Simultaneous determination of midazolam and 1’-hydroxymidazolam in rat plasma by protein precipitation and LC-MS: application to pharmacokinetic study

A sensitive and selective liquid chromatography–mass spectrometry (LC–MS) method for determination of midazolam and its metabolite 1’-hydroxymidazolam in rat plasma was developed and validated. After addition of carbamazepine as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. The chromatographic separation was performed on a Zorbax SB-C18 column (150 × 2.1 mm, 5 μm), using acetonitrile-0.1 % formic acid as the mobile phase with gradient elution, delivered at a flow-rate of 0.4 mL/min. Electrospray ionization (ESI) source was applied and operated in positive ion mode, and selected ion monitoring (SIM) mode used to quantify midazolam and its metabolite 1’- hydroxymidazolam. Calibration curves were linear in the concentration ranges of 5-2000 ng/mL for midazolam and 10-2000 ng/mL for 1’-hydroxymidazolam, with a lower limit of quantification (LLOQ) of 5 ng/mL for midazolam and 10 ng/mL for 1’-hydroxymidazolam, respectively. Intra- and inter-day precision were less than 13 % and the accuracy ranged from -10.7 to 9.5 %. This developed method was successfully used for determination of midazolam and its metabolite 1’-hydroxymidazolam in rat plasma for pharmacokinetic study.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Novel sequences of subgroup J avian leukosis viruses associated with hemangioma in Chinese layer hens

<p>Abstract</p> <p>Background</p> <p>Avian leukosis virus subgroup J (ALV-J) preferentially induces myeloid leukosis (ML) in meat-type birds. Since 2008, many clinical cases of hemangioma rather than ML have frequently been reported in association with ALV-J infection in Chinese layer flocks.</p> <p>Results</p> <p>Three ALV-J strains associated with hemangioma were isolated and their proviral genomic sequences were determined. The three isolates, JL093-1, SD09DP03 and HLJ09MDJ-1, were 7,670, 7,670, and 7,633 nt in length. Their gag and pol genes were well conserved, with identities of 94.5-98.6% and 97.1-99.5%, respectively, with other ALV-J strains at the amino acid level (aa), while the env genes of the three isolates shared a higher aa identity with the env genes of other hemangioma strains than with those of ML strains. Interestingly, two novel 19-bp insertions in the U3 region in the LTR and 5' UTR, most likely derived from other retroviruses, were found in all the three isolates, thereby separately introducing one E2BP binding site in the U3 region in the LTR and RNA polymerase II transcription factor IIB and core promoter motif ten elements in the 5' UTR. Meanwhile, two binding sites in the U3 LTRs of the three isolates for NFAP-1 and AIB REP1 were lost, and a 1-base deletion in the E element of the 3' UTR of JL093-1 and SD09DP03 introduced a binding site for c-Ets-1. In addition to the changes listed above, the rTM of the 3' UTR was deleted in each of the three isolates.</p> <p>Conclusion</p> <p>Our study is the first to discovery the coexistence of two novel insertions in the U3 region in the LTR and the 5' UTR of ALV-J associated with hemangioma symptoms, and the transcriptional regulatory elements introduced should be taken into consideration in the occurrence of hemangioma.</p

MindShift: Leveraging Large Language Models for Mental-States-Based Problematic Smartphone Use Intervention

Problematic smartphone use negatively affects physical and mental health. Despite the wide range of prior research, existing persuasive techniques are not flexible enough to provide dynamic persuasion content based on users' physical contexts and mental states. We first conduct a Wizard-of-Oz study (N=12) and an interview study (N=10) to summarize the mental states behind problematic smartphone use: boredom, stress, and inertia. This informs our design of four persuasion strategies: understanding, comforting, evoking, and scaffolding habits. We leverage large language models (LLMs) to enable the automatic and dynamic generation of effective persuasion content. We develop MindShift, a novel LLM-powered problematic smartphone use intervention technique. MindShift takes users' in-the-moment physical contexts, mental states, app usage behaviors, users' goals & habits as input, and generates high-quality and flexible persuasive content with appropriate persuasion strategies. We conduct a 5-week field experiment (N=25) to compare MindShift with baseline techniques. The results show that MindShift significantly improves intervention acceptance rates by 17.8-22.5% and reduces smartphone use frequency by 12.1-14.4%. Moreover, users have a significant drop in smartphone addiction scale scores and a rise in self-efficacy. Our study sheds light on the potential of leveraging LLMs for context-aware persuasion in other behavior change domains

Auto-tuning MPI Collective Operations on Large-Scale Parallel Systems

MPI libraries are widely used in applications of high performance computing. Yet, effective tuning of MPI colletives on large parallel systems is an outstanding challenge. This process often follows a trial-and-error approach and requires expert insights into the subtle interactions between software and the underlying hardware. This paper presents an empirical approach to choose and switch MPI communication algorithms at runtime to optimize the application performance. We achieve this by first modeling offline, through microbenchmarks, to find how the runtime parameters with different message sizes affect the choice of MPI communication algorithms. We then apply the knowledge to automatically optimize new unseen MPI programs. We evaluate our approach by applying it to NPB and HPCC benchmarks on a 384-node computer cluster of the Tianhe-2 supercomputer. Experimental results show that our approach achieves, on average, 22.7% (up to 40.7%) improvement over the default setting

Ketogenic Diet as a Treatment for Super-Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome

Background: Febrile infection-related epilepsy syndrome (FIRES) is a fatal epileptic encephalopathy associated with super-refractory status epilepticus (SRSE). Several treatment strategies have been proposed for this condition although the clinical outcomes are poor. Huge efforts from neurointensivists have been focused on identifying the characteristics of FIRES and treatment to reduce the mortality associated with this condition. However, the role of ketogenic diet (KD) in FIRES is not fully understood.Methods: We performed a retrospective review of patients who met the diagnostic criteria of FIRES, SRSE, and were treated with KD between 2015 and 2018 at the Department of Pediatrics, Xiangya Hospital of Central South University. The following data were recorded: demographic features, clinical presentation, anticonvulsant treatment, timing and duration of KD and follow-up information. Electroencephalography recordings were reviewed and analyzed.Results: Seven patients with FIRES were put on KD (5 via enteral route, and 2 via intravenous line) for SRSE in the PICU. The median age was 8. Four patients were male and 3 were female. Although patients underwent treatment with a median of 4 antiepileptic drugs and 2 anesthetic agents, the status epilepticus (SE) persisted for 7–31 days before KD initiation. After KD initiation, all patients achieved ketosis and SE disappeared within an average of 5 days (IQR 3.5), although there were minor side effects. In 6 patients, a unique pattern was identified in the EEG recording at the peak period. After initiation of KD, the number of seizures reduced, the duration of seizure shortened, the background recovered and sleep architecture normalized in the EEG recordings. The early initiation of KD (at the onset of SE) in the acute phase of patients decreased the mRS score in the subsequent period (p = 0.012, r = 0.866).Conclusions: The characteristic EEG pattern in the acute phase promoted timely diagnosis of FIRES. Our data suggest that KD may be a safe and promising therapy for FIRES with SRSE, and that early initiation of KD produces a favorable prognosis. Therefore, KD should be applied earlier in the course of FIRES. Intravenous KD can be an effective alternative route of administration for patients who may not take KD enterally

Impact of biogenic SOA loading on the molecular composition of wintertime PM2.5 in urban Tianjin: an insight from Fourier transform ion cyclotron resonance mass spectrometry

Biomass burning is one of the key sources of urban aerosols in the North China Plain, especially in winter when the impact of secondary organic aerosols (SOA) formed from biogenic volatile organic compounds (BVOCs) is generally considered to be minor. However, little is known about the influence of biogenic SOA loading on the molecular composition of wintertime organic aerosols. Here, we investigated the water-soluble organic compounds in fine particles (PM2.5) from urban Tianjin by ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Our results show that most of the CHO and CHON compounds were derived from biomass burning; they contain O-poor and highly unsaturated compounds with aromatic rings, which are sensitive to photochemical reactions, and some of which probably contribute to light-absorbing chromophores. Under moderate to high SOA loading conditions, the nocturnal chemistry is more efficient than photooxidation to generate secondary CHO and CHON compounds with high oxygen content. Under low SOA-loading, secondary CHO and CHON compounds with low oxygen content are mainly formed by photochemistry. Secondary CHO compounds are mainly derived from oxidation of monoterpenes. But nocturnal chemistry may be more productive to sesquiterpene-derived CHON compounds. In contrast, the number- and intensity-weight of S-containing groups (CHOS and CHONS) increased significantly with the increase of biogenic SOA-loading, which agrees with the fact that a majority of the S-containing groups are identified as organosulfates and nitrooxy-organosulfates that are derived from the oxidation of BVOCs. Terpenes may be potential major contributors to the chemical diversity of organosulfates and nitrooxy-organosulfates under photo-oxidation. While the nocturnal chemistry is more beneficial to the formation of organosulfates and nitrooxy-organosulfates under low SOA-loading. The SOA-loading is an important factor associating with the oxidation degree, nitrate group content and chemodiversity of nitrooxy-organosulfates. Furthermore, our study suggests that the hydrolysis of nitrooxy-organosulfates is a possible pathway for the formation of organosulfates.</p