Relationship between olfactory and gustatory functions: The Iwaki health promotion project 2019.

OBJECTIVE: Olfactory and gustatory functions are important sensory aspects in humans. Although they are believed to influence each other, their interrelationship is not well understood. In this study, we aimed to investigate the relationship between the olfactory and gustatory functions based on the results of a large-scale epidemiological study (Iwaki Health Promotion Project) of the general local population. METHODS: We analyzed 565 participants who underwent taste and olfactory tests in the 2019 Iwaki Project. Gustatory function was tested for four taste qualities (sweet, sour, salty, and bitter) using whole-mouth taste tests. Olfactory function was tested using the University of Pennsylvania Smell Identification Test modified for Japanese (UPSIT-J). We evaluated sex-related differences between olfactory and gustatory functions and the effects of various factors on olfactory identification using multivariate analysis. Furthermore, we compared the percentage of accurate UPSIT-J responses between the normal and hypogeusia groups. We also analyzed the effects of taste and olfactory functions on eating. RESULTS: Olfactory and gustatory functions were lower in men than in women. Among the four taste qualities, salty taste was the most closely associated with olfactory identification ability, with lower olfactory scores of salty taste in the hypogeusia group than in the normal group. Moreover, the hyposmia group had higher daily salt intake than the normal olfaction group in women. CONCLUSION: These results suggest that olfactory identification tests may be useful in predicting elevated salt cognitive thresholds, leading to a reduction in salt intake, which may contribute to hypertension prevention.

BRCA2 Frameshift Mutation in de novo Small-Cell Neuroendocrine Carcinoma of the Prostate: A Case Report.

A 66-year-old male was diagnosed with cT4N0M1b small-cell neuroendocrine carcinoma of the prostate. Four months after the administration of combined androgen blockade, multiple novel metastatic regions in the lung and liver and progression of bone metastasis were observed. The patient was referred to our hospital because of biochemical and radiographic progression after four cycles of docetaxel as a first-line therapy for castration-resistant prostate cancer. Transurethral resection of the prostate and hepatic biopsy revealed small-cell carcinoma with positive expression of neuroendocrine markers. The FoundationOne CDx next-generation sequencing test revealed several pathogenic variants, including BRCA2 (W1692fs*3), KEAP1 (R320W), and TP53 (C2385) mutation. After four cycles of chemotherapy with carboplatin plus etoposide (CE), the metastatic regions regressed markedly. The prostate-specific antigen (PSA) and neuron-specific enolase (NSE) level decreased by 96.9% and 91.6%, respectively. However, 2 months after the completion of four cycles of CE, elevation of tumor marker levels, and re-growth of the metastatic regions were observed. Although olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), achieved a 45.2% decrease in NSE, the patient rejected to continue therapy because of G2 adverse events. After receiving an additional two cycles of CE and one cycle of cabazitaxel, the patient died because of cancer progression 24 months after the initial treatment for prostate cancer. Here, we present a case of BRCA2-altered small-cell neuroendocrine prostate cancer treated with both platinum-containing chemotherapy and PARPi. Both therapies achieved an initial response; however, durable responses were not obtained. Additional discussion regarding the optimal treatment strategy for BRCA-altered small-cell/neuroendocrine prostate cancer is required.

The Current Trend of Radiation Therapy for Patients with Localized Prostate Cancer.

A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure.

Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients.

BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .

Optogenetic control of gut movements reveals peristaltic wave-mediated induction of cloacal contractions and reactivation of impaired gut motility.

Gut peristalsis, recognized as a wave-like progression along the anterior-posterior gut axis, plays a pivotal role in the transportation, digestion, and absorption of ingested materials. The embryonic gut, which has not experienced ingested materials, undergoes peristalsis offering a powerful model for studying the intrinsic mechanisms underlying the gut motility. It has previously been shown in chicken embryos that acute contractions of the cloaca (an anus-like structure) located at the posterior end of the hindgut are tightly coupled with the arrival of hindgut-derived waves. To further scrutinize the interactions between hindgut and cloaca, we here developed an optogenetic method that produced artificial waves in the hindgut. A variant form of channelrhodopsin-2 (ChR2(D156C)), permitting extremely large photocurrents, was expressed in the muscle component of the hindgut of chicken embryos using Tol2-mediated gene transfer and in ovo electroporation techniques. The D156C-expressing hindgut responded efficiently to local pulses of blue light: local contractions emerge at an ectopic site in the hindgut, which were followed by peristaltic waves that reached to the endpoint of the hindgut. Markedly, the arrival of the optogenetically induced waves caused concomitant contractions of the cloaca, revealing that the hindgut-cloaca coordination is mediated by signals triggered by peristaltic waves. Moreover, a cloaca undergoing pharmacologically provoked aberrant contractions could respond to pulsed blue light irradiation. Together, the optogenetic technology developed in this study for inducing gut peristalsis paves the way to study the gut movement and also to explore therapeutic methodology for peristaltic disorders.

Effects of body compositions on the associations between ferritin and diabetes parameters among Japanese community dwellers.

BACKGROUND: Ferritin is associated with an increased prevalence of diabetes mellitus. Moreover, the ferritin levels differ across the body compositions. Although there were studies reporting the association of ferritin and diabetes, the alteration in ferritin-diabetes association by body composition differences is rarely explained. Thus, the aim of this study is to identify the effects of body compositions on the association between ferritin and diabetes parameters among the Japanese population. METHODS: This study analyzed the data of a cross-sectional study with 1065 subjects aged over 19 years in the Iwaki area, Japan. Independent variables were ferritin and body compositions, while dependent variables were blood sugar, HbA1c, and diabetes mellitus. Correlations between serum ferritin and blood sugar and HbA1c were analyzed using Spearman's Rank Correlation. Multivariate linear or logistic regressions were used to investigate the effects of body compositions (body fat percentage, muscle mass, or visceral fat level) on the ferritin-diabetes associations by adjusting the confounders. RESULTS: There were significant positive correlations between ferritin and blood sugar in both sexes (p < 0.05), while a significant correlation between ferritin and HbA1c was found only in females (p < 0.001). Higher ferritin was significantly associated with an increase in blood sugar in individuals with normal body fat percentage (lowest vs. highest quartile group, coefficient=5.07, 95 % confidence intervals [CI]: 1.48-8.65), normal visceral fat level (lowest vs. highest quartile group, coefficient=4.84, 95 % CI: 1.74-7.94), and very high muscle mass (lowest vs. highest quartile group, coefficient=14.14, 95 % CI: 5.00-23.29). CONCLUSIONS: By our study findings, individuals' body composition notably influenced the associations of serum ferritin and diabetes parameters, and the association was attenuated in obese individuals.

Chemically Driven Ion Exchanging Synthesis of Na5YSi4O12-Based Glass-Ceramic Proton Conductors.

We have developed 12-membered silica-tetrahedra-ringed Na5YSi4O12-type sodium ion conducting glass-ceramics on the basis of the composition Na3+3x-yR1-xPySi3-yO9 (R: rare earth elements; denoted as Narpsio); especially, the material of Na4Y0.6P0.2Si2.8O9 with the combined parameters of (x, y) = (0.4, 0.2) gives rise to the maximum conductivity of 1 × 10-1 Scm-1 at 300 °C. Because glass-ceramics generally have the advantage of structural rigidity and chemical durability over sintered polycrystalline ceramics, the present study employed glass-ceramic Narpsio to perform chemically driven ion exchange of Na+ with protonated water molecules with an aim to produce a proton conductor. The ion exchange was carried out in a hydrochloric acid solution by changing immersion time, temperature, and acid concentration. The ion exchanged Na4Y0.6P0.2Si2.8O9-based glass-ceramics were analyzed by the complex impedance method, and the proton conductivity was found to exhibit 3 × 10-4 Scm-1 at 300 °C with the activation energy of 59 kJ/mol. The dependence of humidity-sensitive conductivity of the ion exchanged bulk glass-ceramics was also examined; the conductivity increased almost linearly from 0.6 × 10-4 Scm-1 in dry air to 1.5 × 10-4 Scm-1 in 75% humid ambience at 300 °C. Thus, the ion exchanged glass-ceramics can be considered to be high temperature proton conductors as well as humidity sensors.

Correlation between Antimicrobial Resistance and the Hospital-Wide Diverse Use of Broad-Spectrum Antibiotics by the Antimicrobial Stewardship Program in Japan.

Increased antibiotic use and antibiotic homogeneity cause selective pressure. This study investigated the correlation between antibiotic diversity and antimicrobial resistance (AMR) in Gram-negative organisms. The days of therapy/100 patient-days (DOT) for four broad-spectrum antibiotic classes were evaluated for 2015-2022. The antibiotic heterogeneity index (AHI) for the equal use of four classes (25%) and the modified AHI for the equal use of three classes (30%), excluding fluoroquinolones (10%), were measured (target: 1.0). Quarterly antibiotic use markers and the resistance rates against ≥2 anti-Pseudomonas antibiotics were compared. The DOT value was 9.94, and the relative DOT were 34.8% for carbapenems, 32.1% for piperacillin/tazobactam, 24.3% for fourth generation cephalosporins/ceftazidime/aztreonam, and 8.9% for fluoroquinolones. Although no correlation was found between the total DOT and the resistance rate for any bacterium, a significant negative correlation was found between the heterogeneity indices and resistance rates for Pseudomonas aeruginosa and Klebsiella pneumoniae. The significant cutoffs that discriminate the risk of resistance were 0.756 for the AHI and 0.889 for the modified AHI for K. pneumoniae. Antibiotic diversity is more important in preventing AMR than overall antibiotic use. The ideal ratio of broad-spectrum antibiotics should be studied for diversified use to prevent AMR.

Two Distinct Groups Are Shown to Be at Risk of Diabetes by Means of a Cluster Analysis of Four Variables.

Recent attempts to classify adult-onset diabetes using only six diabetes-related variables (GAD antibody, age at diagnosis, BMI, HbA1c, and homeostatic model assessment 2 estimates of b-cell function and insulin resistance (HOMA2-B and HOMA2-IR)) showed that diabetes can be classified into five clusters, of which four correspond to type 2 diabetes (T2DM). Here, we classified nondiabetic individuals to identify risk clusters for incident T2DM to facilitate the refinement of prevention strategies. Of the 1167 participants in the population-based Iwaki Health Promotion Project in 2014 (baseline), 868 nondiabetic individuals who attended at least once during 2015-2019 were included in a prospective study. A hierarchical cluster analysis was performed using four variables (BMI, HbA1c, and HOMA2 indices). Of the four clusters identified, cluster 1 (n = 103), labeled as "obese insulin resistant with sufficient compensatory insulin secretion", and cluster 2 (n = 136), labeled as "low insulin secretion", were found to be at risk of diabetes during the 5-year follow-up period: the multiple factor-adjusted HRs for clusters 1 and 2 were 14.7 and 53.1, respectively. Further, individuals in clusters 1and 2 could be accurately identified: the area under the ROC curves for clusters 1and 2 were 0.997 and 0.983, respectively. The risk of diabetes could be better assessed on the basis of the cluster that an individual belongs to.

Association of the COVID-19 pandemic with changes in objectively measured sedentary behaviour and adiposity.

BACKGROUND: Several studies have reported that the coronavirus disease (COVID-19) pandemic has increased sedentary behaviour and obesity; however, these analyses used self-reported data, and the association between sedentary behaviour and visceral fat and adipocytokines during the COVID-19 pandemic remains unclear. We aimed to investigate the association of the COVID-19 pandemic with objectively measured sedentary behaviour and these obesity-related factors. METHODS: Longitudinal analysis was conducted on 257 Japanese participants who underwent health check-ups in 2018 before and in 2020 during the COVID-19 pandemic. For both time points, sedentary behaviour was measured using an accelerometer for at least 7 days, visceral fat area (VFA) was measured using abdominal bioelectrical impedance analysis, and blood adiponectin level was measured using latex agglutination turbidimetric immunoassay. Multiple linear regression was performed to determine the association between sedentary behaviour and these outcomes. RESULTS: Compared with data in 2018, sedentary behaviour and VFA were significantly increased (P < 0.001, P = 0.006) whereas adiponectin level was significantly decreased (P < 0.001) in 2020. Increased sedentary behaviour was significantly associated with an increase in VFA (ß = 3.85, 95% CI 1.22-6.49, P = 0.004) and a decrease in adiponectin level (ß = -0.04, 95% CI -0.06 to -0.01, P = 0.005). However, the association of sedentary behaviour with adiponectin level was not significant after considering the effects of VFA. CONCLUSIONS: The COVID-19 pandemic was associated with objectively measured sedentary behaviour and obesity-related factors in Japanese adults. Additionally, an increase in sedentary behaviour was associated with an increase in VFA, whereas the association of sedentary behaviour with adiponectin was partly mediated by VFA. These results suggest that avoiding increasing sedentary time is important to prevent visceral adiposity thereby ameliorating adiponectin, especially during behavioural limitations such as the COVID-19 pandemic.

Mimic of transient ischemic attack by anemia-induced asterixis: A novel differential diagnosis of stroke with critical pitfalls.

As most cases of asterixis with metabolic causes are asymptomatic, they have not been considered in the differential diagnosis of stroke. However, an asterixis occasionally resembles a transient ischemic attack (TIA). On the other hand, reports have indicated that anemia is an independent risk factor for brain ischemia. Therefore, both asterixis and anemia are important considerations for stroke diagnosis. A 79-year-old man with frequent leg palsy was initially diagnosed with recurrent TIA at the anterior cerebral artery (ACA) with a tiny callosal infarction and aspirin was prescribed immediately. However, subsequent careful physical examination revealed asterixis at both the wrist and knee joints. Laboratory testing and colonoscopy revealed severe anemia secondary to colon cancer. Blood transfusion immediately improved the asterixis and gait, thus confirming that anemia contributed to the patient's symptoms. This novel etiology of asterixis may be accompanied by misleading anemia-induced brain ischemic lesions detectable on magnetic resonance imaging (MRI). Anemia-induced asterixis should be considered as a novel differential diagnosis of a stroke to avoid pitfalls leading to unnecessary stroke treatment for patients with anemia.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

PURPOSE: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). METHODS: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. RESULTS: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. CONCLUSIONS: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Stiffness of primordial germ cells is required for their extravasation in avian embryos.

Unlike mammals, primordial germ cells (PGCs) in avian early embryos exploit blood circulation to translocate to the somatic gonadal primordium, but how circulating PGCs undergo extravasation remains elusive. We demonstrate with single-cell level live-imaging analyses that the PGCs are arrested at a specific site in the capillary plexus, which is predominantly governed by occlusion at a narrow path in the vasculature. The occlusion is enabled by a heightened stiffness of the PGCs mediated by actin polymerization. Following the occlusion, PGCs reset their stiffness to soften in order to squeeze through the endothelial lining as they transmigrate. Our discovery also provides a model for the understanding of metastasizing cancer extravasation occurring mainly by occlusion.

Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

PURPOSE: Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group. METHODS: Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians. FINDINGS: In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively. IMPLICATIONS: Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.

Epidemiology and bacterial characteristics of invasive group B streptococcus disease: a population-based study in Japan in 2010-2020.

This is the first report on a population-based prospective study of invasive group B streptococcus (GBS) disease among children aged <15 years conducted over a period of 11 years in Japan. This study investigated the incidence and clinical manifestations of invasive GBS disease in children in Chiba Prefecture, Japan, and analysed the serotypes and drug susceptibility of GBS strains isolated during the study period. Overall, 127 episodes of invasive GBS disease were reported in 123 patients. Of these, 124 were observed in 120 patients aged <1 year, and the remaining three episodes were reported in a 9-year-old child and two 14-year-old children with underlying disease. For patients aged <1 year, the incidence rate per 1000 live births was 0.24 (0.15-0.36). The incidences of early-onset disease and late-onset disease were 0.04 (0.0-0.09) and 0.17 (0.08-0.25), respectively. The rate of meningitis was 45.2%, and the incidence of GBS meningitis was higher than that of other invasive diseases among children in Japan. Of the 109 patients for whom prognosis was available, 7 (6.4%) died and 21 (19.3%) had sequelae. In total, 68 strains were analysed. The most common were serotype III strains (n = 42, 61.8%), especially serotype III/ST17 strains (n = 22, 32.4%). This study showed that the incidence of invasive GBS disease among Japanese children was constant during the study period. Because of the high incidence of meningitis and disease burden, new preventive strategies, such as GBS vaccine, are essential.

Newly raised anti-c-Kit antibody visualizes morphology of interstitial cells of Cajal in the developing gut of chicken embryos.

The gut peristaltic movement, a wave-like propagation of a local contraction, is important for the transportation and digestion of ingested materials. Among three types of cells, the enteric nervous system (ENS), smooth muscle cells, and interstitial cells of Cajal (ICCs), the ICCs have been thought to act as a pacemaker, and therefore it is important to decipher the cellular functions of ICCs to further our understanding of gut peristalsis. c-Kit, a tyrosine kinase receptor, has widely been used as a marker for ICCs. Most studies with ICCs have been conducted in mammals using commercially available anti-c-Kit antibody. Recently, the chicken embryonic gut has emerged as a powerful model to study gut peristalsis. However, since the anti-c-Kit antibody for mammals does not work for chickens, cellular mechanisms by which ICCs are regulated have largely been unexplored. Here, we report a newly raised polyclonal antibody against the chicken c-Kit protein. The specificity of the antibody was validated by both western blotting analyses and immunocytochemistry. Co-immunostaining with the new antibody and anti-α smooth muscle actin (αSMA) antibody successfully visualized ICCs in the chicken developing hindgut in the circular muscle and longitudinal muscle layers. As previously shown in mice, common progenitors of ICCs and smooth muscle cells at early stages were double positive for αSMA and c-Kit, and at later stages, differentiated ICCs and smooth muscle cells exhibited only c-Kit and αSMA, respectively. A novel ICC population was also found that radially extended from the submucosal layer to the circular muscle layer. Furthermore, the new antibody delineated individual ICCs in a cleared hindgut. The antibody newly developed in this study will facilitate the study of peristaltic movement in chicken embryos.

Correction of thrombocytopenia caused by linezolid with scheduled sequential tedizolid use in patients with vertebral osteomyelitis by antibiotic resistant Gram-positive organisms.

INTRODUCTION: Because of thrombocytopenia, linezolid treatment tends to be stopped before the completion of therapy for complicated infections that require prolonged antimicrobial administration. In contrast, tedizolid shows a favorable hematologic profile. The primary end-point of this study was to evaluate the efficacy of switching treatment to tedizolid in patients who developed thrombocytopenia during linezolid therapy. METHODS: This retrospective study was conducted in patients with vertebral osteomyelitis (VO) caused by antibiotic-resistant Gram-positive bacteria. Treatment failure was defined as the reappearance of infection signs within 2 weeks after stopping tedizolid and discontinuation of tedizolid because of continued thrombocytopenia or other adverse effects. RESULTS: Eight patients with native VO (n = 3) and postoperative VO (n = 5) were included in the study. The causative organisms were MRSA in all patients except one. Platelet counts decreased from 35.2 ± 11.5 × 104/mm3 to 17.8 ± 6.2 × 104/mm3 during linezolid therapy and improved without washout period in all patients after switching to tedizolid on days 5-7 (28.6 ± 4.9 × 104/mm3, p = 0.002). Tedizolid therapy was completed and treatment failure was not observed in any patient. The duration of treatment was 20.0 ± 11.2 days for linezolid and 30.3 ± 9.5 days for tedizolid (total, 50.3 ± 10.7 days). One patient died because of underlying disease, and there was no recurrence in the remaining 7 patients (median follow-up 501 days). CONCLUSIONS: Switching therapy to tedizolid improved thrombocytopenia that occurred during linezolid therapy, and it enabled the completion of therapy for VO patients.

Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

BACKGROUND: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). METHODS: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. RESULTS: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 µg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1-2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. CONCLUSIONS: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.