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Purpose: Young caregivers experience, on average, poorer mental health outcomes than non-caregiving young people. However, it is unknown to what extent these effects differ with age, or among short-term versus long-term caregivers. Using repeated assessment of young caregiving across multiple waves of a prospective adolescent cohort study, we conducted repeated cross-sectional analyses of caregiver status and contemporaneous depressive symptoms, self-harm, and suicidality in early to middle adolescence., Methods: Four waves of questionnaire data from a large, longitudinal population-based cohort study (Tokyo Teen Cohort) were analyzed. Caregiver status was collected from participants aged 10, 12, 14, and 16 years. Mental health outcomes assessed were depressive symptoms, self-harm and suicidal feelings. Logistic regression analyses were conducted assessing effects of a) young caregiver status and b) new, long-term, and ex-caregiver 2-year categorizations on mental health outcomes at 12, 14, and 16 years, both unadjusted and adjusted for potential confounders (sex, low income, single-parent household, and parental distress)., Results: Depressive symptoms were elevated among long-term caregivers at 14 years (unadjusted odds ratio (uOR): 3.11 [1.33-7.27], adjusted odds ratio (aOR): 2.49 [1.03-5.99]). Borderline associations between long-term caregiving and self-harm (uOR: 3.14 [1.06-9.35], aOR: 2.51 [0.82-7.63]) and suicidal feelings (uOR: 2.49 [0.98-6.34], aOR: 2.06 [0.80-5.33]) were detected at 16 years. No associations were found at age 12 years in primary analyses; sensitivity analyses indicated possible increased depressive symptoms., Discussion: Young caregivers with long-term caregiving roles are at the greatest risk for negative mental health outcomes, with effects concentrated in later adolescence. These findings highlight urgent need for early identification and practical and psychological support for young people shouldering caregiving burdens., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

A 31-year-old Japanese man presented with cerebral and pulmonary cryptococcosis. Cryptococcus gattii (C. gattii) genotype VGIIb was detected in the patient's sputum and cerebrospinal fluid specimens. The serum levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies were elevated in this patient, which has been associated with pulmonary alveolar proteinosis and is considered a risk factor for C. gattii infection. After undergoing >12 months of antifungal treatments, the patient showed improvements in symptoms and findings on brain and lung imaging. Several Japanese patients who develop C. gattii infection have also been reported; however, most of these patients have been infected outside Japan, as C. gattii infection is rare in Japan. Only one patient with C. gattii genotype VGIIb infection has been reported in Japan, and it is believed that this patient contracted the infection in China. In the present case, our patient has never been outside Japan, indicating that the infection originated in Japan. Our findings suggest that C. gattii might be spreading in Japan. Therefore, patients with positive serum anti-GM-CSF antibodies should be thoroughly monitored for C. gattii infection, even those living in Japan., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Trypanosoma brucei brucei is a parasitic protist that expresses cell surface proteins modified with complex-type N-linked glycan (NLG), like multicellular organisms. However, little is known about the role of complex-type NLG. In T. b. brucei, it has been shown that either one of the glycosyltransferases, TbGT11 or TbGT15, is sufficient to initiate the synthesis of complex-type NLG. To clarify the role of complex-type NLG, it is necessary to generate cells lacking both enzymes. Therefore, we deleted TbGT11 and TbGT15 from the genome of T. b. brucei for the phenotypic examination. The mutant strain grew in culture, with reduced maximum cell density; showed decreased susceptibility to normal human serum, which contains trypanolytic factors; and lacked uptake of the haptoglobin-hemoglobin complex. These data indicate that protein modification by complex-type NLG is not essential but is required for receptor function., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The skeletal muscle is a pivotal organ involved in the regulation of both energy metabolism and exercise capacity. There is no doubt that exercise contributes to a healthy life through the consumption of excessive energy or the release of myokines. Skeletal muscles exhibit insulin sensitivity and can rapidly uptake blood glucose. In addition, they can undergo non-shivering thermogenesis through actions of both the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and small peptide, sarcolipin, resulting in systemic energy metabolism. Accordingly, the maintenance of skeletal muscles is important for both metabolism and exercise. Prolyl isomerase Pin1 is an enzyme that converts the cis-trans form of proline residues and controls substrate function. We have previously reported that Pin1 plays important roles in insulin release, thermogenesis, and lipolysis. However, the roles of Pin1 in skeletal muscles remains unknown. To clarify this issue, we generated skeletal muscle-specific Pin1 knockout mice. Pin1 deficiency had no effects on muscle weights, morphology and ratio of fiber types. However, they showed exacerbated obesity or insulin resistance when fed with a high-fat diet. They also showed a lower ability to exercise than wild type mice did. We also found that Pin1 interacted with SERCA and elevated its activity, resulting in the upregulation of oxygen consumption. Overall, our study reveals that Pin1 in skeletal muscles contributes to both systemic energy metabolism and exercise capacity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Evidence on the impact of the COVID-19 pandemic on adolescent mental health is mixed and does not disentangle natural age-related changes. We compared depressive symptoms among 16-year-olds surveyed, at a fourth wave, before or during the pandemic, while accounting for expected trajectories of within-person change based on 3 prior waves., Method: In this longitudinal cohort of 3,171 adolescents in Tokyo, Japan, adolescents were grouped based on their age 16 survey timing: pre-pandemic (February 2019 to February 2020) and during-pandemic (March 2020 to September 2021). Depressive symptoms were self-reported using the Short Mood and Feelings Questionnaire. Mixed-effect models were fitted to assess group differences while controlling for previous trends. Variations by sex, household income, and pandemic phase (early, late first-year, and second-year) were examined., Results: Of 2,034 eligible adolescents, 960 (455 girls) were assessed before and 1,074 (515 girls) during the pandemic. Overall, depressive symptoms increased by 0.80 points (95% CI 0.28-1.31, 0.15 SD of the population average). This increase varied by sex and pandemic phase. For boys the increase emerged in the late first-year phase and enlarged in the second-year phase (mean difference from pre-pandemic: 1.69, 0.14-3.24), whereas for girls it decreased in the early school-closure phase (mean difference: -1.98, -3.54 to -0.41) and returned to the pre-pandemic level thereafter, with no additional increases during the pandemic., Conclusion: Into the second year of the COVID-19 pandemic, depressive symptoms of 16-year-olds worsened above the expected age-related change only in boys. Continuous monitoring and preventive approaches for adolescents at the population level are warranted., Diversity & Inclusion Statement: We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The biosynthesis of N-linked glycan precursors in the endoplasmic reticulum is important for many eukaryotes. In particular, the synthesis of Man 5 GlcNAc 2 -PP-dolichol (M5-DLO) at the cytoplasmic face of the endoplasmic reticulum is essential for maintaining cellular functions. In Trypanosoma brucei, the unicellular organism that causes African trypanosomiasis, homologs of the mannosyltransferases ALG2 and ALG11, which are involved in the biosynthesis of M5-DLO, are found, but the effects of their deletion on cells remain unknown. In this study, we generated conditional gene knockout strains of TbALG2 and TbALG11 in the bloodstream form T. brucei. Decreased N-linked glycosylation and cell death were observed in both strains under non-permissive conditions, with TbALG2 having a greater effect than TbALG11. Transcriptomic analysis of cells losing expression of TbALG11 showed decrease in mRNAs for enzymes involved in glucose metabolism and increase in mRNAs for procyclins and variant surface glycoproteins. These results indicate that the M5-DLO biosynthetic pathway is essential for the proliferation of the bloodstream form T. brucei. They also suggest that the failure of this pathway induces the transcriptomic change., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Context: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation., Objectives: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care., Methods: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738)., Results: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC., Conclusion: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

S-adenosylhomocysteine (SAH) hydrolase is the enzyme responsible for breaking down SAH into adenosine and homocysteine. It has long been believed that a deficiency of this enzyme leads to SAH accumulation, subsequently inhibiting methyltransferases responsible for nucleic acids and proteins, which severely affects cell proliferation. To investigate whether targeting this enzyme could be a viable strategy to combat Trypanosoma brucei, the causative agent of human African trypanosomiasis, we created a null mutant of the SAH hydrolase gene in T. brucei using the Cre/loxP system and conducted a phenotype analysis. Surprisingly, the null mutant, where all five SAH hydrolase gene loci were deleted, exhibited normal proliferation despite the observed SAH accumulation. These findings suggest that inhibiting SAH hydrolase may not be an effective approach to suppressing T. brucei proliferation, making the enzyme a less promising target for antitrypanosome drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Cross-sectional studies have shown an association between lower help-seeking intentions and greater depressive symptoms among adolescents. However, no longitudinal study has examined the direction of this association. The current study investigated whether help-seeking intentions and depressive symptoms are reciprocally associated at the within-person (individual) level during early to mid-adolescence., Methods: Longitudinal data on help-seeking intentions and depressive symptoms in adolescents were obtained from a population-based birth cohort study (Tokyo Teen Cohort; N = 3,171) at four time points (10y, 12y, 14y, and 16y). A random intercept cross-lagged panel model was used to evaluate the within-person prospective associations between help-seeking intentions and depressive symptoms., Results: At the within-person level, significant associations were consistently observed between antecedent greater depressive symptoms and subsequent lower help-seeking intentions across all time points (10y-12y: standardized regression coefficient (β) = -0.12, p < .001; 12y-14y: β = -0.07, p < .05; and 14y-16y: β = -0.09, p < .01). Meanwhile, significant within-person associations were partly observed between antecedent lower help-seeking intentions and subsequent greater depressive symptoms from 10y to 12y (β = -0.07, p < .05) and from 14y to 16y (β = -0.12, p < .001). These prospective associations were almost the same when adjusted for the number of potential confidants as a time-varying confounder., Discussion: Adolescents with worsening depressive symptoms may become increasingly reluctant to seek help over time. Proactive early recognition and intervention with support from parents, teachers, and other individuals may facilitate the management of depression in adolescents., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Cellular senescence is involved in the pathogenesis of various diseases, including acute kidney injury (AKI). AKI is defined as a sudden loss of kidney function. In severe AKI, irreversible loss of kidney cells can occur. Cellular senescence might contribute to this maladaptive tubular repair, though, its pathophysiological role in vivo is incompletely understood. In this study, we used p16-CreERT2-tdTomato mice in which cells with high p16 expression, a prototypical senescent marker, are labeled with tdTomato fluorescence. Then, we induced AKI by rhabdomyolysis and traced the cells with high p16 expression following AKI. We proved that the induction of senescence was observed predominantly in proximal tubular epithelial cells (PTECs) and occurred in a relatively acute phase within 1-3 days after AKI. These acute senescent PTECs were spontaneously eliminated by day 15. On the contrary, the generation of senescence in PTECs persisted during the chronic recovery phase. We also confirmed that the kidney function did not fully recover on day 15. These results suggest that the chronic generation of senescent PTECs might contribute to maladaptive recovery from AKI and lead to chronic kidney disease progression., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Makoto Nakanishi reports financial support was provided by reverSASP Therapeutics Co., Airweave Co. Makoto Nakanishi reports a relationship with Airweave Co., reverSASP Therapeutics Co. that includes: consulting or advisory., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: End-of-life (EOL) care during the coronavirus disease 2019 (COVID-19) pandemic has been a concern under the overwhelming pressure of health care service systems. People with dementia often receive suboptimal EOL care; thus, they may be at particular risk of poor care quality during the COVID-19 pandemic. This study investigated the interaction between dementia and pandemic on the proxies' overall ratings and ratings for 13 indicators., Design: A longitudinal study., Setting and Participants: Data were collected from 1050 proxies for deceased participants in the National Health and Aging Trends Study, a nationally representative sample of community-dwelling Medicare beneficiaries aged ≥65 years. Participants were included if they had died between 2018 and 2021., Methods: Participants were categorized into 4 groups depending on the period of death (before vs during the COVID-19 pandemic) and having no vs probable dementia, as defined by a previously validated algorithm. The quality of EOL care was assessed through postmortem interviews with bereaved caregivers. Multivariable binomial logistic regression analyses were performed to examine the main effects of dementia and pandemic period, and the interaction between dementia and pandemic on ratings of quality indicators., Results: A total of 423 participants had probable dementia at the baseline. People with dementia who died were less likely to talk about religion in the last month of life than those without dementia. Decedents during the pandemic were more likely to have an overall rating of care as being not excellent than those before the onset of the pandemic. However, the interaction between dementia and pandemic was not significant in the 13 indicators and the overall rating of EOL care quality., Conclusion and Implications: Most EOL care indicators preserved the level of quality, regardless of dementia and the COVID-19 pandemic. Disparities in spiritual care may exist across people with and without dementia., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Infectious bronchitis, an acute and highly contagious disease that affects chickens, is caused by the infectious bronchitis virus (IBV). The antigenic variant QX-like IBV was first reported in China in 1996 and is now endemic in many countries. Our previous study reported the first detection and isolation of QX-like IBVs in Japan and that they were genetically related to the recently detected strains in China and South Korea. The pathogenicity of 2 Japanese QX-like IBV strains (JP/ZK-B7/2020 and JP/ZK-B22/2020) was evaluated by inoculating specific pathogen-free (SPF) chickens with 10 2 to 10 6 median embryo infectious dose. Both strains caused clinical signs of respiratory symptoms, gross tracheal lesions, and moderate-to-severe suppression of tracheal ciliostasis. To evaluate the efficacy of commercial IBV live vaccines against the JP/ZK-B7/2020 strain, vaccinated SPF chickens were challenged with the JP/ZK-B7/2020 strain at 10 4 EID 50 (median embryo infectious dose). Only the JP-Ⅲ vaccine provided high levels of protection (reduced suppression of tracheal ciliostasis and reduced viral loads in organs), whereas the Mass vaccine showed little protective effect. Virus neutralization test results and comparisons between IBV genotypes based on the S1 gene suggested that QX-like and JP-III genotypes were closely related. These results suggest that the JP-III IBV vaccine, which has relatively high S1 gene homology with QX-like IBVs, is effective against Japanese QX-like IBV strain., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Coffee consumption has been shown to reduce the risk of developing type 2 diabetes mellitus (T2DM) in humans; however, the exact mechanism is not completely understood. Here, we demonstrate that N-caffeoyltryptophan (CTP), an ingredient of coffee, enhances adipogenic differentiation and promotes glucose uptake into adipocytes. CTP increased lipid accumulation and adipogenic markers (PPARγ, C/EBPα, and FABP4) expression in mouse 3T3-L1 preadipocyte cell lines and primary preadipocytes. In addition, CTP promoted glucose uptake in 3T3-L1 cells. In the oral glucose tolerance test, daily administration of CTP (30 mg/kg/day, i.p.) for a week reduced blood glucose levels in mice. In 3T3-L1 cells, adipogenic differentiation and increased adipogenic markers expression induced by CTP were inhibited by U0126, a selective MEK1/2 inhibitor. Furthermore, mRNA induction of Pparg by CTP was abrogated in SIRT1 siRNA-transfected 3T3-L1 cells. These results suggest the involvement of the MEK/ERK signaling and SIRT1 in the mechanism of adipogenic function of CTP. Taken together, CTP might contribute to the reduction in postprandial glycemia and a subsequent reduction in onset risk for T2DM., Competing Interests: Declaration of Competing Interest The authors have explicitly stated that there are no conflicts of interest in connection with this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Systemic nicotine administration regulates neuronal activities in mouse auditory cortex. How nicotine regulates the spread of the activities across auditory cortical areas is not well known. We investigate this using flavoprotein fluorescence imaging. 20 kHz amplitude-modulated (AM) tones increased the peak intensity of flavoprotein fluorescence in presumptive primary auditory cortex (A1). 5 kHz AM tones activated at least three cortical areas, which are presumably A1, anterior auditory field, and secondary auditory cortex. Nicotine enlarged tone-activated cortical areas and enhanced both 20 kHz and 5 kHz tone-evoked fluorescence intensities at their respective, optimal frequency peak sites and at non-optimal frequency peak sites in A1. The extent of this enhancement was greater at non-optimal frequency sites than at optimal frequency sites. A cortical injection of dihydro-β-erythroidine, an inhibitor of nicotinic acetylcholine receptors composed of α4 and β2-subunits (α4β2*-nAChRs), blocked the enhancement of fluorescence intensity at the peak sites but did not appear to block the enlargement of activated areas. These results suggest that nicotine exposure activates cortical α4β2*-nAChRs to enhance tone-evoked local neuronal activities at an optimal frequency site. The nicotine-induced enlargement of a tone-activated area may depend on the nicotinic enhancement of cortical inputs or other activities., (Copyright © 2022 Japan Neuroscience Society and Elsevier B.V. All rights reserved.)

Purpose: During the COVID-19 pandemic, adolescent carers in the UK may have experienced psychological distress owing to increased caring burden and loss of a break from their caring role. This study investigated longitudinal association between adolescents' caring status and mental health outcomes from 2018/2019 to February-March 2021., Methods: The participants (n = 3,927) answered mental health questions in both the Millennium Cohort Study sweep 7 survey (age 17 years in 2018/2019) and at least one of three waves of the COVID-19 survey from May 2020 to February-March 2021. Caring status at the age of 17 years was assessed using a single question regarding whether the participant regularly looked after anyone who needed care, without being paid. Outcome measures were psychological symptoms, measured using the Kessler Distress Scale, and mental well-being, measured using the Warwick-Edinburgh Mental Well-being Scale., Results: Compared with 3,616 noncarers, 311 (7.9%) adolescent carers reported significantly higher Kessler Distress Scale and lower Warwick-Edinburgh Mental Well-being Scale scores during the pandemic. These associations were largely explained by psychosocial risk factors. Worse outcomes were associated with poor sleep quality, attempted suicide at baseline, low social support, and a strong feeling of loneliness during the pandemic. These factors were significantly more likely to be observed among adolescent carers than noncarers., Discussion: UK adolescent carers exhibited worsened mental health outcomes one year after the first national lockdown. This increased distress may be attributable to psychosocial risk factors during the pre-COVID-19 and current COVID-19 periods, and they require psychosocial support., (Copyright © 2022 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Cluster of differentiation 81 (CD81) is a tetraspanin membrane protein consisting of 4 transmembrane domains and 2 outer membrane loops. CD81 inhibition is a potential treatment for rheumatoid arthritis (RA). Here, we investigated the therapeutic effects of the cytoplasmic RNA vector expressing anti-CD81 antibodies (the anti-CD81 vector) on the ankle joint synovium in collagen-induced arthritis (CIA) rats., Methods: Body weight, paw volume, and clinical scores were measured on days 0, 7, and 10 and daily thereafter. On day 28, the ankle joints of the rats were removed and stained with haematoxylin, eosin, and Safranin O. Arthritic changes such as inflammatory cell infiltration, synovial proliferation, articular cartilage destruction, and bone erosion were evaluated by histological scoring., Results: Symptom onset was delayed in the right lower limbs of the rats administered the cytoplasmic RNA vector (CIA + anti-CD81) compared with that in the control group (CIA + control). The CIA + anti-CD81 rats were heavier than the CIA + control rats. The paw volume and clinical scores were significantly lower in the CIA + anti-CD81 than in the CIA + control. The histological scores indicated significantly milder manifestations of RA in the CIA + anti-CD81 than in the CIA + control., Conclusions: Administration of the cytoplasmic RNA vector expressing anti-CD81 antibodies suppressed arthritis and joint destruction in CIA rats. Our findings suggest that the cytoplasmic RNA vector can be used to treat RA., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Atypical sensory behavior disrupts behavioral adaptation in children with autism spectrum disorder (ASD); however, neural correlates of sensory dysfunction using magnetoencephalography (MEG) remain unclear., Method: We used MEG to measure the cortical activation elicited by visual (uni)/audiovisual (multisensory) movies in 46 children (7-14 years) were included in final analysis: 13 boys with atypical audiovisual behavior in ASD (AAV+), 10 without this condition, and 23 age-matched typically developing boys., Results: The AAV+ group demonstrated an increase in the cortical activation in the bilateral insula in response to unisensory movies and in the left occipital, right superior temporal sulcus (rSTS), and temporal regions to multisensory movies. These increased responses were correlated with severity of the sensory impairment. Increased theta-low gamma oscillations were observed in the rSTS in AAV+., Conclusion: The findings suggest that AAV is attributed to atypical neural networks centered on the rSTS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Programmed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non-small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs)., Patients and Methods: Patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated., Results: Sixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset., Conclusions: Serum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment., (Copyright © 2021. Published by Elsevier Inc.)

The defective and persistent Sendai virus (SeVdp) vector system allows efficient generation of transgene-free induced pluripotent stem cells (iPSCs) from human somatic cells. By leveraging the system, here we report the generation of an iPSC line from somatic fibroblasts of a healthy control donner (female), named KEIOi002-A (also named YG-iPS). The control iPSC line would be a useful resource for stem cell research and regenerative medicine., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Membrane and secretory proteins are synthesized by ribosomes and then enter the endoplasmic reticulum (ER) where they undergo glycosylation and quality control for proper folding. Subsequently, proteins are transported to the Golgi apparatus and then sorted to the plasma membrane or intracellular organelles. Transport vesicles are formed at ER-exit sites (ERES) on the ER with several coat protein complexes. Cargo proteins loaded into the vesicles are selected by specific interactions with cargo receptors and/or adaptors during vesicle formation. p24 family and intracellular lectin ERGIC-53-membrane proteins are the known cargo receptors acting in the early secretory pathway (ER-Golgi). Oligomerization of the cargo receptors have been suggested to play an important role in cargo selection and sorting via posttranslational modifications in fungi and metazoans. On the other hand, the mechanisms involved in the early secretory pathway in protozoa remain unclear. In this review, we focus on Trypanosoma brucei as a representative of protozoan and discuss differences and commonalities in the molecular mechanisms of its early secretory pathway compared with other organisms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cu/Zn superoxide dismutase (SOD1) mutations are associated with amyotrophic lateral sclerosis (ALS). SOD1-positive aggregates in motor neurons, as well as proteins that interact with the aggregates are presumably involved in ALS neurotoxicity. We used a proteomics approach to compare differences in protein expression in spinal cord homogenates from non-transgenic (NTG) and ALS model mice. Using the homogenates, we identified proteins that interacted with SOD1 seeds in vitro. We assessed differences in SOD1-interacting proteins in cell cultures treated with proteasome or autophagy inhibitor. In the first experiment, intermediate filamentous and small heat shock proteins were upregulated in glial cells. We identified 26 protein types that interacted with aggregation cores in ALS model homogenates, and unexpectedly, 40 proteins in were detected in NTG mice. In cell cultures treated with proteasome and autophagy inhibitors, we identified 16 and 11 SOD1-interacting proteins, respectively, and seven proteins in untreated cells. These SOD1-interacting proteins were involved in multiple cellular functions such as protein quality control, cytoskeletal organization, and pathways involved in growth factor signaling and their downstream cascades. The complex interactions between pathways could cause further dysregulation, ultimately leading to fatal cellular dysfunction in ALS., (Copyright © 2020 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Introduction: Helicobacter pylori is an important factor in the development of gastroduodenal ulcers and gastric cancer. Although H. pylori eradication therapy has been employed, the eradication rate has decreased in recent years owing to an increase in clarithromycin-resistant strains. We previously reported the anti-infective effect of herbal medicines against several bacterial species. Here, we evaluated the growth inhibitory activity of herbal medicines alone and in combination with antimicrobials against H. pylori., Methods and Results: Nine of 37 herbal medicines inhibited the growth of H. pylori ATCC700392. In particular, modified Gingyo-san showed the strongest growth inhibitory activity with a minimum inhibitory concentration (MIC) of 512 μg/ml for not only ATCC700392 but also clarithromycin-resistant strains having a 23 S rRNA mutation. Results of Time-Kill Kinetics Assay showed that 1 mg/mL modified Gingyo-san treatment for one hour killed 50% of the H. pylori population. Furthermore, modified Gingyo-san showed additive effects with clarithromycin, amoxicillin, and metronidazole against H. pylori ATCC700392 and clarithromycin-resistant strains., Conclusions: Our findings showed that modified Gingyo-san inhibits the growth of H. pylori and improves antimicrobial susceptibility when used in combination. Therefore, modified Gingyo-san has the potential to enhance the eradication rate of clarithromycin-resistant H. pylori., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Keratin 17 (KRT17) expression promotes the proliferation and invasion of oral squamous cell carcinoma (OSCC), and mutations in TP53 have been reported in 65% to 85% of OSCC cases. We studied the correlation between KRT17 expression and TP53 mutants. Ca9-22 cells, which exhibit low KRT17 expression, carried mutant p53 (p53R248W) and p53R248W knockdown promoted KRT17 expression. p53R248W knockdown in Ca9-22 cells promoted migration and invasion activity. In contrast, in HSC3 cells, which have p53 nonsense mutations and exhibit high KRT17 expression, the overexpression of p53R248W decreased KRT17 expression, cell size, proliferation, and migration and invasion activities. In addition, p53R248W significantly suppressed MMP2 mRNA expression and enzyme activity. Moreover, s.c. and orthotopic xenografts were generated from p53R248W- or p53R248Q-expressing HSC3 cells. Tumors formed from p53R248W-expressing HSC3 cells grew more slowly and had a lower Ki-67 index than those derived from the control or p53R248Q-expressing HSC3 cells. Finally, the survival rate of the mice inoculated with p53R248W-expressing HSC3 cells was significantly higher than that of the control mice. These results indicate that the p53R248W mutant suppresses proliferation and invasion activity through the suppression of KRT17 expression. We propose that OSCC with p53R248W-expressing cells may be classified as a new OSCC type that has a good prognosis., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Legionella spp. can cause severe pneumonia and most Legionella pneumonia (LP) cases are diagnosed using the urine antigen test (UAT). However, diagnosis of LP with negative UAT results (LPNUAT) is challenging. We investigated the clinical and radiological features of LPNUAT., Methods: We retrospectively collected LP cases with positive UAT (LPPUAT) and cases of suspected LP with negative UAT that were examined by Legionella culture between July 2014 and March 2020. We investigated the clinical and CT findings for LP that showed negative UAT results and was diagnosed by culture and compared these findings with those for other pneumonias suspicious for LP with negative results in UAT and Legionella culture (OPSLP)., Results: Eight LPNUAT, 20 LPPUAT, and 19 OPSLP cases were included in this study. There were no significant differences in the clinical and CT findings between LPPUAT and LPNUAT when examined by UAT. In LPNUAT, dyspnea, renal dysfunction, liver dysfunction, and bilateral lesions were more commonly observed and inflammatory changes and the number of affected lobes were significantly higher when examined by culture than when examined by UAT. Comparison to OPSLP, LPNUAT did not show such differences, but rather showed disturbances in consciousness, hyponatremia and rhabdomyolysis. Furthermore, lobar consolidation was observed more frequently and bronchial wall thickening and centrilobular nodules were observed less frequently in LPNUAT., Conclusions: LP characteristics such as disturbance of consciousness, hyponatremia, rhabdomyolysis, lobar consolidation, and less bronchial wall thickening and centrilobular nodule contribute to the diagnosis of LP in patients with negative UAT results., Competing Interests: Conflict of Interest The authors declared no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Mismatch negativity (MMN) and P3a are event-related potential measures of early auditory information processing that are increasingly used as translational biomarkers in the development of treatments for neuropsychiatric disorders. These responses are reduced in schizophrenia patients over the frontocentral scalp electrodes and are associated with important domains of cognitive and psychosocial functioning. While MMN and P3a responses are generated by a dynamic network of cortical sources distributed across the temporal and frontal brain regions, it is not clear how these sources independently contribute to MMN and P3a at the primary frontocentral scalp electrode or to abnormalities observed in schizophrenia. This study aimed to determine the independent source contributions and characterize the magnitude of impairment in source-level MMN and P3a responses in schizophrenia patients., Methods: A novel method was applied to back-project the contributions of 11 independent cortical source components to Fz, the primary scalp sensor that is used in clinical studies, in n = 589 schizophrenia patients and n = 449 healthy comparison subjects., Results: The groups showed comparable individual source contributions underlying both MMN and P3a responses at Fz. Source-level responses revealed an increasing magnitude of impairment in schizophrenia patients from the temporal to more frontal sources., Conclusions: Schizophrenia patients have a normal architecture of source contributions that are accompanied by widespread abnormalities in source resolved mismatch and P3a responses, with more prominent deficits detected from the frontal sources. Quantification of source contributions and source-level responses accelerates clarification of the neural networks underlying MMN reduction at Fz in schizophrenia patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: No study has investigated the capability of high-resolution computed tomography (HRCT) to detect a lateral bronchus abnormality, degree of air bronchogram, and distribution of affected lesions in the diagnosis of Mycoplasma pneumoniae pneumonia (MPP)., Methods: We prospectively enrolled patients with serologically-confirmed MPP or culture-confirmed other bacterial pneumonia (OBP). The distribution of affected areas, abnormalities in lateral bronchial lesions, the degree of air bronchogram, and previously reported findings on HRCT were evaluated for MPP and OBP. Predictive HRCT findings for MPP were determined by logistic regression analysis. We provisionally designed our HRCT criteria (negative, probable, or highly suspected) for diagnosing MPP and investigated the diagnostic yield of the HRCT criteria., Results: Sixty-three MPP and 126 OBP patients were included in this study. Logistic regression analysis showed that the absence of peripheral predominance, bronchial wall thickening, lateral bronchial wall thickening, intralobular or lobular ground-glass opacities, intralobular ground-glass opacities connected to a lateral bronchus, and less air bronchogram in infiltrates were significant predictors of MPP. Our HRCT criteria showed that the sensitivity and specificity in negative, probable, and highly suspected MPP were 0.0 and 0.33, 1.0 and 0.69, and 0.5 and 0.98, respectively., Conclusions: HRCT had considerable ability to detect a lateral bronchial abnormality and to diagnose or rule out MPP based on the distribution of affected areas, abnormalities in lateral bronchial lesions, and the degree of air bronchogram in the infiltrates., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The purpose of the present study was to characterize current biopharmaceutics modeling and simulation software regarding the prediction of the fraction of a dose absorbed (Fa) in humans. As commercial software products, GastroPlus™ and Simcyp® were used. In addition, the gastrointestinal unified theoretical framework, a simple and publicly accessible model, was used as a benchmark. The Fa prediction characteristics for a total of 96 clinical Fa data of 27 model drugs were systematically evaluated using the default settings of each software product. The molecular weight, dissociation constant, octanol-water partition coefficient, solubility in biorelevant media, dose, and particle size of model drugs were used as input data. Although the same input parameters were used, GastroPlus™, Simcyp®, and the gastrointestinal unified theoretical framework showed different Fa prediction characteristics depending on the rate-limiting steps of oral drug absorption. The results of the present study would be of great help for the overall progression of physiologically based absorption models., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Casitas B-lineage lymphoma (c-Cbl) is a recently identified ubiquitin ligase of nuclear β-catenin and a suppressor of colorectal cancer (CRC) growth in cell culture and mouse tumor xenografts. We hypothesized that reduction in c-Cbl in colonic epithelium is likely to increase the levels of nuclear β-catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APC Δ14/+ ) mouse model. Haploinsufficient c-Cbl mice (APC Δ14/+ c-Cbl +/- ) displayed a significant (threefold) increase in atypical hyperplasia and adenocarcinomas in the small and large intestines; however, no differences were noted in the adenoma frequency. In contrast to the APC Δ14/+ c-Cbl +/+ mice, APC Δ14/+ c-Cbl +/- crypts showed nuclear β-catenin throughout the length of the crypts and up-regulation of Axin2, a canonical Wnt target gene, and SRY-box transcription factor 9, a marker of intestinal stem cells. In contrast, haploinsufficiency of c-Cbl +/- alone was insufficient to induce tumorigenesis regardless of an increase in the number of intestinal epithelial cells with nuclear β-catenin and SRY-box transcription factor 9 in APC +/+ c-Cbl +/- mice. This study demonstrates that haploinsufficiency of c-Cbl results in Wnt hyperactivation in intestinal crypts and accelerates CRC progression to adenocarcinoma in the milieu of APC Δ14/+ , a phenomenon not found with wild-type APC. While emphasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial loss of c-Cbl and inactivation of APC significantly contribute to CRC tumorigenesis., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We established three iPSC lines from postmortem-cultured fibroblasts derived following the sudden unexpected death of an 8-year-old girl with Lennox-Gastaut syndrome, who turned out to have the R551H-mutant STXBP1 gene. These iPSC clones showed pluripotent characteristics while retaining the genotype and demonstrated trilineage differentiation capability, indicating their utility in disease-modeling studies, i.e., STXBP1-encephalopathy. This is the first report on the establishment of iPSCs from a sudden death child, suggesting the possible use of postmortem-iPSC technologies as an epoch-making approach for precise identification of the cause of sudden death., (Copyright © 2019. Published by Elsevier B.V.)

Background: Blockade of the programmed death receptor-1 (PD-1) pathway is effective against solid tumors including lung cancer. PD-ligand 1 (PD-L1) expression on tumor tissue serves as a predictive biomarker for the efficacy of PD-1 pathway blockade. Here, we evaluated the expression of PD-L1 on circulating tumor cells (CTCs) in patients with lung cancer., Materials and Methods: Peripheral whole blood (3 mL) was collected from patients, and CTCs and PD-L1 expression were detected using a microcavity array (MCA) system. Immunohistochemistry for PD-L1 detection was also performed using matched tumor tissues., Results: Sixty-seven patients with lung cancer were enrolled in the study between July 2015 and April 2016 at Wakayama Medical University Hospital. The characteristics of the patients were as follows: median age, 71 years (range, 39-86 years); male, 72%; stage II to III/IV, 14%/85%; non-small-cell lung cancer/small-cell lung cancer/other, 73%/21%/6%. CTCs were detected in 66 of 67 patients (median, 19; range, 0-115), and more than 5 CTCs were detected in 78% of patients. PD-L1-expressing CTCs were detected in 73% of patients, and the proportion score of PD-L1-expressing CTCs ranged from 3% to 100%, suggesting intra-patient heterogeneity of PD-L1 expression on CTCs. Tumor tissues were available from 27 patients and were immunostained for PD-L1, and no correlation was observed between tumor tissues and CTCs based on the proportion score (R 2  = 0.0103)., Conclusion: PD-L1 expression was detectable on CTCs in patients with lung cancer, and intra-patient heterogeneity was observed. No correlation was observed between PD-L1 expression in tumor tissues and CTCs., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Streptococcus mutans, a bacterium mainly inhabiting the tooth surface, is a major pathogen of dental caries. The bacterium metabolizes sugars to produce acids, resulting in an acidic microenvironment in the dental plaque. Hence, S. mutans should possess a mechanism for surviving under acidic conditions. In the current study, we report the effects of inhibitors of Escherichia coli proton-pumping F-type ATPase (F-ATPase) on the activity of S. mutans enzyme, and the growth and survival of S. mutans under acidic conditions. Piceatannol, curcumin, and demethoxycurcumin strongly reduced the ATPase activity of S. mutans F-ATPase. Interestingly, these compounds inhibited the growth of S. mutans at pH 5.3 but not at pH 7.3. They also significantly reduced the colony-forming ability of S. mutans after incubation at pH 4.3, while showing essentially no effect at pH 7.3. These observations indicate that S. mutans is highly sensitive to F-ATPase inhibitors under acidic conditions and that F-ATPase plays an important role in acid tolerance of this bacterium., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Osteoclast lysosomes secrete lytic enzymes into bone resorption lacunae, and sort the lysosomal proton pumping vacuolar-type ATPase (V-ATPase) to the plasma membrane to form the acidic environment required for bone digestion. The a3 isoform of V-ATPase is essential for outward trafficking of the secretory lysosomes and interacts physically with Rab7, a small GTPase that regulates trafficking of late endosomes and lysosomes, to recruit it to lysosomes. However, it is unclear whether organelle acidification by V-ATPase is required for the lysosome trafficking. Here, we showed that incubation of osteoclasts with the V-ATPase inhibitor bafilomycin A1 abolished the osteoclast-characteristic peripheral localization of secretory lysosomes, Rab7, and α-tubulin. Although bafilomycin A1 had little or no effect on Rab7 activation and its interaction with a3, treatment with the inhibitor significantly reduced the lysosomal localization of Rab7. Even constitutively active Rab7 did not localize to lysosomes in the presence of the inhibitor. These results suggest that organelle acidification by V-ATPase is required for localization of activated Rab7 to lysosomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Porphyromonas gingivalis is a well-known Gram-negative bacterium that causes periodontal disease. The bacterium metabolizes amino acids and peptides to obtain energy. An ion gradient across its plasma membrane is thought to be essential for nutrient import. However, it is unclear whether an ion-pumping ATPase responsible for the gradient is required for bacterial growth. Here, we report the inhibitory effect of protonophores and inhibitors of a proton-pumping ATPase on the growth of P. gingivalis. Among the compounds examined, curcumin and citreoviridin appreciably reduced the bacterial growth. Furthermore, these compounds inhibited the ATPase activity in the bacterial membrane, where the A-type proton-pumping ATPase (A-ATPase) is located. This study suggests that curcumin and citreoviridin inhibit the bacterial growth by inhibiting the A-ATPase in the P. gingivalis membrane., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Transgene-free induced pluripotent stem cells (iPSCs) are valuable for both basic research and potential clinical applications. We previously reported that a replication-defective and persistent Sendai virus (SeVdp) vector harboring four reprogramming factors (SeVdp-iPS) can efficiently induce generation of transgene-free iPSCs. This vector can express all four factors stably and simultaneously without chromosomal integration and can be eliminated completely from reprogrammed cells by suppressing vector-derived RNA-dependent RNA polymerase. Here, we describe an improved SeVdp-iPS vector (SeVdp(KOSM)302L) that is automatically erased in response to microRNA-302 (miR-302), uniquely expressed in pluripotent stem cells (PSCs). Gene expression and genome replication of the SeVdp-302L vector, which contains miRNA-302a target sequences at the 3' untranslated region of L mRNA, are strongly suppressed in PSCs. Consequently, SeVdp(KOSM)302L induces expression of reprogramming factors in somatic cells, while it is automatically erased from cells successfully reprogrammed to express miR-302. As this vector can reprogram somatic cells into transgene-free iPSCs without the aid of exogenous short interfering RNA (siRNA), the results we present here demonstrate that this vector may become an invaluable tool for the generation of human iPSCs for future clinical applications., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The F 1 sector of ATP synthase (F O F 1 ) synthesizes or hydrolyses ATP via a rotational catalysis mechanism that couples chemical reaction with subunit rotation. Phytopolyphenols such as curcumin can inhibit bulk phase F 1 ATPase activity by extending the catalytic dwell time during subunit rotation (Sekiya, M., Hisasaka, R., Iwamoto-Kihara, A., Futai, M., Nakanishi-Matsui, M., Biochem. Biophys. Res. Commun. 452 (2014) 940-944). Citreoviridin, a polyene α-pyrone mycotoxin isolated from Penicillium sp, also inhibits ATPase activity. Molecular docking and mutational analysis indicated that these compounds interact with a region near the β-subunit Arg398 residue that lies at the interface with the α-subunit. Binding of these inhibitors lowered the rotation rate and increased the duration of the catalytic dwell synergistically with substitution of β-subunit Ser174 to Phe (βS174F), which rendered the enzyme defective for conformational transmission between β-subunits of different catalytic stages. Furthermore, substitution of α-subunit Glu402 to Ala (αE402A) in the α/β-interface also decreased the rotation rate by increasing the duration of the catalytic dwell. Interestingly, this mutation restored the catalytic dwell of the βS174F variant to that of the wild-type enzyme. These results suggest that the α/β-interface is involved in conformational changes of the β-subunit during rotational catalysis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We report the generation-characterization of a fetal liver (FL) B-cell progenitor (BCP)-derived human induced pluripotent stem cell (hiPSC) line CRISPR/Cas9-edited to carry/express a single copy of doxycycline-inducible Cas9 gene in the "safe locus" AAVS1 (iCas9-FL-BCP-hiPSC). Gene-edited iPSCs remained pluripotent after CRISPR/Cas9 genome-edition. Correct genomic integration of a unique copy of Cas9 was confirmed by PCR and Southern blot. Cas9 was robustly and specifically expressed on doxycycline exposure. T7-endonuclease assay demonstrated that iCas9 induces robust gene-edition when gRNAs against hematopoietic transcription factors were tested. This iCas9-FL-BCP-hiPSC will facilitate gene-editing approaches for studies on developmental biology, drug screening and disease modeling., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Acute kidney injury (AKI) often occurs in patients with acute myocardial infarction (AMI), and is associated with adverse outcomes. However, it remains unclear how timing of AKI affects it. This study assessed impact of timing of AKI on prognosis after AMI., Methods: This study consisted of 760 patients with AMI who were admitted within 48h after symptom onset. AKI was diagnosed as increase in creatinine ≥0.3mg/dl or ≥50% within any 48h after admission. Patients were classified into 3 groups according to the occurrence and timing of AKI: no-AKI, early-AKI (within 48h after admission) and late-AKI (>48h). Early-AKI was classified into transient early-AKI, defined as creatinine returning to the level below the criteria of AKI, and persistent early-AKI., Results: Early-AKI occurred in 64 patients (9%) and late-AKI in 32 patients (4%). Patients with early-AKI had significantly higher mortality (35%) than those with late-AKI (7%, p<0.001) and no-AKI (3%, p<0.001). Multivariate analysis showed early-AKI was an independent predictor of in-hospital mortality (OR: 3.38, 95% CI: 1.30-8.76, p=0.013), but late-AKI was not. Among patients with early-AKI, mortality was significantly higher even if AKI was transient (23%, p<0.001). Patients with persistent early-AKI had the highest mortality (66%, p<0.001)., Conclusions: Early-AKI was associated with worse outcome. Even if renal function once returned to baseline level, patients with early-AKI tended to be at high risk of mortality., (Copyright © 2016. Published by Elsevier Ltd.)

Background: The 24-h creatinine clearance (24-h Ccr) and the Cockcroft-Gault equation (CG) are commonly used as markers of renal function in clinical practice. However, the utility of the Japanese equation for estimating glomerular filtration rate (eGFR) in cancer patients has not yet been evaluated. The aim of this cross-sectional study was to investigate the extent and correlating factors for differences between eGFR and both 24-h Ccr and CG in advanced-stage thoracic cancer patients., Methods: eGFR, 24-h Ccr, and CG were calculated in 90 patients with thoracic malignancies. We evaluated how these three parameters are affected by clinical factors, including age, body surface area, serum creatinine concentration, and body mass index., Results: eGFR and CG were significantly correlated with 24-h Ccr (r=0.64, p<0.001 and; r=0.67, p<0.001, respectively). However, the median value derived from eGFR was higher than the median 24-h Ccr and the CG value (74.0, 65.2, and 63.9mL/min, respectively). Age had a significant positive correlation with the differences between eGFR and both 24-h Ccr and CG value (r=0.30, p=0.005 and; r=0.47, p<0.001, respectively). The differences between eGFR and the other two parameters were significantly higher in older patients (age≥70 years) than in younger patients (age<70 years) (p=0.023, p<0.001, respectively)., Conclusions: eGFR is likely to overestimate the renal function of elderly cancer patients. A modified equation for evaluating the renal function of Japanese older patients might be needed., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: There is no systematic analysis to identify problems involved with instruction on inhalation therapy for elderly patients. We conducted a nationwide questionnaire survey for patients and medical professionals., Methods: A questionnaire survey was conducted of adult patients on inhaled drugs (ages 18-92 years, 820 individuals) and medical professionals (pharmacists or nurses) who provided instruction on inhalation therapy to these patients in 23 institutions in Japan to investigate the technique and the level of understanding (knowledge) of the inhalation therapy. Changes in the recognition of performance of inhalation technique and inhalation knowledge with increasing age were analyzed., Results: According to patients' subjective assessment, there was no deterioration in the performance of the inhalation technique or loss of the knowledge with increasing age. On the other hand, medical professionals' objective assessment revealed a significant loss of both inhalation technique and knowledge with increasing age. Not many elderly patients noticed their own problems themselves, revealing a great perception gap between elderly patients and medical professionals. Thus, there was concern that patients would unconsciously practice the inhalation procedure improperly. On the other hand, in comparison with non-elderly patients, elderly patients were less resistant to continuation of therapy, suggesting that they would be more likely to accept instruction on inhalation therapy., Conclusions: Elderly patients are apt to assume that they "understand well", therefore, in order to recognize and close the perception gap between elderly patients and medical professionals, it is necessary to provide them with more aggressive (frequent) instructions on inhalation therapy., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Objectives: Japanese special nursing homes provide permanent residence to elderly people under the public long-term care insurance program. However, a quarter of discharges occur via death in hospital, and a fifth occur via admission to hospital. The objective was to identify factors associated with discharge destinations for residents of Japanese special nursing homes., Design: A retrospective design for data collected in 2007, 2010, and 2013., Setting: We used data from the Survey of Institutions and Establishments for Long-Term Care, which is a nationally representative cross-sectional survey that assessed discharge from special nursing homes in September every 3 years., Participants: There were 2426 discharged residents included in the analysis., Measurements: Discharge destination was categorized as death at facility, death in hospital, hospital admission, and another care setting. Multivariate multinomial logistic regression analysis was conducted with discharge destination as the dependent variable., Results: Of the 2426 discharged residents included in the analysis, 874 (36.0%) were deceased at the facility, 773 (31.9%) were deceased in hospital, 652 (26.9%) were admitted to hospital, and 127 (5.2%) were admitted to another care setting. Residents of facilities in the regions with fewer nursing home beds or more hospital beds were more likely to be discharged via admittance to hospital or another care setting relative to being deceased at the facility., Conclusion: The regional supply of nursing home and hospital beds could have affected end-of-life care locations for residents of special nursing homes. To promote end-of-life care in special nursing homes, regional supply of nursing home beds should be reinforced while controlling oversupply of hospital beds., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)