APC/PIK3CA mutations and ß-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

BACKGROUND: Aberrant WNT/ß-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, ß-catenin repressors. Tankyrase inhibitors block WNT/ß-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven ß-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity. METHODS: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582. RESULTS: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active ß-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a ß-catenin-independent manner. CONCLUSIONS: APC/PIK3CA mutations and ß-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

The fatal case of "Pigmentibacter" bacteremia following aspiration pneumonia in elderly patient.

"Pigmentibacter ruber" was first reported in 2021, a novel bacterium of the family Silvanigrellaceae, isolated from human blood of the patient with aspiration pneumonia after the drowning accident in Republic of China. However, until now, there is only one report describing "P. ruber" infection, and no case of isolation from natural environment has been reported so far. Thus, the infectivity and pathogenicity of "Pigmentibacter" spp. has not been clearly understood. In this report, we described the fatal case of "Pigmentibacter" bacteremia subsequently occurred after aspiration pneumonia probably due to accidental ingestion of irrigation water in the elderly patient. Despite administration of broad-spectrum antibiotic, the patient dramatically deteriorated and eventually deceased. Whole-genome sequencing showed the strain isolated from the patient was identified as "Pigmentibacter" sp. (designated as strain Takaoka) and antimicrobial sensitivity testing showed it displayed high minimum inhibitory concentrations against various antibiotics including ß-lactam. Further studies are needed to clarify the clinical characteristics of "Pigmentibacter" and its relative's infections and their antimicrobial sensitivity; however, the present case supported the clinical characteristics of "Pigmentibacter" infection, which can lead to bacteremia following aspiration pneumonia caused by mis-swallowing contaminated water, and poor outcome potentially due to multidrug resistances.

Comorbidities and co-medications among 28 089 people living with HIV: A nationwide cohort study from 2009 to 2019 in Japan.

OBJECTIVES: Comorbidities are associated with a high burden of disease in people living with HIV (PLWH). The objective was to investigate the prevalence of chronic comorbidities and use of co-medications in PLWH in Japan. METHODS: This study retrospectively analysed clinical information from PLWH receiving antiretroviral therapy (ART) between April 2009 and March 2019. Demographic characteristics, numbers and types of chronic comorbidities, and numbers and types of non-ART co-medications, were described by age groups. The source of data was the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). RESULTS: Overall, 28 089 PLWH (male 91.9%) who used ART were identified. Out of 28 089 PLWH, 81.5% had at least one chronic comorbidity. The numbers of AIDS-defining cancers and non-AIDS-defining cancers in this Japanese cohort were 2432 (8.7%) and 2485 (8.8%), respectively. The cumulative burden of comorbidities including non-AIDS-defining cancer increased with age. Changes in trend between 2009 and 2019 were observed, including a higher proportion of PLWH diagnosed at ≥ 70 years old [2019 (4.7%) vs. 2009 (2.4%)] and a decreasing percentage of patients with AIDS-defining cancers (down from 6.3% to 4.8% between 2009 and 2019). The most common co-medications during the most recent 3-month period were lipid-regulating/anti-atheroma preparations (11.3%), antacids, antiflatulents and anti-ulcerants (9.6%), and agents acting on the renin-angiotensin system (8.1%). The three most common therapeutic categories of co-medications during the study period were antacids, antiflatulents and anti-ulcerants (35.0%), systemic antihistamines (33.7%) and psycholeptics (27.1%). More than 30% of PLWH aged > 40 years used at least one co-medication in a 3-month period, while more than half of PLWH aged > 30 years had at least one co-medication prescribed concomitantly for a total of ≥ 90 days during the study period, and the numbers of co-medications used were greater in the older age groups. CONCLUSIONS: The burden of chronic comorbidities and co-medication were found to be greater in older, as compared to younger patients, among 28 089 PLWH in a nationwide study in Japan. This finding suggests the need to identify elderly PLWH and to appropriately manage their HIV and comorbidities.

Delayed diagnosis of human immunodeficiency virus infection in people diagnosed with syphilis: A nationwide cohort study from 2011 to 2018 in Japan.

Early treatment of HIV infection depends on timely diagnosis, but many persons living with HIV/AIDS (PLWHA) are unaware of their infection. Though many patients seeking medical attention for sexually transmitted diseases have HIV, many patients' HIV co-infection is undiagnosed in Japan. This is the first report to analyze the timing of syphilis infection in PLWHA of all ages through the use of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), containing clinical data of the largest group of HIV-positive patients available in Japan. Overall, 1521 PLWHA (male 93.2%) newly diagnosed and started on antiretroviral therapy were identified in 2016, and 646 (42.5%) patients had a diagnosis of syphilis between 2011 and 2018. Although 100 patients were diagnosed with syphilis before their HIV diagnosis, only 17 (17.0%) had been tested for HIV. Over 50 patients per year became infected with syphilis even after their HIV diagnosis (2017, n = 65 (4.3%); 2018, n = 58 (3.8%)). Although early diagnosis of HIV infection is important, most syphilis patients in Japan had not been properly tested for HIV infection. Since a certain number of HIV patients developed syphilis after HIV diagnosis, education for newly diagnosed HIV patients is important.

Syphilis in people living with HIV does not account for the syphilis resurgence in Japan.

OBJECTIVES: This study aimed to determine whether the current syphilis resurgence in Japan is attributable to incident syphilis in people living with HIV (PLWH). METHODS: This observational, retrospective, population-based study used data from the Japanese National Database. Data were extracted for PLWH who received antiretroviral treatment between January 2009 and December 2018. Using these data, along with the annual number of PLWH and syphilis diagnoses in the total population of Japan acquired from the National Institute of Infectious Diseases, the fraction of PLWH with syphilis compared to the total number of syphilis patients reported each year was calculated. RESULTS: There was a dramatic increase in syphilis cases during the study period. However, the incidence of syphilis in PLWH was stable during 2010-2018; the fraction of PLWH with newly diagnosed syphilis remaining at approximately 2% of the total PLWH cases in Japan each year. The proportion of newly diagnosed syphilis cases in PLWH decreased during the study period and accounted for <10% of the total syphilis cases in Japan since 2016 (14.9% in 2015 to 9.5% in 2016 and 5.9% in 2018). An increasing trend in the number of newly diagnosed syphilis cases in PLWH aged >50 years was observed (7.4% in 2010 to 10.4% in 2014 and 14.9% in 2018). CONCLUSIONS: The recent dramatic increase in syphilis cases in Japan was not seen in PLWH. Thus, the resurgence of syphilis in Japan cannot be attributed to its transmission in the PLWH population.

A preliminary analysis of the performance of a targeted HIV electronic medical records alert system: A single hospital experience.

Early treatment of HIV relies on a timely detection of the infection, but many people living with HIV/AIDS are unaware of their infection. In the current study, we applied an electronic medical records (EMR)-based alert system flagging high-risk patients previously diagnosed with infections of syphilis, hepatitis A virus, hepatitis B virus, and/or hepatitis C virus, and those aged 20-50 years with a prior diagnosis of shingles. During the study period (April to October 2019), a total of 47 individuals among 22,264 patients visiting our department were identified as having high-risk of carrying HIV, and 14 of these individuals underwent HIV testing. Two males aged below 65 years with a previous diagnosis of syphilis were subsequently tested positive for HIV. This preliminary analysis of the EMR alert system facilitated the identification of high-risk people possibly carrying HIV, but the test rate remains to be improved.

Pneumococcal vaccination reduces in-hospital mortality, length of stay and medical expenditure in hospitalized elderly patients.

Pneumococcal vaccination has been shown to reduce occurrence of invasive pneumococcal diseases in elderly patients. In this study, we investigated the real-world efficacy of pneumococcal vaccination implemented in elderly individuals in Japan. We reviewed the in-patient database of Juntendo University Hospital and selected elderly patients (≥65 years-old) who had received in-patient care in the general medicine department during 2014-2018. A total of 1355 patients were retrospectively enrolled and comprised of 1045 unvaccinated and 315 vaccinated elderly individuals. Prior vaccination was found associated with all-cause shorter hospital stays (adjusted RR = 0.66, 95% CI = 0.57 to 0.76) and less medical expenditure (adjusted RR = 0.76, 95% CI = 0.66 to 0.87) compared with no vaccination, as well as protection for all-cause in-hospital mortality (adjusted OR = 0.42, 95% CI = 0.22 to 0.83). The association of shorter hospital stays and less medical expenditure with vaccination was also observed in the context of pneumonia, although no altered risk in mortality was observed. In conclusion, this study is one of the first reporting real-world data after the initiation of pneumococcal vaccination program in 2014 in Japan. The national PPV23 vaccination program contributed to the reduction of all-cause in-patient days, mortality, and medical expenses in the elderly aged ≥65 years. Further data is warranted to evaluate the contribution from influenza vaccination and protein-conjugate based pneumococcal vaccine.

The estimated impact of the 5-year national vaccination program on the trend of 23-valent pneumococcal polysaccharide vaccine vaccination rates in the elderly in Japan, 2009-2018.

Pneumonia is the third most common cause of death in Japan. Low vaccination rates are thought to be related to low levels of public subsidy. Since 2014, the Japanese government has offered subsidies through a 5-year national routine vaccination program of the 23-valent pneumococcal polysaccharide vaccine (PPV23) for older adults at age ≥65 years with 5-year age intervals. We previously reported that, 2 years into the 5-year program, the estimated vaccination rate was 40.6% at the end of 2015, a significant increase compared with periods before the program introduced. Here, we present an update on the estimated vaccination coverage of the 5-year national routine vaccination program at the end of 2018. The PPV23 vaccination rates were calculated by dividing the cumulative amount shipped to each municipality by the population aged ≥65 years. At the end of 2018, the completion of the 5-year national immunization program, the estimated cumulative vaccination rate was 74%. Stepwise regression analysis revealed that the annual PPV23 vaccination rate significantly increased after 2014 (from 2 to 5% prior to 2014, to 10-11% after 2014), and remained steady for 2014-2018. Our findings suggest that the 5-year national routine vaccination subsidy program was successful in achieving a steady and higher vaccination rate of PPV23 in Japan.

Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D -driven tumor promotion.

Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-rasG12D -expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably-treated K-rasG12D -expressing mice did not. H&E-staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly-mutant vs K-rasG12D mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-rasG12D -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-rasG12D -only mice. Moreover, AKT phosphorylation increased in K-rasG12D -expressing/Ppp6c-deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. Finally, increased numbers of K14-positive cells were present in the suprabasal layer of doubly-mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX-positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-rasG12D -dependent tumor promotion.

Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.

The CALM-AF10 fusion gene, which results from a t(10;11) translocation, is found in a variety of hematopoietic malignancies. Certain HOXA cluster genes and MEIS1 genes are upregulated in patients and mouse models that express CALM-AF10. Wild-type clathrin assembly lymphoid myeloid leukemia protein (CALM) primarily localizes in a diffuse pattern within the cytoplasm, whereas AF10 localizes in the nucleus; however, it is not clear where CALM-AF10 acts to induce leukemia. To investigate the influence of localization on leukemogenesis involving CALM-AF10, we determined the nuclear export signal (NES) within CALM that is necessary and sufficient for cytoplasmic localization of CALM-AF10. Mutations in the NES eliminated the capacity of CALM-AF10 to immortalize murine bone-marrow cells in vitro and to promote development of acute myeloid leukemia in mouse models. Furthermore, a fusion of AF10 with the minimal NES can immortalize bone-marrow cells and induce leukemia in mice. These results suggest that during leukemogenesis, CALM-AF10 plays its critical roles in the cytoplasm.

The ADP-ribosylation factor 1 gene is indispensable for mouse embryonic development after implantation.

ADP-ribosylation factor (Arf) 1 is thought to affect the morphologies of organelles, such as the Golgi apparatus, and regulate protein trafficking pathways. Mice have six Arf isoforms. In knockdown experiments with HeLa cells, no single Arf isoform among Arf1-5 is required for organelle morphologies or any membrane trafficking step. This suggests that the cooperation of two or more Arfs is a general feature. Although many cell biological and biochemical analyses have proven the importance of Arf1, the physiological roles of Arf1 in mice remain unknown. To investigate the activity of Arf1 in vivo, we established Arf1-deficient mice. Arf(-/-) blastocysts were identified at the expected Mendelian ratio. The appearance of these blastocysts was indistinguishable from that of wild-type and Arf(+/-) blastocysts, and they grew normally in an in vitro culture system. However, Arf(-/-) embryos were degenerated at E5.5, and none survived to E12.5, suggesting that they died soon after implantation. These data establish for the first time that the Arf1 gene is indispensable for mouse embryonic development after implantation.

A case of coronary artery compression syndrome resulting from peri-valvular regurgitation and long-standing atrial fibrillation.

A man in his 70s with a history of mitral valve replacement (MVR) and long-standing persistent atrial fibrillation (AF) presented with effort angina. Coronary angiography revealed severe stenosis of the left main coronary artery (LMCA). As it was an emergent case, PCI (percutaneous coronary intervention) was selected for treatment. Intravascular ultrasonography revealed no atherosclerotic lesions in the LMCA. The LMCA was effectively dilated by the drug-eluting stent. No elevation in intracardiac pressure was observed in cardiac catheterization after PCI. Computed tomography scan indicated potential compression of the LMCA by the surrounding structures. In cases of long-standing persistent AF and an enlarged atrium after MVR, the possibility of LMCA stenosis due to anatomical changes should be considered. Learning Objectives: ◾Peri-valvular regurgitation and long-standing persistent atrial fibrillation can potentially cause atrial enlargement.◾Coronary artery stenosis without atherosclerosis can occur due to compression from surrounding structures or shifting of the coronary artery.◾Stent therapy provides a temporary solution and coronary artery bypass grafting or switching should be considered if re-stenosis occurs.

A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer.

Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.

Isolation and identification of Wickerhamiella tropicalis from blood culture by MALDI-MS.

Wickerhamiella is a genus of budding yeast that is mainly isolated from environmental samples, and 40 species have been detected. The yeast isolated from human clinical samples usually only contain three species: W. infanticola, W. pararugosa and W. sorbophila. In this study, we isolated W. tropicalis from a blood sample of a six-year-old female with a history of B-cell precursor lymphoblastic leukemia in Japan in 2022. Though the strain was morphologically identified as Candida species by routine microbiological examinations, it was subsequently identified as W. tropicalis by sequencing the internal transcribed spacer (ITS) of ribosomal DNA (rDNA). The isolate had amino acid substitutions in ERG11 and FKS1 associated with azole and echinocandin resistance, respectively, in Candida species and showed intermediate-resistant to fluconazole and micafungin. The patient was successfully treated with micafungin. Furthermore, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) detected three novel peaks that are specific for W. tropicalis, indicating that MALDI-MS analysis is useful for rapid detection of Wickerhamiella species in routine microbiological examinations.

3-ß-Glucosyl-3'-ß-quinovosyl zeaxanthin, a novel carotenoid glycoside synthesized by Escherichia coli cells expressing the Pantoea ananatis carotenoid biosynthesis gene cluster.

Escherichia coli cells that express the full six carotenoid biosynthesis genes (crtE, crtB, crtI, crtY, crtZ, and crtX) of the bacterium Pantoea ananatis have been shown to biosynthesize zeaxanthin 3,3'-ß-D-diglucoside. We found that this recombinant E. coli also produced a novel carotenoid glycoside that contained a rare carbohydrate moiety, quinovose (chinovose; 6-deoxy-D-glucose), which was identified as 3-ß-glucosyl-3'-ß-quinovosyl zeaxanthin by chromatographic and spectroscopic analyses. The chirality of the aglycone of these zeaxanthin glycosides had been shown to be 3R,3'R, in which the hydroxyl groups were formed with the CrtZ enzyme. It was here demonstrated that zeaxanthin synthesized from ß-carotene with CrtR or CYP175A1, the other hydroxylase with similar catalytic function to CrtZ, possessed the same stereochemistry. It was also suggested that the singlet oxygen-quenching activity of zeaxanthin 3,3'-ß-D-diglucoside, which has a chemical structure close to the new carotenoid glycoside, was superior to that of zeaxanthin.

Heat-Killed Levilactobacillus brevis as a Candidate Postbiotics Through Immunostimulation Mediated by Macrophage-Inducible C-Type Lectin.

To understand the beneficial health-promoting effects of lactic acid bacteria (LAB) on immune cells, it is necessary to understand the relationship between LAB and innate immune receptors. We investigated the possible involvement of C-type lectin receptors (CLRs) in the immune-stimulating function of LAB in several strains. We found that levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 were reduced by the addition of inhibitors for spleen tyrosine kinase (syk), a signaling molecule used by several CLRs. Furthermore, employing CLR-Fc fusion proteins and reporter cells, we found that macrophage-inducible C-type lectin (Mincle) binds to Levilactobacillus brevis strain La37. Interestingly, this interaction was only observed in heat-killed L. brevis and disappeared after proteinase K treatment. Seven strains of L. brevis from different sources were also examined; among them, six strains showed Mincle reactivity, and the characteristics of the ligand were similar to those of La37. These results may facilitate a better understanding of the immunomodulatory effects of LAB for the development of functional foods.

A Mobile Medication Support App and Its Impact on People Living With HIV: 12-Week User Experience and Medication Compliance Pilot Study.

BACKGROUND: The continuity of care between hospital visits conducted through mobile apps creates new opportunities for people living with HIV in situations where face-to-face interventions are difficult. OBJECTIVE: This study investigated the user experience of a mobile medication support app and its impact on improving antiretroviral therapy compliance and facilitating teleconsultations between people living with HIV and medical staff. METHODS: Two clinics in Japan were invited to participate in a 12-week trial of the medication support app between July 27, 2018, and March 31, 2021. Medication compliance was assessed based on responses to scheduled medication reminders; users, including people living with HIV and medical staff, were asked to complete an in-app satisfaction survey to rate their level of satisfaction with the app and its specific features on a 5-point Likert scale. RESULTS: A total of 10 people living with HIV and 11 medical staff were included in this study. During the trial, the medication compliance rate was 90%, and the mean response rates to symptom and medication alerts were 73% and 76%, respectively. Overall, people living with HIV and medical staff were satisfied with the medication support app (agreement rate: mean 81% and 65%, respectively). Over 80% of medical staff and people living with HIV were satisfied with the ability to record medications taken (9/11 and 8/10 medical staff and people living with HIV, respectively), record symptoms of concern (10/11 and 8/10),and inquire about drug combinations (8/10, 10/10). And further, 90% of people living with HIV were satisfied with the function for communication with medical staff (9/10). CONCLUSIONS: Our preliminary results demonstrate the feasibility of the medication support app in improving medication compliance and enhancing communication between people living with HIV and medical staff.

Association between serum uric acid levels and achievement of target blood pressure among Japanese community residents with hypertension.

The authors examined the sex-specific association between serum uric acid (SUA) levels and achievement of target blood pressure among Japanese patients with hypertension. This cross-sectional study was conducted between January 2012 and December 2015 and examined 17 113 eligible participants (6499 men; 10 614 women) with hypertension among 66 874 Japanese community residents who underwent voluntary health checkups. Multivariate analysis was used to estimate the association between high SUA level (≥7.0 mg/dL for men and ≥6.0 mg/dL for women) and "therapeutic failure" in achieving target blood pressure (BP) of 140/90 and 130/80 mmHg in both sexes. Multivariate analysis revealed that high SUA level was significantly associated with failure to achieve the 130/80 mmHg treatment goal among men (AOR = 1.24, 95% CI = 1.03-1.50, p = .03). Among women, high SUA level was significantly associated with failure to achieve both the 130/80 and 140/90 mmHg treatment goals (AOR = 1.33, 95% CI = 1.20-1.47, p < .01 and AOR = 1.17, 95% CI = 1.04-1.32, p < .01, respectively). Each increase in SUA quartile was positively associated with increases in systolic BP (SBP) and diastolic BP (DBP) (p < .01 for trend) in both sexes. SBP and DBP in each quartile (Q2-Q4) were also significantly higher compared with those of Q1 in both sexes (p < .01). Our data confirms the difficulties in maintain goal BP control in those with elevated SUA.

Integrated Extrinsic and Intrinsic Self-Healing of Polysiloxane Materials by Cleavable Molecular Cages Encapsulating Fluoride Ions.

Self-healing ability is crucial to increasing the lifetime and reliability of materials. In this study, spatiotemporal control of the healing of a polysiloxane material is achieved using a cleavable cage compound encapsulating a fluoride ion (F- ), which triggeres the dynamic rearrangement of the siloxane (Si-O-Si) networks. A self-healing siloxane-based elastomer is prepared by cross-linking polydimethylsiloxane (PDMS) with a F- -encapsulating cage-type germoxane (Ge-O-Ge) compound. This material can self-heal repeatedly under humid conditions. The F- released by hydrolytic cleavage of the cage framework contributes to rejoining of the cut pieces by promoting the local rearrangement of the siloxane networks. The use of a molecular cage encapsulating a catalyst for dynamic bond rearrangement provides a new concept for designing self-healing polysiloxane materials based on integrated extrinsic and intrinsic mechanisms.

Successful Treatment of a Case of Metallo-Beta-Lactamase-Producing Raoultella ornithinolytica Bacteremia by Antimicrobial Stewardship Team Intervention and Therapeutic Drug Monitoring-Based Amikacin Treatment.

An 80-year-old woman underwent pancreatoduodenectomy. Post-operation, she experienced a fever, and a culture of blood revealed metallo-beta-lactamase-producing Raoultella ornithinolytica. For treatments with aminoglycoside antimicrobial agents, a therapeutic drug monitoring-based dosing design can lower the risk of adverse events and enable appropriate treatment. Key Clinical Message. When aminoglycoside antimicrobial agents are administered for MBL-producing bacteremia, prescription suggestions based on TDM by antimicrobial stewardship team can reduce the occurrence of adverse events and enable appropriate treatment.