Role of inflammatory markers in the assessment of meningitis in adult patients with fever and headache.

BACKGROUND: Meningitis, especially of bacterial origin, is a medical emergency that must be diagnosed promptly. However, due to the associated risks of complications of lumbar puncture, it is crucial to identify individuals who truly need it. The aim of this study was to assess the diagnostic role of inflammatory markers in distinguishing among patients without meningitis, those with aseptic meningitis, and those with bacterial meningitis. METHODS: This was a retrospective, diagnostic study at an acute care hospital, involving adult patients who presented to either ambulatory care or the emergency department with fever and headache, but without altered mental status or neurological deficits. Inflammatory markers (C-reactive protein [CRP], mean platelet volume, neutrophil-lymphocyte ratio, and red cell distribution width) were assessed as index tests. An expert panel classified patients into three groups: no meningitis, aseptic meningitis, and bacterial meningitis using predefined criteria. RESULTS: Of the 80 patients, 52 had no meningitis, 27 had aseptic meningitis, and 1 had bacterial meningitis. Of the inflammatory markers investigated, only CRP showed potential usefulness in differentiating these three diagnostic groups, with median values of 5.6 (interquartile range [IQR] 2.1, 11.3) mg/dL in those without meningitis, 0.2 (IQR 0.1, 1.2) mg/dL in those with aseptic meningitis, and notably elevated at 21.7 mg/dL in the patient with bacterial meningitis. CONCLUSION: In adult patients presenting with fever and headache in an emergency setting, CRP was the only marker that demonstrated potential diagnostic utility in distinguishing among those with no meningitis, aseptic meningitis, and bacterial meningitis.

Monte Carlo Thompson sampling-guided design for antibody engineering.

Antibodies are one of the predominant treatment modalities for various diseases. To improve the characteristics of a lead antibody, such as antigen-binding affinity and stability, we conducted comprehensive substitutions and exhaustively explored their sequence space. However, it is practically unfeasible to evaluate all possible combinations of mutations owing to combinatorial explosion when multiple amino acid residues are incorporated. It was recently reported that a machine-learning guided protein engineering approach such as Thompson sampling (TS) has been used to efficiently explore sequence space in the framework of Bayesian optimization. For TS, over-exploration occurs when the initial data are biasedly distributed in the vicinity of the lead antibody. We handle a large-scale virtual library that includes numerous mutations. When the number of experiments is limited, this over-exploration causes a serious issue. Thus, we conducted Monte Carlo Thompson sampling (MTS) to balance the exploration-exploitation trade-off by defining the posterior distribution via the Monte Carlo method and compared its performance with TS in antibody engineering. Our results demonstrated that MTS largely outperforms TS in discovering desirable candidates at an earlier round when over-exploration occurs on TS. Thus, the MTS method is a powerful technique for efficiently discovering antibodies with desired characteristics when the number of rounds is limited.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

Assessment of the frequency dependence of acoustic properties on material, composition, and scatterer size of the medium.

PURPOSE: The aim of this study was to elucidate the frequency dependence of the speed of sound (SoS) and attenuation coefficients in phantoms with controlled attenuation properties (scatterer density, scatterer size, absorption control material) and rat livers. METHODS: The frequency dependence of SoS and attenuation coefficients were evaluated with ultrasound (1-15 MHz) by observing multiple phantoms with different scatterer sizes, densities, and presence or absence of evaporated milk as absorbing media. Normal and fatty model rat livers were examined with the same protocol. RESULTS: The phantom results revealed that the scatterer density and SoS of the base media were the dominant factors causing the changes in SoS. Frequency dependence was not observed in SoS. Assessment of the attenuation coefficient showed that the frequency dependence was mainly affected by absorption attenuation when the scatterer was as small as a hepatocyte (i.e. ≤ 10 µm). Scattering attenuation was also observed to affect frequency dependence when the scatterer was as large as lipid droplets (i.e. ≤ 40 µm). CONCLUSION: Assuming a consistent size of the main scatterers in the evaluation medium, the frequency dependence of the SoS and attenuation coefficients may provide insight into the scatterer density and the contribution of absorption and scattering attenuation. Further studies in the higher frequency band (up to about 50 MHz) are expected to advance the clinical application of high-frequency ultrasound.

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods, applications and regulatory compliance.

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.

A Comparative Assessment of Mechanisms and Effectiveness of Radiosensitization by Titanium Peroxide and Gold Nanoparticles.

The development of potentially safe radiosensitizing agents is essential to enhance the treatment outcomes of radioresistant cancers. The titanium peroxide nanoparticle (TiOxNP) was originally produced using the titanium dioxide nanoparticle, and it showed excellent reactive oxygen species (ROS) generation in response to ionizing radiation. Surface coating the TiOxNPs with polyacrylic acid (PAA) showed low toxicity to the living body and excellent radiosensitizing effect on cancer cells. Herein, we evaluated the mechanism of radiosensitization by PAA-TiOxNPs in comparison with gold nanoparticles (AuNPs) which represent high-atomic-number nanoparticles that show a radiosensitizing effect through the emission of secondary electrons. The anticancer effects of both nanoparticles were compared by induction of apoptosis, colony-forming assay, and the inhibition of tumor growth. PAA-TiOxNPs showed a significantly more radiosensitizing effect than that of AuNPs. A comparison of the types and amounts of ROS generated showed that hydrogen peroxide generation by PAA-TiOxNPs was the major factor that contributed to the nanoparticle radiosensitization. Importantly, PAA-TiOxNPs were generally nontoxic to healthy mice and caused no histological abnormalities in the liver, kidney, lung, and heart tissues.

Ultrasound assessment of translation of microbubbles driven by acoustic radiation force in a channel filled with stationary fluid.

In this report, a method is proposed to quantify the translation of ultrasound contrast agent (UCA) microbubbles driven by acoustic radiation for the detection of channels filled with stationary fluid. The authors subjected UCA microbubbles in a channel with diameters of 0.1 and 0.5 mm to ultrasound pulses with a center frequency of 14.4 MHz. The translational velocity of the UCA microbubbles increased with the sound pressure and pulse repetition frequency (PRF) of the transmitted ultrasound. The mean translational velocity reached 0.75 mm/s at a negative peak sound pressure of 2.76 MPa and a PRF of 2 kHz. This trend agreed with the theoretical prediction, which indicated that the translational velocity was proportional to the square of the sound pressure and the PRF. Furthermore, an experiment was carried out with a phantom that mimics tissue and found that the proposed method aided in detection of the channel, even in the case of a low contrast-echo to tissue-echo ratio. The authors expect to develop the proposed method into a technique for detecting lymph vessels.

Scientific Skill Assessment of Basic Surgical Dissection and Overall Laparoscopic Performance.

To improve surgical education, objective and scientific skill assessments are required. There are two types of skill evaluations: assessments of basic surgical skills and assessments of overall surgical performance. To establish a reliable assessment method for surgical dissection, we measured the force applied on the tip of a surgical instrument during dissection of the renal vessels of pigs. The experiments revealed that, during surgical dissection, expert laparoscopic surgeons applied vertical force at the beginning of the stroke and then horizontal force, with minimum vertical force, at the end of the stroke. As an assessment of overall surgical performance, the Endoscopic Surgical Qualification system was developed and has been used for 12 years in Japan. More than 3700 surgeons, including urologists, were determined to have appropriate laparoscopic surgical skills after assessments of unedited videos by referees.

Assessment of Parametrial Response by Growth Pattern in Patients With International Federation of Gynecology and Obstetrics Stage IIB and IIIB Cervical Cancer: Analysis of Patients From a Prospective, Multicenter Trial (EMBRACE).

PURPOSE: To assess disease response along the parametrial space according to tumor morphology in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB and IIIB cervical cancer at the time of image-guided adaptive brachytherapy. METHODS AND MATERIALS: Patients with FIGO stage IIB and IIIB cervical cancer registered as of November 2013 in the EMBRACE study were evaluated. Tumors were stratified according to morphologic subtype on magnetic resonance imaging (expansive and infiltrative), and the characteristics of those subtypes were analyzed. Parametrial involvement at diagnosis and at brachytherapy was evaluated, and the response to chemo-radiotherapy was classified as good, moderate, or poor. The response grade was compared between the 2 groups and analyzed with regard to tumor volumes, and dosimetric parameters. RESULTS: A total of 452 patients were evaluated, of whom 186 had expansive growth type and 266 had infiltrative morphology. Patients with infiltrative tumors had more extensive disease, as indicated by a higher rate of FIGO stage IIIB disease, as well as radiologic evidence of extension into the distal parametrial space and to the pelvic side wall on magnetic resonance imaging. Cervical necrosis was more common in the infiltrative group. Good response was more common in the expansive group (34% vs 24%; P=.02), and poor response was more common in the infiltrative group (11% and 19%; P=.02). Mean gross tumor volume at diagnosis was equal in both groups (51.7 cm(3)). The high-risk clinical target volume was larger in infiltrative tumors (37.9 cm(3) vs 33.3 cm(3), P=.005). The mean high-risk clinical target volume D90 was slightly higher in expansive tumors (92.7 Gy and 89.4 Gy, P<.001). CONCLUSION: Infiltrative tumors are more advanced at presentation and respond less favorably to chemo-radiotherapy when compared with expansive tumors that are more or less equivalent in size. The use of image-guided adaptive brachytherapy allows achieving reasonably high doses in both groups.

Korean, Japanese, and Chinese populations featured similar genes encoding drug-metabolizing enzymes and transporters: a DMET Plus microarray assessment.

BACKGROUND: Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. METHODS: The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. RESULTS: On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. CONCLUSION: Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.

[Objective assessment forms for laparoscopic surgery in urology].

To facilitate the spread of safe techniques in laparoscopic surgery, in medical faculties in Japan we created two forms for laparoscopic nephrectomy and prostatectomy that consisted of a global rating scale (GS) and our task checklist (TS) using objective structured assessment of technical skill (OSATS). We examined the correlation between the global rating scale total score (GS) and the task checklist total score (TS), and the difference in GS and TS between the instructor' s assessment and the practitioner' s self-assessment, and compared the differences in the scores at each operative step. GS was found to be closely correlated with TS (P<0.05). Where there were differences between GS and TS, the instructor-assessed GS was higher than the self-assessed score in nephrectomy (P<0.05). However, there was no significant difference between instructor- and self-assessed scores in prostatectomy. In nephrectomy, the instructor-assessed score was higher than the self-assessed score (P<0.05) for "creation of an operating field" and "dissection of surrounding tissue of the kidney". Assessment forms created using OSATS would be useful for quantifying the surgical skill in laparoscopic surgery. In the future, we plan to use the assessment forms to assist in surgical education and assessment.