Improvement of motion artifacts using dynamic whole-body 18F-FDG PET/CT imaging.

PURPOSE: Serial dynamic whole-body PET imaging is valuable for assessing serial changes in tracer uptake. The purpose of this study was to evaluate the improvement of motion artifacts in patients using serial dynamic whole-body 18F-fluorodeoxyglyucose (FDG) PET/CT imaging. MATERIALS AND METHODS: In 797 consecutive patients, serial 3-min dynamic whole-body FDG PET imaging was performed seven times, at 60 or 90 min after FDG administration. In cases with large body motion during imaging, we tried to improve the images by summing the images before body motion. An image quality study was performed on another 50 patients without obvious body motion using the same acquisition mode. RESULTS: Obvious body movement was observed in 106 of 797 cases (13.3%), and severe motion artifacts which interfered image interpretation were observed in 18 (2.3%). In these 18 cases, summation of the images before the body movement enabled us to obtain images that excluded the effect of the body motion. In the visual evaluation of the image quality in another 50 patients studied, acceptable image quality was obtained when 2 or more times the serial 3-min image data were added. CONCLUSION: Serial dynamic whole-body FDG PET imaging can minimize body motion artifacts by summation of the images before the body motion. Such serial dynamic study may be a choice for PET imaging to eliminate motion artifacts.

A Survey of Pharmacy Students' Satisfaction with a Basic Life Support Course and an Exploration of Factors Related to Awareness Change Before and After the Course.

The model core curriculum for pharmacy education and professional standards for pharmacists established by the Japan Pharmaceutical Association aim to inculcate knowledge and skills on basic life support (BLS) and ensure that pharmacy students are well equipped with knowledge on BLS. In this study, pharmacy students were enrolled in the PUSH course, a BLS training course for citizens, and a questionnaire survey was conducted before and after the course to evaluate the change in students awareness about BLS and overall satisfaction with the course. The participants enrolled for the course were fourth-year students from the School of Pharmacy, Hyogo Medical University, who consented to participate in the study. A total of ninety-nine participants were included in this study. After the completion of the course, the participants displayed greater confidence, preparedness, and willingness to teach BLS, and decreased anxiety about BLS. Factor analysis revealed four factors based on the questionnaire answers before the course, while three factors were extracted based on the answers after the course. Lack of confidence in BLS, extracted as one of the factors before the course was inverted and gave rise to a new factor. Some participants displayed increased awareness about BLS after completion of the PUSH course. Hierarchical cluster analysis before and after the course divided respondents into three groups. The results showed that lesser number of participants displayed anxiety over BLS after the course. The results also indicated high levels of satisfaction among the participants after the completion of the PUSH course.

Incidence of severe infection in patients with rheumatoid arthritis taking biologic agents: a systematic review.

OBJECTIVE: The objective of this review was to estimate the population-based incidence and determine the types of severe infection and deaths experienced by patients with rheumatoid arthritis taking biologic agents. INTRODUCTION: Since the late 1990s, various biologic and synthetic drugs have been developed to treat rheumatoid arthritis. In recent years, the incidence of severe infection in patients with rheumatoid arthritis in Western nations has been determined by observational studies; however, no systematic review has been conducted on this topic. INCLUSION CRITERIA: The following inclusion criteria were considered: i) observational studies on patients with rheumatoid arthritis treated with biologic agents; ii) studies reporting the number of severe infections requiring hospitalization for treatment; iii) studies reporting person-years of observation data; and iv) studies based on rheumatoid arthritis registries, medical records from rheumatology centers, or insurance claim databases. METHODS: PubMed, CINAHL, Embase, and Web of Science were searched to identify published studies. The reference lists of all studies selected for critical appraisal were screened for additional studies. Unpublished studies were searched on MedNar and OpenGrey databases. All the searches were updated on December 6, 2021. After removing the duplicates, 2 independent reviewers screened titles and abstracts against the inclusion criteria and then assessed full texts against the criteria. Two reviewers independently appraised the study and outcome levels for methodological quality using the critical appraisal instrument for cohort studies from JBI. Two reviewers extracted the relevant information related to severe infection and drugs. RESULTS: Fifty-two studies from 21 countries reported severe infection rates associated with using 8 biologic agents, plus nonbiologic disease-modifying antirheumatic drugs. In total, 18,428 infections with 395,065 person-years of biologic drug exposure were included in the analysis. Thirty-five studies included infections in outpatients receiving intravenous antibiotic therapy. Fifteen studies reported the first episode of infection, and the remaining studies did not specify either the first or all of the episodes of infection. Inclusion of viral infection and/or opportunistic infection varied among studies. Fifteen studies reported the site of infection; respiratory, skin/soft tissue, urinary tract, and sepsis/bacteremia were commonly reported. Ten studies reported the case fatality rates, ranging from 2.5% to 22.2%. Meta-analysis was conducted for 8 biologic agents and conventional disease-modifying antirheumatic drugs. The infection rate varied from 0.9 to 18.1/100 person-years. The meta-analysis revealed an infection rate of 5.0/100 person-years (95% CI 3.8-6.7) among patients receiving tumor necrosis factor inhibitors (heterogeneity 98.2%). The meta-analysis for the other 3 biologic agents revealed a point estimate of 5.5 to 8.7/100 person-years with high heterogeneity. Sensitivity analysis indicated that registry-based studies were less likely to have very low or very high infection rates compared with other data sources. The definition of infection, the patient composition of the cohorts, and the type of databases appeared to be the primary sources of clinical and methodological heterogeneity. CONCLUSIONS: Due to high statistical heterogeneity, the meta-analysis was not suited to estimating a summary measure of the infection rate. Developing standardized data collection is necessary to compare infection rates across studies. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020175137.

[Survey in Hyogo Prefecture on the Current Status of Pharmacists in Home Health Care and Exploration of Factors Causing Psychological Burden].

There is a need for pharmacists to be actively involved in home healthcare through a wide range of collaboration in healthcare and welfare. However, insufficient evidence is available to search for factors that prevent pharmacists from being proactive in home healthcare. In this study, we conducted an extensive questionnaire survey among pharmacists engaged in home pharmacy work who belong to the Hyogo Pharmaceutical Society regarding the current status of pharmacists' work in home medical care and their psychological burden; we also explored the factors that may hinder the future development of home medical care. As a result, 925 (44%) valid responses were obtained, and seven factors- "current multidisciplinary cooperation", "relationships with patients and their families", "emotional burden for home healthcare", "attitude toward patients", "ideal of multidisciplinary cooperation", "anxiety about aggressive intervention", and "anxiety about talking to and dealing with patients"- were extracted. Furthermore, it was suggested that pharmacists' mental burden and anxiety are closely related to their successful experiences in building relationships with patients and patients' families as well as with multidisciplinary cooperation in home healthcare. Therefore, to train pharmacists to be actively involved in home healthcare, it is important not only to impart knowledge and skills but also for them to gain experience practicing their contributions as pharmacists in the field of home healthcare with multiple professions, patients, and patients' families.

Common Motor Drive Triggers Response of Prime Movers When Two Fingers Simultaneously Respond to a Cue.

This study investigated whether the motor execution process of one finger movement in response to a start cue is influenced by the participation of another finger movement and whether the process of the finger movement is dependent on the movement direction. The participants performed a simple reaction time (RT) task, the abduction or flexion of one (index or little finger) or two fingers (index and little fingers). The RT of the prime mover for the finger abduction was significantly longer than that for the flexion, indicating that the time taken for the motor execution of the finger response is dependent on the movement direction. The RT of the prime mover was prolonged when the abduction of another finger, whose RT was longer than the flexion, was added. This caused closer RTs between the prime movers for a two-finger response compared with the RTs for a one finger response. The absolute difference in the RT between the index and little finger responses became smaller when two fingers responded together compared with one finger response. Those results are well explained by a view that the common motor drive triggers the prime movers when two fingers move together in response to a start cue.

Severe infection risk in patients treated with biologics for rheumatoid arthritis: a systematic review protocol.

OBJECTIVE: The objective of this review is to estimate the population-based incidence and to determine the types of severe infection experienced by patients with rheumatoid arthritis who are taking biological agents. INTRODUCTION: Since the late 1990s, a variety of biological and synthetic drugs have been developed to treat rheumatoid arthritis. In recent years, the incidence of severe infection in patients with rheumatoid arthritis in Western nations has been reported by observational studies; however, no systematic review has been conducted on this topic. INCLUSION CRITERIA: The following criteria will be considered for inclusion: i) observational studies on patients with rheumatoid arthritis who are taking biological agents; ii) studies reporting the number of severe infections requiring hospitalization for treatment; and iii) studies with person-years of observational data. METHODS: MEDLINE, CINAHL, Embase, and Web of Science will be searched to identify published studies. The reference lists of all studies that are selected for critical appraisal will be screened for additional studies. The search for unpublished studies will include MedNar and OpenGrey. Only studies published in English from 1999 to the present will be included. Screening of studies, assessment of methodological quality, and data extraction will be performed by two independent reviewers. If possible, studies will be pooled in statistical meta-analysis. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020175137.

Effect of variability of sequence length of go trials preceding a stop trial on ability of response inhibition in stop-signal task.

This study investigated whether the variability of the sequence length of the go trials preceding a stop trial enhanced or interfered with inhibitory control. The hypotheses tested were either inhibitory control improves when the sequence length of the go trials varies as a consequence of increased preparatory effort or it degrades as a consequence of the switching cost from the go trial to the stop trial. The right-handed participants abducted the left or right index finger in response to a go cue during the go trials. A stop cue was given at 50, 90, or 130 ms after the go cue, with 0.25 probability in the stop trial. In the less variable session, a stop trial was presented after two, three, or four consecutive go trials. In the variable session, a stop trial was presented after one, two, three, four, or five consecutive go trials. The reaction time and stop-signal reaction time were not significantly different between the sessions and between the response sides. Nevertheless, the probability of successful inhibition of the right-hand response in the variable session was higher than that in the less variable session when the stop cue was given 50 ms after a go cue. This finding supports the view that preparatory effort due to less predictability of the chance of a forthcoming response inhibition enhances the ability of the right-hand response inhibition when the stop process begins earlier.

Effect of the loci of visual cues on ability of polyrhythmic bimanual movement.

The present study investigated whether the deviation of the performed movement cycle from the required cycle during polyrhythmic bimanual (BM) movement depends on the loci of the visual cues that guide the rhythm of finger movements. Twelve healthy right-handed males rhythmically abducted and adducted the index finger or index fingers with the rhythm of the visual cues. During UM movement, the visual cue guiding the rhythm of finger movement was provided in the left or right visual hemifield. During 2:3 polyrhythmic BM movement, two visual cues, one guiding the rhythm of the left finger movement and another guiding the rhythm of the right finger movement, were provided in a single visual hemifield, or each visual cue guiding each finger movement was provided in each visual hemifield. During polyrhythmic BM movement, the cycle duration of the slower side of the movement guided by the rhythm of the visual cues provided in one visual hemifield was shorter than the required cycle duration, and the magnitude of the shortage in this condition was greater than that guided by each visual cue provided in each visual hemifield. Slower side of the movement is more precisely performed by each visual cue guiding each finger movement in each visual hemifield rather than that guided by visual cues provided in one visual hemifield during polyrhythmic BM movement. This may be explained by bottle-neck model in which visual information overflows the processing capacity when two visual processes are simultaneously provided in a single visual cortex.

Postural perturbation does not reset stepping rhythm in humans, but brief intermission does.

In the present study, we tested a hypothesis that the rhythm generator in humans keeps the rhythm of periodic motor output during brief inactivation of the pattern generator. This investigation was made through testing whether the step rhythm was reset after an interruptive event. A reset of the step rhythm was defined as an observation that the step re-emerges at random timing after an interruptive event regardless of the step rhythm before the interruption. This observation reflects an intermission of rhythm-keeping activity. Healthy participants stepped on a platform that could translate forward or backward. They continued stepping after the platform translation (non-stop session) or stopped briefly after the translation before resuming step with their own timing (stop session). In the non-stop session, the second step after the platform translation appeared at the integer multiple of the pre-existing step period in most participants, indicating that step rhythm was not reset. This finding indicates that postural perturbation does not interfere the rhythm-keeping activity. In the stop session, the step immediately after the intermission of stepping appeared at random time regardless of the step rhythm before the intermission in most participants. The actual side of the first step after the intermission was consistent with the predicted first step side at a 0.5 probability. Those findings indicate that step rhythm is reset after brief intermission of stepping, and contradict with the hypothesis that the activity of the rhythm generator is maintained, while the pattern generator is temporally inactive during a brief intermission of periodic motor output. This analysis could help to determine whether rhythm-keeping activity is inactivated by an interruptive event during periodic motor activity.

Processes of anticipatory postural adjustment and step movement of gait initiation.

The purpose of this study was to elucidate whether the anticipatory postural adjustment (APA) and focal step movement of gait initiation are produced as a single process or different processes and whether the APA receives an inhibitory drive from the ongoing stop process of gait initiation. Healthy humans initiated gait in response to a first visual cue that instructed the initial swing leg. In some trials, a switch or stop cue was also provided after the first cue. When the stop cue was provided, participants withheld gait initiation. When the switch cue was provided, participants immediately switched the initial swing leg. In both the stop and switch tasks, the APA in response to the first cue, represented by the S1 period of the displacement of the center of pressure, appeared in more than half of the trials in which the withholding of gait initiation or switching of the initial swing leg was successfully completed. These findings indicate that the APA and focal step movement of gait initiation are produced as a dual process. In trials in which the APA in response to the first cue appeared, the amplitude and duration of the APA were decreased when the participants switched the initial swing leg or withheld gait initiation. This finding indicates that the ongoing stop process of gait initiation produces an inhibitory drive over the APA. The decreases in the amplitude and duration of the APA during the switching of the initial swing leg were similar to those during the withholding of gait initiation; moreover, the decreases during the switching of the initial swing leg were positively correlated with the decreases during the withholding of gait initiation. Thus, the stop processes during switching the initial swing leg and withholding gait initiation likely share a common inhibitory mechanism over the APA.

Interhemispheric Inhibition Induced by Transcranial Magnetic Stimulation Over Primary Sensory Cortex.

The present study investigated whether the long-interval interhemispheric inhibition (LIHI) is induced by the transcranial magnetic stimulation over the primary sensory area (S1-TMS) without activation of the conditioning side of the primary motor area (M1) contributing to the contralateral motor evoked potential (MEP), whether the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and whether the pathways mediating the LIHI are different from those mediating the M1-TMS-induced LIHI. In order to give the TMS over the S1 without eliciting the MEP, the intensity of the S1-TMS was adjusted to be the sub-motor-threshold level and the trials with the MEP response elicited by the S1-TMS were discarded online. The LIHI was induced by the S1-TMS given 40 ms before the test TMS in the participants with the attenuation of the tactile perception of the digit stimulation (TPDS) induced by the S1-TMS, indicating that the LIHI is induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP in the participants in which the pathways mediating the TPDS is sensitive to the S1-TMS. The S1-TMS-induced LIHI was positively correlated with the attenuation of the TPDS induced by the S1-TMS, indicating that the S1-TMS-induced LIHI is dependent on the effect of the S1-TMS on the pathways mediating the TPDS at the S1. In another experiment, the effect of the digit stimulation given before the conditioning TMS on the S1- or M1-TMS-induced LIHI was examined. The digit stimulation produces tactile input to the S1 causing change in the status of the S1. The S1-TMS-induced LIHI was enhanced when the S1-TMS was given in the period in which the tactile afferent volley produced by the digit stimulation just arrived at the S1, while the LIHI induced by above-motor-threshold TMS over the contralateral M1 was not enhanced by the tactile input. Thus, the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and the pathways mediating the sub-motor-threshold S1-TMS-induced LIHI are not the same as the pathways mediating the above-motor-threshold M1-TMS-induced LIHI.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in ß-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.

Discovery of G Protein-Biased EP2 Receptor Agonists.

To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma.

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.

Asymmetric synthesis and catalytic activity of 3-methyl-ß-proline in enantioselective anti-Mannich-type reactions.

Enantiomerically pure 3-methyl-ß-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-ß-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted ß-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.

Efficacy and safety of the losartan-hydrochlorothiazide combination tablet in patients with hypertension uncontrolled by angiotensin II receptor antagonist therapy: the Aichi Research on Combination therapy for Hypertension (ARCH) Study.

BACKGROUND: The guidelines recommend combination therapy for patients who are unable to achieve target BP with monotherapy; some fixed dose therapies including an angiotensin II receptor blocker (ARB) and diuretics are available in Japan. However, to date there have been few reports on this long-term treatment and the patient profiles suited for this combination remain ambiguous. METHOD: The Aichi Research on Combination therapy for Hypertension Study was a multicenter, open-label, prospective observational study that investigated the efficacy and safety of 1-year treatment with the losartan-hydrochlorothiazide (HCTZ) combination tablet in patients with hypertension uncontrolled by either ARB monotherapy or combination therapy with a calcium channel blocker (CCB). An ARB was switched to a losartan-HCTZ tablet after a pre-observation period. RESULTS: A total of 614 of 648 patients were evaluable (mean age, 66.3 years; 52.8% men; mean baseline blood pressure, BP, 157.7/87.9 mmHg). The BP had decreased significantly to 138.0/78.2 mmHg by month 3 (p<0.001, t-test), and 36.2% of the patients had achieved their target BP. The hypotensive effect lasted for 1 year and was found equally in the losartan-HCTZ arm and the losartan-HCTZ plus CCB arm. A stratified analysis showed significant hypotensive effects in patients with higher baseline BP, women, and patients who did not drink alcohol (p<0.001, unpaired t-test). CONCLUSION: The losartan-HCTZ combination tablet was found to have an early hypotensive effect, good tolerability, and stable long-term benefits in patients with hypertension uncontrolled by ARB monotherapy or combination therapy with a CCB.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system.

BACKGROUND: Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. METHODS: The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 µM), quinine (0.3 - 2.4 µM), halofantrine (0.1 - 2.0 µM) and mefloquine (0.1 - 2.0 µM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. RESULTS: Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. CONCLUSIONS: In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.

3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 3: Synthesis, metabolic stability, and biological evaluation of optically active analogs.

A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes.

Discovery of novel N-acylsulfonamide analogs as potent and selective EP3 receptor antagonists.

A series of novel N-acylsulfonamide analogs were synthesized and evaluated for their binding affinity and antagonist activity for the EP3 receptor subtype. Representative compounds were also evaluated for their inhibitory effect on PGE(2)-induced uterine contraction in pregnant rats. Among those tested, a series of N-acylbenzenesulfonamide analogs were found to be more potent than the corresponding carboxylic acid analogs in both the in vitro and in vivo evaluations. The structure activity relationships (SAR) are also discussed.