[Redo Mitral Valve Replacement for Prosthetic Valve Endocarditis in a Patient with End Stage Colon Cancer:Report of a Case].

Prosthetic valve endocarditis (PVE) is rare but devastating. A 69-year old man admitted for active endocarditis caused by Streptococcus pasteurianus. Antibiotic therapy was started, but the patient developed bowel obstruction owing to cancer with multiple liver metastases, and underwent transverse colectomy. Following colectomy, antibiotic agent was given continued for 4 weeks after and mitral valve replacement( MVR) using a bioprosthesis was performed. Oral antibiotic therapy was continued for six months after MVR to avoid infection recurrence. One year after MVR, the size of multiple liver metastases increased despite oral anticancer drugs administration. A totally implantable central venous access port( CV port) was placed and intravenous chemotherapy was started for progressive metastatic colorectal cancer. But the CV port was removed due to device infection caused by multiple drug resistant Staphyrococcus lugdunensis one month later, but the patient developed prosthetic valve endocarditits( PVE) due to the same bacterium, that caused valve stenosis. Redo MVR was indicated because of progressive dyspnea and uncontrollable fever. The patient was discharged one month after redo MVR, but suffered carcinomatous peritonitis, and eventually died eight months post-discharge. Chemotherapy needs caution because of potential risk of PVE in patients with prosthetic valves, especially for those with a history of infectious endocarditis.

Modified ESR-based photosafety test (ESR-PT) detecting singlet oxygen and free radical formation.

The electron spin resonance-based photosafety test (ESR-PT) was modified using a new parameter, photoreactivity index (PRI), to detect singlet oxygen and free radical photoproducts simultaneously. With this modification, the modified ESR-PT is expected to reduce the number of false negative results due to chemicals producing free radical photoproducts other than singlet oxygen. The assay performance of the modified ESR-PT was evaluated using 56 chemicals, including hydrophobic chemicals. When using the PRI cutoff value of 2.0 in the modified ESR-PT, the accuracy relative to photosafety reference data was 91.1%, and the applicability (100%) was better than the other non-animal photosafety test. Among the chemicals producing positive results, bithionol, fenticlor, and doxycycline HCl were considered positive based on the detection of free radical photoproducts, suggesting that these three chemicals may have phototoxic or photoallergic potential via radical reactions. Additionally, this finding demonstrated the fundamental advantage of the modified ESR-PT using ESR spectroscopy, which can detect radicals selectively and quantitatively. Accordingly, the new parameter PRI is effective for photosafety evaluations based on not only singlet oxygen but also free radical photoproducts generated from chemicals. Therefore, the modified ESR-PT has a great potential for a photosafety test method applicable to various chemicals.

Shaken adult syndrome due to ocean wave: an autopsy case.

Severe intracranial trauma during torture or assault is reportedly caused by shaken adult syndrome. However, intracranial traumas caused by natural forces, excluding human factors and collision impact, are extremely rare. We report an autopsy case of shaken adult syndrome caused by ocean wave forces. A man in his 40s without any medical history was washed away by a wave during recreational fishing. He was found approximately 500 m away from the fishing point drifting on the ocean in a state of cardiopulmonary arrest and was confirmed dead, with no response to cardiopulmonary resuscitation, 3 h after the accident. The autopsy revealed no mechanical trauma to the entire body surface, including the head. Both lungs were inflated, and pleural effusion was observed. The brain was swollen and congested, and subarachnoid hemorrhage was observed in the interhemispheric fissure and the convexity of the parietal occipital lobe. Macroscopic and microscopic hemorrhage spots were found in the brain, and the results of the blood alcohol test and urinary toxicological screening were negative. The cause of death was determined as drowning. This case demonstrates a rare but notable mechanism of injury observed in immersed bodies.

[Anomalous Origin of Right Coronary Artery with Intramural Course, Aortic Valve Stenosis and Coronary Artery Stenosis:Report of a Case].

Anomalous origin of the coronary artery is a rare congenital malformation that can cause myocardial ischemia and arrhythmia in patients with or without atherosclerotic lesions. We present a case of aortic stenosis (AS) and coronary artery stenosis complicated by anomalous origin of the right coronary artery (RCA) from the aortic valve sinus and its intramural course. The patient was a 66-year-old woman who was diagnosed with AS 4 years prior, and scheduled for surgery owing to gradual progression of stenosis. Preoperative coronary angiography revealed an abnormal origin of the RCA, and during the surgery, the RCA was found located within the aortic wall close to the aortotomy. Thus, bypass surgery was performed using a great saphenous vein, to prevent ischemia of the RCA territory. The patient had good intraoperative and postoperative course, and a coronary computed tomography scan clearly showed the reconstructed RCA.

Cellular Release of Infectious Hepatitis C Virus Particles via Endosomal Pathways.

Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The release of infectious HCV particles from infected hepatocytes is a crucial step in viral dissemination and disease progression. While the exact mechanisms of HCV particle release remain poorly understood, emerging evidence suggests that HCV utilizes intracellular membrane trafficking and secretory pathways. These pathways include the Golgi secretory pathway and the endosomal trafficking pathways, such as the recycling endosome pathway and the endosomal sorting complex required for transport (ESCRT)-dependent multivesicular bodies (MVBs) pathway. This review provides an overview of recent advances in understanding the release of infectious HCV particles, with a particular focus on the involvement of the host cell factors that participate in HCV particle release. By summarizing the current knowledge in this area, this review aims to contribute to a better understanding of endosomal pathways involved in the extracellular release of HCV particles and the development of novel antiviral strategies.

A household survey of intrafamily norovirus transmission.

Norovirus (NoV) is a leading cause of epidemic and sporadic gastroenteritis in people of all ages. Humans are the primary source of NoV and household contact is one of the risk factors for NoV transmission. However, the mechanisms underlying person-to-person NoV transmission are poorly understood. Here we conducted a survey to profile the frequency and characteristics of intrafamily NoV transmission. Stool samples were collected every week from three households between 2016 and 2020; the total number of samples was 1105. The detection of NoV and the genotyping were performed by reverse transcription-polymerase chain reaction targeting the capsid region and direct sequencing methods. NoV was detected in 3.4% of all samples. Eight NoV genotypes were identified. The most common genotype was GII.17, followed in order by GII.6, GI.6, GII.4, GI.3, and GI.2/GI.8/GI.9. Most NoV-positive samples were obtained from asymptomatic individuals. The highest number of NoV transmissions was found in household 3 (6 infections), followed by household 2 (2 infections), while household 1 had no NoV transmission, suggesting that asymptomatic NoV carriers play a major role in infection as NoV reservoirs in the households. Further clarification of the mode of infection will contribute to improved understanding and an appropriate prevention.

Real-world efficacy and safety of advanced therapies in hospitalized patients with ulcerative colitis.

BACKGROUND: This multicenter observational cohort study aimed to evaluate the utilization and short-term efficacy of advanced therapy (AT) in hospitalized patients with acute severe ulcerative colitis (ASUC). METHODS: In total, 221 patients with ASUC were enrolled between August 2020 and July 2021. The primary endpoint was clinical remission (CR, defined as a patient-reported outcome score < 2 with no blood in the stool) rate on Day 7 and 14 in hospitalized patients who received corticosteroids (CS) and AT. RESULTS: Among patients with ASUC, 120 and 101 patients received CS or any AT as first-line treatment, respectively. The CR rates on Day 7 and 14 were 22.5% and 35.0%, respectively, in hospitalized patients who received CS as first-line treatment. Most patients who used ATs had CS-dependent or frequent recurrences. Eight different ATs (apheresis, tacrolimus, infliximab, golimumab, tofacitinib, vedolizumab, ustekinumab, and cyclosporine) were used as first-line treatment in patients with ASUC, and the CR rates on Day 7 and 14 were 16.8% and 29.7%, respectively. Twenty-five patients received the second ATs after hospitalizations, and the CR rates on Day 7 and 14 were 0% and 12%, respectively. The CR rates on Day 14 were significantly higher in patients who changed to AT than in those whose dose of CS increased (34.0% vs 10.7%, p = 0.020) among patients who had already used CS before hospitalization. CONCLUSION: Most first-use ATs were effective for patients with ASUC, while second-use ATs might have had limited benefits in inducing CR. These findings may contribute to considerations for the management of hospitalized patients.

Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication.

IMPORTANCE: The Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress. We previously reported that a cellular hydrogen peroxide scavenger protein, peroxiredoxin 1, a target gene of transcription factor Nrf2, acts as a novel HBV X protein (HBx)-interacting protein and negatively regulates hepatitis B virus (HBV) propagation through degradation of HBV RNA. This study further demonstrates that the Nrf2/ARE signaling pathway is activated during HBV infection, eventually leading to the suppression of HBV replication. We provide evidence suggesting that Keap1 interacts with HBx, leading to Nrf2 activation and inhibition of HBV replication via suppression of HBV core promoter activity. This study raises the possibility that activation of the Nrf2/ARE signaling pathway is a potential therapeutic strategy against HBV. Our findings may contribute to an improved understanding of the negative regulation of HBV replication by the antioxidant response.

Transcription Factor JunB Suppresses Hepatitis C Virus Replication.

We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. Activation of JNK contributes to the development of liver diseases, including metabolic disorders, steatosis, liver cirrhosis and hepatocellular carcinoma. JNK is known to have numerous target genes, including JunB, a member of activator protein-1 transcription factor family. However, the roles of JunB in the HCV life cycle and HCV-associated pathogenesis remain unclear. To clarify a physiological role of JunB in HCV infection, we investigated the phosphorylation of JunB in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of JunB. The small interfering RNA (siRNA) knockdown of JunB significantly increased the amount of intracellular HCV RNA as well as the intracellular and extracellular HCV infectivity titers. Conversely, overexpression of JunB significantly reduced the amount of intracellular HCV RNA and the intracellular and extracellular HCV infectivity titers. These results suggest that JunB plays a role in inhibiting HCV propagation. Additionally, HCV-mediated JunB activation promoted hepcidin promoter activity and hepcidin mRNA levels, a key factor in modulating iron homeostasis, suggesting that JunB is involved in HCV-induced transcriptional upregulation of hepcidin. Taken together, we propose that the HCV-induced ROS/JNK/JunB signaling pathway plays roles in inhibiting HCV replication and contributing to HCV-mediated iron metabolism disorder.

Hepatitis C Virus Disrupts Annexin 5-Mediated Occludin Integrity through Downregulation of Protein Kinase Cα (PKCα) and PKCη Expression, Thereby Promoting Viral Propagation.

Annexins (ANXs) comprise a family of calcium- and phospholipid-binding proteins and are implicated in the hepatitis C virus (HCV) life cycle. Here, we demonstrate a novel role of ANX5 in the HCV life cycle. Comparative analysis by quantitative PCR in human hepatoma cells revealed that ANX2, ANX4, and ANX5 were highly expressed among the ANX family proteins. Knockdown of ANX5 mRNA resulted in marked enhancement of HCV RNA replication but had no effect on either HCV translation or assembly. Using the HCV pseudoparticle (HCVpp) system, we observed enhancement of HCVpp infectivity in ANX5 knockdown Huh-7OK1 cells, suggesting that ANX5 is involved in suppression of HCV entry. Additionally, we observed that subcellular localizations of tight-junction proteins, such as claudin 1 (CLDN1) and occludin (OCLN), were disrupted in the ANX5 knockdown cells. It was reported that HCV infection was facilitated by disruption of OCLN distribution and that proper distribution of OCLN was regulated by its phosphorylation. Knockdown of ANX5 resulted in a decrease of OCLN phosphorylation, thereby disrupting OCLN distribution and HCV infection. Further analysis revealed that protein kinase C (PKC) isoforms, including PKCα and PKCη, play important roles in the regulation of ANX5-mediated phosphorylation and distribution of OCLN and in the restriction of HCV infection. HCV infection reduced OCLN phosphorylation through the downregulation of PKCα and PKCη expression. Taken together, these results suggest that ANX5, PKCα, and PKCη contribute to restriction of HCV infection by regulating OCLN integrity. We propose a model that HCV disrupts ANX5-mediated OCLN integrity through downregulation of PKCα and PKCη expression, thereby promoting HCV propagation. IMPORTANCE Host cells have evolved host defense machinery to restrict viral infection. However, viruses have evolved counteracting strategies to achieve their infection. In the present study, we obtained results suggesting that ANX5 and PKC isoforms, including PKCα and PKCη, contribute to suppression of HCV infection by regulating the integrity of OCLN. The disruption of OCLN integrity increased HCV infection. We also found that HCV disrupts ANX5-mediated OCLN integrity through downregulation of PKCα and PKCη expression, thereby promoting viral infection. We propose that HCV disrupts ANX5-mediated OCLN integrity to establish a persistent infection. The disruption of tight-junction assembly may play important roles in the progression of HCV-related liver diseases.

Functional connectivity changes between frontopolar cortex and nucleus accumbens following cognitive behavioral therapy in major depression: A randomized clinical trial.

Cognitive behavioral therapy (CBT) is a psychotherapy that challenges distorted cognitions; however, the neural mechanisms that underpin CBT remain unclear. Hence, we aimed to assess the treatment-related resting-state functional connectivity (rsFC) changes in the brain regions associated with future thinking and the associations between rsFC changes and clinical improvements. Thirty-eight adult patients with MDD were randomly assigned with equal likelihood to receive 16-week individual CBT or talking control with a 12-month follow-up period. We evaluated the rsFC changes in the frontal regions, nucleus accumbens, amygdala, and limbic structures key to the depression pathophysiology and future thinking with 2 ×  2 mixed ANOVA interaction analysis. Pearson's correlation analysis with Bonferroni's correction was also performed to examine the associations with clinical symptoms, such as depression severity and automatic thoughts in follow-up evaluations. Treatment-specific changes include enhancement in frontopolar connectivity with the nucleus accumbens. An increased rsFC was associated with lower negative automatic thoughts postoperatively, together with lower depressive symptoms and higher positive automatic thoughts at follow-up. Conclusively, rsFC changes in the fronto-limbic neural control circuit after CBT, particularly between the frontal pole and nucleus accumbens, may be clinically meaningful functional changes related to the depression recovery process.

Manual reduction for incarcerated obturator hernia.

Emergent surgery is a common approach for incarcerated obturator hernias, with high morbidity and mortality rates. Moreover, there have been reports of elective surgery cases after noninvasive manual reduction. For a decade, the initial approach in our institution is also manual reduction unless bowel viability is poor. This study aimed to clarify the efficacy and safety of manual reduction followed by elective surgery. We retrospectively reviewed 50 cases of incarcerated obturator hernia from 2010 to 2022 at Iwate Prefectural Iwai Hospital. Manual reduction was attempted in 31 (62%) patients. The reduction was successful in 21 (42%) patients, and most of them received mesh repair using the extraperitoneal approach as elective surgery. However, two patients underwent emergent surgery in the waiting period because of late-onset constriction and a small bowel perforation. Patients with irreducible hernia underwent emergent surgery, except for two patients who received the best supportive care. Postoperative complications were observed in 5% and 22% of reducible and irreducible cases, respectively. Postoperative mortality was zero in both groups. Manual reduction is useful in some cases, but careful observation is needed because late-onset constriction and perforation could occur.

The effect of cognitive behavioral therapy on future thinking in patients with major depressive disorder: A randomized controlled trial.

Background: Pessimistic thinking about the future is one of the cardinal symptoms of major depression. Few studies have assessed changes in pessimistic thinking after undergoing cognitive behavioral therapy (CBT). A randomized clinical trial (RCT) was conducted with patients diagnosed with major depressive disorder (MDD) to determine whether receiving a course of CBT affects pessimistic future thinking using a future thinking task. Methods: Thirty-one patients with MDD were randomly assigned to either CBT (n = 16) or a talking control (TC) (n = 15) for a 16-week intervention. The main outcomes were the change in response time (RT) and the ratio of the responses for positive valence, measured by the future thinking task. Secondary outcomes included the GRID-Hamilton Depression Rating Scale, the Beck Depression Inventory-Second Edition (BDI-II), the Dysfunctional Attitude Scale (DAS), and the word fluency test (WFT). Results: Regarding the main outcomes, the CBT group showed reduced RT for the positive valence (within-group Cohen's d = 0.7, p = 0.012) and negative valence (within-group Cohen's d = 0.6, p = 0.03) in the distant future condition. The ratio of positive valence responses in both groups for all temporal conditions except for the distant past condition increased within group (distant future: CBT: Cohen's d = 0.5, p = 0.04; TC: Cohen's d = 0.8, p = 0.008; near future: CBT: Cohen's d = 1.0, p < 0.001; TC: Cohen's d = 1.1, p = 0.001; near past: CBT: Cohen's d = 0.8, p = 0.005; TC: Cohen's d = 1.0, p = 0.002). As for secondary outcomes, the CBT group showed greater improvement than the TC group regarding the need for social approval as measured by the DAS (p = 0.012). Conclusion: Patients with MDD who received CBT showed a reduced RT for the positive and negative valence in the distant future condition. RT in the future thinking task for depressed patients may be a potential objective measure for the CBT treatment process. Because the present RCT is positioned as a pilot RCT, a confirmatory trial with a larger number of patients is warranted to elucidate the CBT treatment process that influences future thinking. Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000021028, identifier UMIN000018155.

Complete genome analyses of G12P[8] rotavirus strains from hospitalized children in Surabaya, Indonesia, 2017-2018.

Rotavirus A (RVA) is a major viral cause of acute gastroenteritis (AGE) worldwide. G12 RVA strains have emerged globally since 2007. There has been no report of the whole genome sequences of G12 RVAs in Indonesia. We performed the complete genome analysis by the next-generation sequencing of five G12 strains from hospitalized children with AGE in Surabaya from 2017 to 2018. All five G12 strains were Wa-like strains (G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1) and were clustered into lineage-III of VP7 gene phylogenetic tree. STM430 sample was observed as a mixed-infection between G12 and G1 strains: G12/G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. A phylogenetic tree analysis revealed that all five Indonesian G12 strains (SOEP379, STM371, STM413, STM430, and STM433) were genetically close to each other in all 11 genome segments with 98.0%-100% nucleotide identities, except VP3 and NSP4 of STM430, suggesting that these strains have originated from a similar ancestral G12 RVA. The VP3 and NSP4 genome segments of STM430-G12P[8] were separated phylogenetically from those of the other four G12 strains, probably due to intra-genotype reassortment between the G12 and G1 Wa-like strains. The change from G12P[6] lineage-II in 2007 to G12P[8] lineage-III 2017-2018 suggests the evolution and diversity of G12 RVAs in Indonesia over the past approximately 10 years.

Rituximab therapy for intractable pemphigus: A multicenter, open-label, single-arm, prospective study of 20 Japanese patients.

This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%-91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti-desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19-positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients.

A study of the risk factors for phlebitis in patients stratified using the acute physiology and chronic health evaluation II score and admitted to the intensive care unit: A post hoc analysis of the AMOR-VENUS study.

Introduction: Peripheral intravascular catheters (PIVCs) are inserted in most patients admitted to the intensive care unit (ICU). Previous research has discussed various risk factors for phlebitis, which is one of the complications of PIVCs. However, previous studies have not investigated the risk factors based on the patient's severity of illness, such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Different treatments can be used based on the relationship of risk factors to the illness severity to avoid phlebitis. Therefore, in this study, we investigate whether the risk factors for phlebitis vary depending on the APACHE II score. Materials and methods: This study was a post hoc analysis of the AMOR-VENUS study involving 23 ICUs in Japan. We included patients with age ≥ 18 years and consecutive admissions to the ICU with PIVCs inserted during ICU admission. The primary outcome was phlebitis, and the objective was the identification of the risk factors evaluated by hazard ratio (HR) and 95% confidence interval (CI). The cut-off value of the APACHE II score was set as ≤15 (group 1), 16-25 (group 2), and ≥26 (group 3). Multivariable marginal Cox regression analysis was performed for each group using the presumed risk factors. Results: A total of 1,251 patients and 3,267 PIVCs were analyzed. Multivariable marginal Cox regression analysis reveals that there were statistically significant differences among the following variables evaluated HR (95%CI): (i) in group 1, standardized drug administration measures (HR, 0.4 [0.17-0.9]; p = 0.03) and nicardipine administration (HR, 2.25 [1.35-3.75]; p < 0.01); (ii) in group 2, insertion in the upper arm using the forearm as a reference (HR, 0.41 [0.2-0.83]; p = 0.01), specified polyurethane catheter using polyurethane as a reference (HR, 0.56 [0.34-0.92]; p = 0.02), nicardipine (HR, 1.9 [1.16-3.12]; p = 0.01), and noradrenaline administration (HR, 3.0 [1.52-5.88]; p < 0.01); (iii) in group 3, noradrenaline administration (HR, 3.39 [1.14-10.1]; p = 0.03). Conclusion: We found that phlebitis risk factors varied according to illness severity. By considering these different risk factors, different treatments may be provided to avoid phlebitis based on the patient's severity of illness.

Clinical and immunological effects of hydroxychloroquine in patients with active rheumatoid arthritis despite antirheumatic treatment.

OBJECTIVE: To investigate the efficacy and safety of hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA, despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), were recruited. HCQ was administered for 24 weeks, in addition to prior treatment. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 achievement at week 24, compared to that of a propensity score matched historical control group. RESULTS: Sixty patients were enrolled and administered HCQ. We also identified 276 patients as candidates for the historical control group. Propensity score matching yielded 46 patients in each group. The proportion of ACR20 achievements at week 24 was significantly higher in the HCQ group than that in the control group (54.4% vs. 28.3%, P = 0.007). The proportion of ACR50 and ACR70 achievement at week 24 were also higher in the HCQ group than those in the control group (ACR50, 30.4% vs. 4.3%, P = 0.006; ACR70, 17.4% vs. 0%, P = 0.005). Neither hydroxychloroquine retinopathy nor any new safety signal was observed during the study. CONCLUSION: The addition of HCQ to csDMARDs was effective, with no new safety signal in patients with RA.

Comparison of inspiratory and expiratory airway volumes and luminal areas among standing, sitting, and supine positions using upright and conventional CT.

Upright computed tomography (CT) provides physiologically relevant images of daily life postures (sitting and standing). The volume of the human airway in sitting or standing positions remains unclear, and no clinical study to date has compared the inspiratory and expiratory airway volumes and luminal areas among standing, sitting, and supine positions. In this prospective study, 100 asymptomatic volunteers underwent both upright (sitting and standing positions) and conventional (supine position) CT during inspiration and expiration breath-holds and the pulmonary function test (PFT) within 2 h of CT. We compared the inspiratory/expiratory airway volumes and luminal areas on CT among the three positions and evaluated the correlation between airway volumes in each position on CT and PFT measurements. The inspiratory and expiratory airway volumes were significantly higher in the sitting and standing positions than in the supine position (inspiratory, 4.6% and 2.5% increase, respectively; expiratory, 14.9% and 13.4% increase, respectively; all P < 0.001). The inspiratory and expiratory luminal areas of the trachea, bilateral main bronchi, and average third-generation airway were significantly higher in the sitting and standing positions than in the supine position (inspiratory, 4.2‒10.3% increases, all P < 0.001; expiratory, 6.4‒12.8% increases, all P < 0.0001). These results could provide important clues regarding the pathogenesis of orthopnea. Spearman's correlation coefficients between the inspiratory airway volume on CT and forced vital capacity and forced expiratory volume in 1 s on PFT were numerically higher in the standing position than in the supine position (0.673 vs. 0.659 and 0.669 vs. 0.643, respectively); however, no statistically significant differences were found. Thus, the airway volumes on upright and conventional supine CT were moderately correlated with the PFT measurements.

False-negative chemicals in ESR-based photosafety test (ESR-PT) and their significance for photosafety evaluations: examples of bithionol, fenticlor and cilnidipine.

The electron spin resonance (ESR)-based photosafety test (ESR-PT) is a non-animal prediction test for photosafety evaluations that can be used even for hydrophobic chemicals; the method is based on the detection of singlet oxygen generation using ESR spectroscopy and showing high accuracy for compounds with known photosafety information. During the process of extending the application data for ESR-PT, we found three false-negative chemicals: bithionol, fenticlor and cilnidipine. These chemicals did not show the characteristic triplet signal of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl (4-hydroxy-TEMPO), which is used as a classifier for positive or negative chemicals; instead, bithionol and fenticlor induced an apparent single peak signal with a g-value of 2.0048, while cilnidipine produced a small, fragmented signal. Bithionol and fenticlor reportedly induce free radicals, and positive phototoxic or photoallergic evidence have been reported. Although the small, fragmented signal observed for cilnidipine was confirmed to be identical to that of a phenylnitroxy radical by the computer simulation, the significance of this chemical for photosafety considerations may be low because cilnidipine has quite a low incidence of phototoxic or photoallergic reactions in humans. Accordingly, the current ESR-PT protocol should be improved to detect free radical photoproducts generated from chemicals such as bithionol and fenticlor, thereby helping to reduce false negatives in ESR-PT.

Risk factors for peripheral intravascular catheter-related phlebitis in critically ill patients: analysis of 3429 catheters from 23 Japanese intensive care units.

BACKGROUND: Phlebitis is an important complication occurring in patients with peripheral intravascular catheters (PIVCs). The risk factors for phlebitis in the intensive care unit (ICU) was examined. METHODS: A secondary analysis of a prospective multicenter cohort study was conducted, involving 23 ICUs in Japan-the AMOR-VENUS study. Consecutive patients aged ≥ 18 years admitted to the ICU with newly inserted PIVCs after ICU admission were enrolled. Characteristics of the ICU, patients, PIVCs, and the drugs administered via PIVCs were recorded. A marginal Cox regression model was used to identify the risk factors associated with phlebitis. RESULTS: A total of 2741 consecutive patients from 23 ICUs were reviewed for eligibility, resulting in 1359 patients and 3429 PIVCs being included in the analysis population. The median dwell time was 46.2 h (95% confidence interval [CI], 21.3-82.9). Phlebitis occurred in 9.1% (95% CI, 8.2-10.1%) of catheters (3.5 cases/100 catheter days). The multivariate analysis revealed that the only factors that increased the risk of developing phlebitis were drugs administered intravenously. This study included 26 drugs, and 4 were associated with increased phlebitis: nicardipine (HR, 1.85; 95% CI, 1.29-2.66), noradrenaline (HR, 2.42; 95% CI, 1.40-4.20), amiodarone (HR, 3.67; 95% CI, 1.75-7.71) and levetiracetam (HR, 5.65; 95% CI, 2.80-11.4). Alternatively, factors significantly associated with a reduced risk of phlebitis were: standardized drug administration measures in the ICU (HR, 0.35; 95% CI, 0.17-0.76), 30≤ BMI (HR, 0.43; 95% CI, 0.20-0.95), catheter inserted by a doctor as nurse reference (HR, 0.55; 95% CI, 0.32-0.94), and upper arm insertion site as forearm reference (HR, 0.52; 95% CI, 0.32-0.85). The nitroglycerin was associated with a reduced phlebitis risk (HR, 0.22; 95% CI, 0.05-0.92). CONCLUSION: Various factors are involved in the development of phlebitis caused by PIVCs in critically ill patients, including institutional, patient, catheter, and drug-induced factors, indicating the need for appropriate device selection or models of care in the ICU. TRIAL REGISTRATION: UMIN-CTR, the Japanese clinical trial registry (registration number: UMIN000028019, July 1, 2017).