Association of Relative Dysglycemia With Hospital Mortality in Critically Ill Patients: A Retrospective Study.

OBJECTIVES: Relative dysglycemia has been proposed as a clinical entity among critically ill patients in the ICU, but is not well studied. This study aimed to clarify associations of relative hyperglycemia and hypoglycemia during the first 24 hours after ICU admission with in-hospital mortality and the respective thresholds. DESIGN: A single-center retrospective study. SETTING: An urban tertiary hospital ICU. PATIENTS: Adult critically ill patients admitted urgently between January 2016 and March 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximum and minimum glycemic ratio (GR) was defined as maximum and minimum blood glucose values during the first 24 hours after ICU admission divided by hemoglobin A1c-derived average glucose, respectively. Of 1700 patients included, in-hospital mortality was 16.9%. Nonsurvivors had a higher maximum GR, with no significant difference in minimum GR. Maximum GR during the first 24 hours after ICU admission showed a J-shaped association with in-hospital mortality, and a mortality trough at a maximum GR of approximately 1.12; threshold for increased adjusted odds ratio for mortality was 1.25. Minimum GR during the first 24 hours after ICU admission showed a U-shaped relationship with in-hospital mortality and a mortality trough at a minimum GR of approximately 0.81 with a lower threshold for increased adjusted odds ratio for mortality at 0.69. CONCLUSIONS: Mortality significantly increased when GR during the first 24 hours after ICU admission deviated from between 0.69 and 1.25. Further evaluation will necessarily validate the superiority of personalized glycemic management over conventional management.

Cardiovascular Outcomes after Paclitaxel-Coated Balloon Angioplasty versus Drug-Eluting Stent Placement for Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

Background: We conducted a systematic review and meta-analysis to examine the feasibility of paclitaxel-coated balloon (PCB) angioplasty for de novo lesions in patients with acute coronary syndrome (ACS) by comparing with drug-eluting stent (DES) placement. Methods: By a systematic literature search, nine (five randomized controlled, two retrospective propensity-score matched, and two retrospective baseline-balanced) studies comparing the midterm clinical and angiographic outcomes after PCB angioplasty and DES placement were included, yielding 974 and 1130 ACS cases in PCB and DES groups, respectively. Major adverse cardiac event (MACE) was defined as a composite of cardiac mortality (CM), all-cause mortality (ACM), myocardial infarction (MI), target vessel revascularization (TVR), and target lesion revascularization (TLR). Late luminal loss (LLL) and bleeding events (BLD) were also estimated. Results: The frequencies of MACE in PCB and DES groups were 8.42% and 10.62%, respectively. PCB angioplasty had no significant impacts on all of MACE (risk ratio: 0.90, 95%CI: 0.68-1.18, p = 0.44), CM, ACM, MI, TVR, TLR, BLD, and LLL, compared to DES placement in random-effects model. Conclusions: The present systematic review and meta-analysis showed the feasibility of PCB angioplasty for the de novo lesions in patients with ACS in comparison with DES placement by the emergent procedures.

Multiple roles of brassinosteroid signaling in vascular development.

Brassinosteroids (BRs) are plant steroid hormones that control growth and stress responses. In the context of development, BRs play diverse roles in controlling cell differentiation and tissue patterning. The vascular system, which is essential for transporting water and nutrients throughout the plant body, initially establishes a tissue pattern during primary development and then dramatically increases the number of vascular cells during secondary development. This complex developmental process is properly regulated by a network consisting of various hormonal signalling pathways. Genetic studies have revealed that mutants defective in BR biosynthesis or the BR signalling cascade exhibit a multifaceted vascular development phenotype. Furthermore, BR crosstalk with other plant hormones, including peptide hormones, coordinately regulates vascular development. Recently, the involvement of BR in vascular development, especially in xylem differentiation, has also been suggested in plant species other than the model plant Arabidopsis thaliana. In this review, we briefly summarize the recent findings on the roles of BR in primary and secondary vascular development in Arabidopsis and other species.

A non-canonical BZR/BES transcription factor regulates the development of haploid reproductive organs in Marchantia polymorpha.

Gametogenesis, which is essential to the sexual reproductive system, has drastically changed during plant evolution. Bryophytes, lycophytes and ferns develop reproductive organs called gametangia-antheridia and archegonia for sperm and egg production, respectively. However, the molecular mechanism of early gametangium development remains unclear. Here we identified a 'non-canonical' type of BZR/BES transcription factor, MpBZR3, as a regulator of gametangium development in a model bryophyte, Marchantia polymorpha. Interestingly, overexpression of MpBZR3 induced ectopic gametangia. Genetic analysis revealed that MpBZR3 promotes the early phase of antheridium development in male plants. By contrast, MpBZR3 is required for the late phase of archegonium development in female plants. We demonstrate that MpBZR3 is necessary for the successful development of both antheridia and archegonia but functions in a different manner between the two sexes. Together, the functional specialization of this 'non-canonical' type of BZR/BES member may have contributed to the evolution of reproductive systems.

A case of hypophosphatemia and elevated intact fibroblast growth factor 23 levels after short-term saccharated ferric oxide administration in a young woman and database analysis of adverse drug reactions in Japan.

Intravenous iron replacement therapy is a common treatment for iron deficiency. Commonly used agents in this treatment include ferric carboxymaltose, ferric derisomaltose, and saccharated ferric oxide (SFO). These drugs are known to elevate fibroblast growth factor 23 levels, resulting in hypophosphatemia, but in past reports, hypophosphatemia attributable to SFO treatment has been associated mainly with prolonged administration over several weeks. The present study details our experience of a case of moderate hypophosphatemia (<2 mg/dL) in a 22-year-old woman who had no specific history of hypophosphatemia during the first 5 days of SFO treatment, and showed an increase in intact fibroblast growth factor 23 levels within the first week of treatment. Cases of hypophosphatemia have been reported as occurring as early as 1 week after the start of SFO administration in the Japanese Adverse Drug Event Report database. These cases, along with our case, underline the need for awareness of the possibility of hypophosphatemia from the early stage of SFO administration, regardless of the patient's age or dosage, as well as the need to monitor patients to prevent complications.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Potential effect of physical exercise on the downregulation of BDNF mRNA expression in rat hippocampus following intracerebral hemorrhage.

OBJECTIVES: Physical exercise is known to induce expression of the neuroprotective brain derived neurotrophic factor (BDNF) in the hippocampus. This study examined the effects of physical exercise on hippocampal BDNF expression and the potential benefits for preventing remote secondary hippocampal damage and neurological impairment following intracerebral hemorrhage (ICH). MATERIALS AND METHODS: Wistar rats were randomly assigned to sham-operated, ICH, and ICH followed by exercise (ICH/Ex) groups. The two ICH groups were injected with type IV collagenase into the left basal ganglia, while sham animals were injected with equal-volume saline. The ICH/Ex group rats ran on a treadmill at 11 m/min for 30 min/day from day 3 to 16 post-ICH. All animals were examined for neurological function on day 2 pretreatment and from day 3 to 15 posttreatment, for spontaneous motor activity in the open field on day 15, and for cognitive ability using the object location test on day 16. Animals were then euthanized and bilateral hippocampi collected for gene expression analyses. RESULTS: Experimental ICH induced neurological deficits that were not reversed by exercise. In contrast, ICH did not alter spontaneous activity or object location ability. Expression of BDNF mRNA of the ICH group was significantly downregulated in the ipsilateral hippocampus compared to the SHAM group, but this downregulation was not shown in the ICH/Ex group. The ICH/Ex group showed the downregulation of caspase-3 mRNA expression in the contralateral hippocampus compared to the SHAM group, while neither ICH nor exercise influenced toll-like receptor 4 mRNA expression. CONCLUSIONS: ICH induced the secondary BDNF downregulation in the hippocampus remote from the lesion, whereas physical exercise might partially mitigate the downregulation.

Factors promoting research activities among Japanese pharmacists: a questionnaire survey.

Pharmacists are expected to demonstrate their expertise in clinical practice and conduct research activities to generate new evidence. However, the factors promoting research activities among pharmacists remain unclear. Therefore, we investigated the research activities of Japanese pharmacists through a questionnaire survey and examined the factors contributing to the promotion of research activities. A web-based questionnaire using Google Forms was disseminated across pharmacists working in community pharmacies, drugstores, hospitals, and clinics. The questionnaire included respondents' backgrounds, research activities, and research environments. Logistic regression analysis was used to examine the factors promoting pharmacists' research activities, with experience in research paper acceptance as the objective variable. In total, 401 responses were included in the analysis. Of the respondents, 54.1% were hospital pharmacists, and 77.1% were pharmacists with > 5 years of pharmacist experience. Furthermore, 50.4% of the pharmacists had presented at conferences, and 22.2% had experience in research paper acceptance. The influential factors were "master's degree or higher," "number of affiliated academic societies," "acquisition of specialists/certified pharmacists," and "daily availability of a consultant for writing research papers." This study revealed the factors contributing to the promotion of research activities among pharmacists. We believe that our findings will help promote research among pharmacists.

Epigenetic modification of histone acetylation in the sensorimotor cortex after intracerebral hemorrhage.

Epigenetic regulation is involved in post-stroke neuroplasticity. We investigated the effects of intracerebral hemorrhage (ICH) on histone acetylation and gene expression related to neuronal plasticity in the bilateral sensorimotor cortices, which may affect post-stroke sensorimotor function. Wistar rats were randomly divided into the SHAM and ICH groups. We performed ICH surgery stereotaxically based on the microinjection of a collagenase solution in the ICH group. Foot fault and cylinder tests were performed to evaluate motor functions at 4-time points, including pre-ICH surgery. The amount of acetyl histones and the mRNA expression of neurotrophic factors crucial to neuroplasticity in the bilateral sensorimotor cortices were analyzed approximately 2 weeks after ICH surgery. Sensorimotor functions of the ICH group were inferior to those of the SHAM group during 2 weeks post-ICH. ICH increased the acetylation of histone H3 and H4 over the sham level in the ipsilateral and contralateral cortices. ICH increased the mRNA expression of IGF-1, but decreased the expression of BDNF compared with the sham level in the ipsilateral cortex. The present study suggests that histone acetylation levels are enhanced in bilateral sensorimotor cortices after ICH, presenting an altered epigenetic platform for gene expressions related to neuronal plasticity.

Evaluation of a creatinine clearance correction equation based on body fat mass in older Japanese patients with diabetes.

Background: The estimation of creatinine clearance (CCr) in older adult patients with diabetes is subject to deviations from the results of actual measurements because of changes in body composition. In the present study, we aimed to create a correction for the equation used for the estimation of CCr in older adult Asian patients with diabetes using body composition parameters. Methods: We enrolled 50 older Japanese patients with diabetes in whom the measured values of CCr were compared with values estimated using the Cockcroft-Gault equation. The relationships between the error in the estimated CCr and body composition parameters were investigated, and the Cockcroft-Gault equation was corrected using the appropriate parameters. To evaluate the generalizability of the corrected equation, the utility of the Cockcroft-Gault equation, which was corrected on the basis of body composition measured using a household body composition meter, was also investigated. Results: Body fat mass (BFM) was closely correlated with the error in the estimated CCr. The BFM-corrected Cockcroft-Gault equation was more accurate than the original equation. Similarly, the error became smaller using BFM measured with a household body composition meter. Conclusion: The BFM-corrected Cockcroft-Gault equation may provide an accurate method of estimating CCr that can be used in general practice.

Structural Validity of the Mini-Balance Evaluation Systems Test in Individuals With Spinocerebellar Ataxia: A Rasch Analysis Study.

OBJECTIVE: To examine the structural validity of the Mini-Balance Evaluation Systems Test (Mini-BESTest) in individuals with spinocerebellar ataxia (SCA). DESIGN: Methodological research on data gathered in a cross-sectional study. A Rasch analysis was conducted (partial credit model). SETTING: Inpatients in a hospital rehabilitation setting. PARTICIPANTS: A pooled sample of patients with SCA (N=65 [total 110 data]; 23 women, 42 men; mean±SD age 63.1±9.9y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We evaluated the Mini-BESTest's category structure, unidimensionality, and measurement accuracy (0: unable to perform or requiring help to 2: normal performance). RESULTS: The Mini-BESTest rating scale fulfilled the category functioning criteria. The analysis of the standardized Rasch residuals showed the scale's unidimensionality, but there were 7 item pairs indicating local dependence. All of the items fit the underlying scale construct (dynamic balance), with the exception of item #1, "Sit to stand," which was an underfit. The Mini-BESTest demonstrated adequate reliability (person separation reliability=.87) and separated the patients into 5 strata. The item-difficulty measures ranged from -4.49 to 2.02 logits, and the person ability-item difficulty matching was very good (the mean of person ability=-.07 logits and the mean of item difficulty=.00). No floor or ceiling effects were detected. The keyform identified items with small (#11, "Walk with head turns, horizontal") and large (#3, "Stand on 1 leg") item thresholds. CONCLUSIONS: The Mini-BESTest has a unidimensional balance assessment scale with good category structure and reliability even for individuals with SCA. However, it also has some inherent shortcomings such as fit statistics, local item dependencies, and item thresholds. The results obtained when the Mini-BESTest is administered to patients with cerebellar ataxia should, thus, be interpreted cautiously.

Fasudil inhibits the expression of C/EBP homologous protein to protect against liver injury in acetaminophen-overdosed mice.

Acetaminophen (APAP) overdoses can cause severe liver injury. In this study, the protective effect of fasudil against APAP-induced liver injury was investigated. APAP (400 mg/kg) was administered to male C57BL/6J mice to induce liver injury, and fasudil (20 or 40 mg/kg) was injected 30 min before APAP administration. Fasudil markedly suppressed APAP-induced elevation in serum transaminase activity and hepatic necrosis and significantly reduced an increase in nitrotyrosine and DNA fragmentation. However, fasudil did not affect cytochrome P450 2E1 expression, N-acetyl-p-benzoquinone imine production or c-jun N-terminal kinase activation. In contrast, fasudil significantly inhibited an APAP-induced increase in expression of the transcription factor C/EBP homologous protein (CHOP) in the liver, accompanied by transcriptional suppression of ER stress-related molecules such as Ero1α, Atf4 and Grp78. These findings indicate that suppression of CHOP expression by fasudil exhibits a remarkable protective effect against APAP liver injury by regulating ER stress. We suggest that fasudil is a promising therapeutic candidate for treating APAP-induced liver injury.

Ureter Injury in Laparoscopic Para-Aortic Lymphadenectomy for Endometrial Cancer by the Transperitoneal Approach.

The patient was 66 years old, had three pregnancies and two deliveries, and was menopausal at the age of 51. She had irregular bleeding and was found to have a chicken-egg-sized uterus and a thickened endometrium (23 mm). She underwent laparoscopic surgery for uterine endometrial cancer (endometrioid carcinoma G1, stage IB). Laparoscopic simple hysterectomy, bilateral adnexectomy, pelvic lymph node dissection, para-aortic lymph node dissection, and partial omentectomy were performed using the transperitoneal approach (TPA). The patient was obese, with a height of 148 cm, a weight of 68 kg, and a body mass index of 31 kg/m2. She had a large amount of visceral fat, which made it difficult to expand the surgical field during para-aortic lymph node dissection. A laparoscopic fan retractor (EndoRetract II, Medtronic) was used to lift the intestinal tracts and expand the field of view. It broke the fat around the left kidney, and the exposed left ureter was heat-damaged using a vessel sealing device (LigaSure, Medtronic). Postoperatively, a left ureteral stent was placed, and continuous urine draining into the retroperitoneum was performed. To prevent injury to the left ureter, the left ovarian vein branching from the left renal vein should be exposed as a landmark before the left ureter running parallel to it is isolated. It is essential that the fat around the left kidney is not broken during this operation. The left iliopsoas muscle should be exposed, and using this as a base, the left ovarian vein, left ureter, and left perirenal fat should be compressed and moved to the left side using a fan retractor to ensure a safe operation.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann-Pick disease type C treatment.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear. METHODS: We estimated CD-UC complexation for nine CD derivatives derived from native α-, ß-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models. FINDINGS: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability. CONCLUSIONS: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

Ureter Injury in Total Laparoscopic Hysterectomy.

Objective: To identify surgical manipulations that caused ureter injury during total laparoscopic hysterectomy (TLH) and evaluate the surgical manipulations to identify ways to prevent such injury. Patients and Methods. This single-center, cross-sectional study included 1135 cases of TLH performed for benign diseases from January 2009 to December 2021. Seven cases (0.6%) that needed ureteral stent placement intra- or postoperatively for ureter injury were included. We identified the surgical manipulations that caused ureter injury from surgical videos. Results: Two cases had adhesions around the bladder pillar, and the ureter sustained a thermal injury during the cardinal ligament transection. One case had severe endometriosis, and the ureter was bluntly damaged when the adhesion was released. In one case, the ureter was thermally damaged during bipolar hemostasis for uterine artery bleeding. In two cases, the obliterated umbilical artery was mistaken for the ureter, and the real ureter was injured. In one case, ureteral peristalsis was inhibited by a pelvic abscess caused by postoperative infection. Conclusion: To prevent ureter injury during TLH, the ureter should be isolated in case of severe adhesion. Moreover, the following could be considered: (1) expand Okabayashi's pararectal space lateral to the uterosacral ligament, (2) perform dissection sharply using a monopolar or scissors forceps when releasing adhesion, (3) clarify the anatomy around the ureter for cases needing hemostasis, (4) repeatedly confirm the ureter with its peristalsis even after its isolation, (5) for severe adhesion cases, reduce infection risk by drain placement and administering antibiotics, and (6) use a delineator cup.