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Kazuma Sugimoto,1 Tsuneaki Kenzaka,1,2 Ryu Sugimoto,1 Akihito Kitao,3 Hozuka Akita1 1Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba, Hyogo, Japan; 2Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; 3Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, JapanCorrespondence: Tsuneaki KenzakaDivision of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2-1-5, Arata-cho, Hyogo-ku, Kobe, Hyogo, 652-0032, JapanTel +81 78 382 6732Fax +81 78 382 6283Email smile.kenzaka@jichi.ac.jpBackground: Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.Case Presentation: Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.Conclusion: VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence–Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.Keywords: acyclovir neurotoxicity, valacyclovir, herpes zoster, Bence–Jones proteinuria

Tsuneaki Kenzaka,1,2 Ayako Kumabe,2 Koki Kosami,2 Yuki Ueda,2 Takeshi Takahashi,3 Yuya Yamamoto,4 Yurika Hayashi,4 Akihito Kitao,4 Masanobu Okayama5 1Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe, Japan; 2Division of General Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan; 3Department of Community and Family Medicine, Yuzawa Community Medical Center, Yuzawa, Japan; 4Department of General Medicine, Toyooka Public Hospital, Toyooka, Japan; 5Division of Community Medicine and Medical Education, Kobe University Graduate School of Medicine, Kobe, Japan Purpose: The aim of this study was to investigate whether the day of starting oral intake affects the clinical course of patients with aspiration pneumonia.Patients and methods: We conducted a retrospective cohort study of 392 patients who were hospitalized for aspiration pneumonia but tolerated oral intake. Patients were divided into two groups according to the day of starting oral intake: Monday to Friday (midweek group) and Saturday or Sunday (weekend group). Underlying diseases, severity of pneumonia, time to oral intake, hospital duration, discontinuation of oral intake, and death during hospitalization were compared between the groups. Multivariate analysis was performed using hospital duration and discontinuation of oral intake due to aspiration as the dependent variables.Results: The cohort comprised 244 men and 148 women with a mean age of 79.3 ± 13.1 years. The weekend (n = 98) and midweek (n = 294) groups exhibited similar age, sex, and underlying diseases. There were no significant differences in pneumonia-related factors, such as CURB-65 score, A-DROP score, extent of shadow on chest radiograph, incidence of bacteremia, and ventilator use. The weekend group exhibited a significantly shorter time to oral intake and hospital duration, as well as a significantly lower incidence of discontinuation of oral intake than the midweek group. Multivariate analysis revealed that starting oral intake on the weekend was independently associated with a lower incidence of discontinuation of oral intake due to aspiration. Conclusion: The weekend group exhibited a shorter total hospital duration and a lower incidence of discontinuation of oral intake due to aspiration. Keywords: discontinuation of oral intake, hospital duration, health economics, weekend

Tsuneaki Kenzaka,1,2 Taro Takeshima,3 Koki Kosami,2 Ayako Kumabe,2 Yuki Ueda,2 Takeshi Takahashi,4 Yuya Yamamoto,5 Yurika Hayashi,5 Akihito Kitao,5 Masanobu Okayama6 1Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe, 2Division of General Medicine, 3Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, 4Department of Community and Family Medicine, Yuzawa Community Medical Center, Yuzawa, 5Department of General Medicine, Toyooka Public Hospital, Toyooka, 6Division of Community Medicine and Medical Education, Kobe University Graduate School of Medicine, Kobe, Japan Purpose: To assess the factors involved in oral intake discontinuation in elderly patients with recurrent aspiration pneumonia. Patients and methods: This study included patients with pneumonia who were treated at Jichi Medical University Hospital between 2007 and 2013, at Toyooka Public Hospital between 2011 and 2013 and at Yuzawa Community Medical Center between 2010 and 2012. We consecutively enrolled patients with aspiration pneumonia. The primary study point was oral intake discontinuation after the initiation of oral intake during hospitalization in cases of recurrent aspiration. Various parameters were recorded at admission, at the initiation of intake, and during hospitalization; these parameters were statistically evaluated. Results: A total of 390 patients were assigned to either a “no reaspiration of intake” group (n=310) or a “reaspiration of intake” group (n=80), depending on whether intake was discontinued owing to aspiration during hospitalization. At admission, the following items significantly differed between the groups: level of consciousness, respiratory rate, oxygen saturation, CURB-65 score, extent of infiltration/opacity on chest radiography, albumin levels, blood urea nitrogen levels, and application of swallowing function assessment. At the initiation of intake, level of consciousness, pulse rate, and albumin levels significantly differed between the groups. The following items did not significantly differ between groups: systolic blood pressure, pulse rate, C-reactive protein, bacteremia, use of ventilator at admission, oxygen administration, respiratory rate, and systolic blood pressure at initiation of intake. Multivariate analysis revealed that application of swallowing function assessment, level of consciousness at the initiation of intake, and extent of infiltration/opacity on chest radiography were significant predictive variables for discontinuation of intake. Conclusion: A low level of consciousness at the initiation of intake and a greater extent of infiltration/opacity on chest radiography and the application of a swallowing function are important factors. These factors may be helpful to determine a suitable timing for resumption of oral intake. Keywords: assessment of swallowing function, level of consciousness, recurrent aspiration, resumption of oral intake

Abstract Aims Anaemia has been reported as poor predictor in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the impact of changes in haemoglobin (Hb) from discharge to 1 year after discharge on the prognosis using a lower cut‐off value of Hb than the World Health Organization (WHO) criteria. Methods and results First, 547 HFpEF cases were divided into two groups, Hb

Abstract Background Bacillus cereus is a Gram-positive, spore-forming bacterium that produces a spectrum of effectors integral to bacterial niche adaptation and the development of various infections. Among those is EsxA, whose secretion depends on the EssC component of the type VII secretion system (T7SS). EsxA’s roles within the bacterial cell are poorly understood, although postulations indicate that it may be involved in sporulation. However, the T7SS repertoire in B. cereus has not been reported, and its functions are unestablished. Methods We used the type strain, B. cereus ATCC14579, to generate ΔessC mutant through homologous recombination using the homing endonuclease I-SceI mediated markerless gene replacement. Comparatively, we analyzed the culture supernatant of type strain and the ΔessC mutant through Liquid chromatography-tandem mass spectrometry (LC-MS/MS). We further generated T7SSb-specific gene mutations to explore the housekeeping roles of the T7SSb-dependent effectors. The sporulation process of B. cereus ATCC14579 and its mutants was observed microscopically through the classic Schaeffer-Fulton staining method. The spore viability of each strain in this study was established by enumerating the colony-forming units on LB agar. Results Through LC-MS/MS, we identified a pair of nearly identical (94%) effector proteins named EsxA belonging to the sagEsxA-like subfamily of the WXG100 protein superfamily in the culture supernatant of the wild type and none in the ΔessC mutant. Homology analysis of the T7SSb gene cluster among B. cereus strains revealed diversity from the 3’ end of essC, encoding additional substrates. Deletions in esxA1 and esxA2 neither altered cellular morphology nor growth rate, but the ΔesxA1ΔesxA2 deletion resulted in significantly fewer viable spores and an overall slower sporulation process. Within 24 h culture, more than 80% of wild-type cells formed endospores compared to less than 5% in the ΔesxA1ΔesxA2 mutant. The maximum spore ratios for the wild type and ΔesxA1ΔesxA2 were 0.96 and 0.72, respectively. Altogether, these results indicated that EsxA1 and EsxA2 work cooperatively and are required for sporulation in B. cereus ATCC14567. Conclusion B. cereus ATCC14579 possesses two nearly identical T7SSb-dependent effectors belonging to the sagEsxA-like proteins. Simultaneous deletion of genes encoding these effectors significantly delayed and reduced sporulation, a novel finding for EsxA.

Abstract The radioisotope thorium-229 (229Th) is renowned for its extraordinarily low-energy, long-lived nuclear first-excited state. This isomeric state can be excited by vacuum ultraviolet (VUV) lasers and 229Th has been proposed as a reference transition for ultra-precise nuclear clocks. To assess the feasibility and performance of the nuclear clock concept, time-controlled excitation and depopulation of the 229Th isomer are imperative. Here we report the population of the 229Th isomeric state through resonant X-ray pumping and detection of the radiative decay in a VUV transparent 229Th-doped CaF2 crystal. The decay half-life is measured to 447(25) s, with a transition wavelength of 148.18(42) nm and a radiative decay fraction consistent with unity. Furthermore, we report a new “X-ray quenching” effect which allows to de-populate the isomer on demand and effectively reduce the half-life. Such controlled quenching can be used to significantly speed up the interrogation cycle in future nuclear clock schemes.

Abstract The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.

Tsuneaki Kenzaka,1 Masanobu Okayama,2 Shigehiro Kuroki,1 Miho Fukui,3 Shinsuke Yahata,3 Hiroki Hayashi,3 Akihito Kitao,3 Eiji Kajii,2 Masayoshi Hashimoto41Division of General Medicine, 2Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke; 3Department of General Medicine, Toyooka Public Hospital, Toyooka; 4Department of Family and Community Medicine, Kobe University Graduate School of Medicine, Kobe, JapanBackground: The aim of this study was to evaluate the clinical usefulness of a semiquantitative procalcitonin kit for assessing severity of sepsis and early determination of mortality in affected patients.Methods: This was a prospective, observational study including 206 septic patients enrolled between June 2008 and August 2009. Disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured, along with semiquantitative procalcitonin concentrations. Patients were divided into three groups based on their semiquantitative procalcitonin concentrations (group A,

A 53-year-old female with primary biliary cholangitis was referred for the evaluation of a hepatic nodule identified during routine imaging. Ultrasonography revealed a homogeneous, hypoechoic, 18 mm nodule in segment 3 of the liver. On dynamic CT and MRI, the nodule showed mild enhancement at the hepatic artery-dominant phase. On diffusion-weighted images, the nodule exhibited pronounced hyperintensity with accompanying wedge-shaped perinodular hyperintensity (comet and comet-tail appearance). The nodule showed a portal perfusion defect on CT during arterial portography, and mild enhancement on CT during hepatic arteriography (CTHA). A nodular and wedge-shaped perinodular enhancement (comet and comet-tail appearance) in the CTHA was also clearly observed. The nodule demonstrated abnormal FDG uptake on 18F-FDG-PET/CT. An excisional biopsy was performed for histopathological diagnosis, and the nodule was diagnosed as reactive lymphoid hyperplasia (RLH). Diagnosing hepatic RLH by imaging is challenging due to its imaging findings overlapping with those of various malignant tumors, especially the nodular type of lymphomas, making differentiation particularly difficult. However, radiologists should note the perinodular early enhancement and the perinodular hyperintensity on diffusion weighted images, which are thought to be key imaging findings of RLH, along with other characteristics such as a single, small, homogeneous nodule with mild early enhancement and marked restricted diffusion. We propose to name the nodular lesion with perinodular early enhancement/hyperintensity on diffusion weighted images as 'comet and comet-tail appearances'.

Purpose: This study examines periductal infiltration in intrahepatic mass-forming cholangiocarcinoma (IMCC), focusing on its importance for differentiating hepatic tumors and its influence on post-surgical survival in IMCC patients. Methods: Eighty-three consecutive patients with IMCC (n = 43) and liver cancer whose preoperative images showed intrahepatic bile duct dilatation adjacent to the tumor for differential diagnosis from hepatocellular carcinoma (HCC) [n = 21], metastatic liver cancer (MLC) [n = 16] and combined hepatocellular-cholangiocarcinoma (cHCC-CC) [n = 3] were enrolled. CT and MRI findings of simple bile duct compression, imaged periductal infiltration, and imaged intrabiliary growth adjacent to the main tumor were reviewed. Clinicopathological and imaging features were compared in each group. The sensitivity, specificity, and odds ratio were calculated for each imaging finding of IMCC versus the other tumor groups. Overall survival was compared between cases of IMCC with and without imaged periductal infiltration. Results: Simple bile duct compression and imaged intrabiliary growth were more frequently observed in HCC than in the others (p

Rab GTPases are representative targets of manipulation by intracellular bacterial pathogens for hijacking membrane trafficking. Legionella pneumophila recruits many Rab GTPases to its vacuole and exploits their activities. Here, we found that infection-associated regulation of Rab10 dynamics involves ubiquitin signaling cascades mediated by the SidE and SidC families of Legionella ubiquitin ligases. Phosphoribosyl-ubiquitination of Rab10 catalyzed by the SidE ligases is crucial for its recruitment to the bacterial vacuole. SdcB, the previously uncharacterized SidC-family effector, resides on the vacuole and contributes to retention of Rab10 at the late stages of infection. We further identified MavC as a negative regulator of SdcB. By the transglutaminase activity, MavC crosslinks ubiquitin to SdcB and suppresses its function, resulting in elimination of Rab10 from the vacuole. These results demonstrate that the orchestrated actions of many L. pneumophila effectors fine-tune the dynamics of Rab10 during infection.

Abstract Background Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. HIC is originally calculated by post-load insulin and C-peptide from the oral glucose tolerance test (OGTT). However, OGTT or meal tolerance tests are a burden for patients, and OGTT is not suitable for overt diabetes due to the risk of hyperglycemia. If we can calculate the HIC from the fasting state, it is preferable. We hypothesized that fasting HIC correlates with postprandial HIC in both participants with T2DM and without diabetes. We investigated whether fasting HIC correlates with postprandial HIC in overt T2DM and nondiabetes subjects (non-DM) evaluated by using glucose clamp and meal load. Methods We performed a meal tolerance test and hyperinsulinemic–euglycemic clamp in 70 subjects, 31 patients with T2DM and 39 non-DM subjects. We calculated the postprandial C-peptide AUC-to-insulin AUC ratio as the postprandial HIC and the fasting C-peptide-to-insulin ratio as the fasting HIC. We also calculated whole-body insulin clearance from the glucose clamp test. Results The fasting HIC significantly correlated with postprandial HIC in T2DM (r_S = 0.82, P

Abstract Sinusoidal obstruction syndrome (SOS) is a fatal complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis for SOS can improve clinical outcomes significantly. Here, we performed a retrospective study to investigate the Cairo diagnostic criteria, in which SOS was defined as the development of two or more in seven events, including transfusion‐refractory thrombocytopenia. Among 154 cases of allogeneic HSCT, 10 cases of SOS using the European Society for Blood and Marrow Transplantation criteria (EBMT16) as the reference standard were identified. The original Cairo criteria could diagnose SOS 5 days earlier than any other established criteria, with some false‐positive results (sensitivity = 100.0%; specificity = 72.2%). When the cutoff was set to three events for the Cairo criteria, the diagnosis of SOS could be made 3 days earlier than that using the EBMT16 criteria, with comparable precision (specificity = 86.1%). The accuracy of the Cairo criteria improved further when the cutoff point was set to four (specificity = 93.8%). The fulfillment of the Cairo criteria was associated with high mortality. Based on our results, the Cairo criteria were also considered clinically useful, especially at three or four cutoff points. Further studies are required to validate and refine the criteria.

ObjectiveTo compare preferences, uptake, and cofactors for unassisted home-based oral self-testing (HB-HIVST) versus clinic-based rapid diagnostic blood tests (CB-RDT) for maternal HIV retesting.DesignProspective cohort.MethodsBetween November 2017 and June 2019, HIV-negative pregnant Kenyan women receiving antenatal care were enrolled and given a choice to retest with HB-HIVST or CB-RDT. Women were asked to retest between 36 weeks gestation and 1-week post-delivery if the last HIV test was ResultsOverall, 994 women enrolled and 33% (n = 330) selected HB-HIVST. HB-HIVST was selected because it was private (n = 224, 68%), convenient (n = 211, 63%), and offered flexibility in the timing of retesting (n = 207, 63%), whereas CB-RDT was selected due to the trust of providers to administer the test (n = 510, 77%) and convenience of clinic testing (n = 423, 64%). Among 905 women who reported retesting at follow-up, 135 (15%) used HB-HIVST. Most (n = 595, 94%) who selected CB-RDT retested with this strategy, compared to 39% (n = 120) who selected HB-HIVST retesting with HB-HIVST. HB-HIVST retesting was more common among women with higher household income and those who may have been unable to test during pregnancy (both retested postpartum and delivered ConclusionsWhile most women preferred CB-RDT for maternal retesting, HB-HIVST was acceptable and feasible and could be used to expand HIV retesting options.