drought for additional storage development and potential applications of water trading across counties. New water risk indicators are presentedSpatial competition between counties and water storage required is exposedFuture scenarios for water trading and value of water can be developed

Centrifugal pumps will not pass gross quantities of gaseous emboli due to the nonocclusive nature of the pump. However, retrograde flow can occur under circumstances that include: product malfunctions, low flows, and human errors. Negative pressure created by falling arterial perfusate can draw air into the cannula. Food and Drug Administration (FDA) records about centrifugal pump malfunctions were obtained. Out of 350,000 cases completed with centrifugal pumps over a 23 month period, the FDA received reports of 68 malfunctions, 22 electrical burning smells, and three speed surges, yielding a failure rate of 1 in 3,763 cases. FDA records revealed five death reports and three serious injury reports. A survey was sent to 2,424 Society of Thoracic Surgeons' members to obtain more information; 285 who use centrifugal pumps responded. Sixty surgeons (21%) reported 108 malfunctions, including 46 complete pump failures. Fiftyone of 243 surgeons (21%) who use centrifugal pumps for bypass reported that perfusionists have forgotten to clamp the pump line, resulting in backflow. We conclude centrifugal pumps are generally safe, but malfunctions, low flows, and human errors can lead to retrograde flow and occasionally air embolization. There are valves that can be added to the bypass circuitry to prevent this risk.

Retrograde blood flow through the aortic cannula into the cardiopulmonary circuit may lead to aortic air emboli when nonocclusive centrifugal pumps are used. Perfusionists have been taught to clamp the arterial line to prevent retrograde flow when the pump fails. They also have to protect against the possibility of air entering the arterial cannula when low flows are requested or when the patient is taken off bypass. The present report details the advantages of having a check valve placed in-line with the arterial cannula during centrifugal blood pumping. It will allow weaning patients from cardiopulmonary bypass without the use of arterial line clamping.

Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [14C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [14C]canagliflozin dose was 1.2%–7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.

CeCl3·7H2O-SiO2is an efficient and recyclable catalyst for a three component one-pot reaction of an amine, aldehydes and diethyl phosphite to synthesize α-diaminophosphonate derivatives under microwave irradiation exploiting neat reaction conditions.

The relationship between alcohol consumption, sensitivity, and tolerance is an important question that has been addressed in humans and rodent models. Studies have shown that alcohol consumption and risk of abuse may correlate with (1) increased sensitivity to the stimulant effects of alcohol, (2) decreased sensitivity to the depressant effects of alcohol, and (3) increased alcohol tolerance. However, many conflicting results have been observed. To complement these studies, we utilized a different organism and approach to analyze the relationship between ethanol consumption and other ethanol responses. Using a set of 20 Drosophila melanogaster mutants that were isolated for altered ethanol sensitivity, we measured ethanol-induced hyperactivity, ethanol sedation, sedation tolerance, and ethanol consumption preference. Ethanol preference showed a strong positive correlation with ethanol tolerance, consistent with some rodent and human studies, but not with ethanol hyperactivity or sedation. No pairwise correlations were observed between ethanol hyperactivity, sedation, and tolerance. The evolutionary conservation of the relationship between tolerance and ethanol consumption in flies, rodents, and humans indicates that there are fundamental biological mechanisms linking specific ethanol responses.

Understanding the water balance of a catchment in relation to its regional climate forcings and catchment characteristics is critical for predicting current and future water resources amid changing climate and land cover. This study intends to improve Zhang's monthly water balance model (a physics‐based conceptual hydrologic model) that reflects the physical partitioning process of the hydrological cycle at the basin level based on regional climate and catchment characteristics. The existing model does not include snow process and has confronted evident limitations in snow‐affected areas, which is a critical aspect since snowmelt water has been a significant source of water resources for many regions, especially in the temperate and frigid zones. We introduce a snow module based on surface energy balance and Budyko‐limits on melting and combine it with the existing water balance equations. Moreover, monthly parameterization is applied to the model to better explain the time‐varying hydrological characteristics of a catchment. The proposed model involves five different monthly parameters, which determine the physical partitioning process of the hydrological cycle, and they are regionally calibrated and validated under Budyko‐type constraints. The model is applied to 1,210 basins across the continental United States (CONUS), and the simulated streamflow is compared to the observed data. The proposed model significantly outperformed the original model, improving the median NSE by 31% (from 0.51 to 0.67) and increasing the number of catchments with an acceptable NSE by 58%. The spatial variability of the basin characteristics across the CONUS is also investigated based on the calibrated parameters. A parsimonious snow module is developed based on Budyko's framework to improve an existing physics‐based dynamic water balance modelA monthly parameterization is proposed to reflect the seasonal behavior of catchment characteristicsThe augmented model that includes snow with monthly parameterization shows significant improvements in simulating monthly streamflow A parsimonious snow module is developed based on Budyko's framework to improve an existing physics‐based dynamic water balance model A monthly parameterization is proposed to reflect the seasonal behavior of catchment characteristics The augmented model that includes snow with monthly parameterization shows significant improvements in simulating monthly streamflow

Large dams degrade the river’s health by heavily regulating the natural flows. Despite a long history of research on flow regulation due to dams, most studies focused only on the impact of a single dam and ignored the combined impact of flow regulation on a river network. We propose a new Dynamic Flow Alteration Index (DFAI) to quantify the local and cumulative degree of regulation by comparing the observed controlled flows with the naturalized flows based on a moving time horizon for the highly regulated Colorado River Basin. The proposed DFAI matches closely to dam’s localized regulation for headwater gages and starts to diverge as we move downstream due to increase in cumulative impact of the dams. DFAI considers the impact of dam operations on flow characteristics such as shifting of peak flow occurrence and dampening of peak flows. DFAI estimates the degree of regulation to be small for upstream dams and finds the maximum network regulation to be 2.52 years at Glen Canyon reservoir. DFAI also successfully captures the reduction in cumulative regulation when dam operations (e.g., Hoover Dam) bring the altered flow in synchronization with natural regime due to downstream flow requirements. The impact of San Juan River Basin Recovery Implementation Program is also captured by DFAI as the reduction in network regulation drops by 1.5 years for Navajo Dam. Our findings using DFAI suggest the need to develop naturalized flows for major river basins to quantify the flow alteration under continually changing climate and human influences. A new Dynamic Flow Alteration Index is proposed to compute the cumulative degree of regulation for complex river networksThe time‐varying regulation metric captures the human influence due to reservoir operations and water managementEstimated local and cumulative regulation compare well against traditionally used residence time estimates A new Dynamic Flow Alteration Index is proposed to compute the cumulative degree of regulation for complex river networks The time‐varying regulation metric captures the human influence due to reservoir operations and water management Estimated local and cumulative regulation compare well against traditionally used residence time estimates

ABSTRACTIn this open-label, single-center study, eight healthy men each received a single 500-mg dose of [14C]doripenem, containing 50 μCi of [14C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from β-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting. Further metabolite profiling was conducted on urine samples using liquid chromatography coupled to radiochemical detection and high-resolution mass spectrometry. Unchanged doripenem and doripenem-M-1 accounted for means of 80.7% and 12.7% of the area under the plasma total-radioactivity-versus-time curve (area under the concentration-time curve extrapolated to infinity) and exhibited elimination half-lives of 1.1 and 2.5 h, respectively. Total clearance of doripenem was 16 liters/h, and renal clearance was 12.5 liters/h. At 7 days after the single dose, 95.3% of total doripenem-related radioactivity was recovered in urine and 0.72% in feces. A total mean of 97.2% of the administered dose was excreted in the urine as unchanged doripenem (78.7% ± 5.7%) and doripenem-M-1 (18.5% ± 2.6%). Most of the urinary recovery occurred within 4 h of dosing. Three additional minor metabolites were identified in urine: the glycine and taurine conjugates of doripenem-M-1 and oxidized doripenem-M-1. These results show that doripenem is predominantly eliminated in urine as unchanged drug, with only a fraction metabolized to doripenem-M-1 and other minor metabolites.