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Objective: This study assessed the real-world safety and efficacy of coil embolization during endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAA) for prophylactic endoleak prevention or as a reintervention for endoleak repair, using the Cerenovus family of coils (Cerenovus, Irvine, CA, USA)., Methods: This was a multicenter, retrospective cohort study of consecutive patients who underwent embolization of branching arteries during EVAR of an AAA, or as a reintervention for endoleak repair, using Cerenovus coils between January 2017 and December 2021 in Japan. The primary outcome was 30-day reintervention-free survival, defined as cardiovascular mortality or any complication requiring reintervention within 30 days post procedure. Secondary outcomes included conversion to open surgical repair; length of hospitalization; and the following outcomes through 30 days and 1-year post procedure: occurrence of endoleak (Type I-V), reintervention, complications not requiring reintervention, aneurysm-related mortality, coil migration, and all-cause mortality., Results: A total of 306 patients (mean age 76.7±7.8; 16.7% [51/306] female) were included in the study. Infrarenal AAA were most common (175/306; 57.2%), and the mean aneurysm size was 52.1±10.9 mm. At 30 days, reintervention-free survival was achieved in 96.4% (295/306) of patients; 9 (2.9%) patients required reintervention, and 2 (0.7%) died from cardiovascular causes through 30 days. One (1/305; 0.3%) patient underwent conversion to open repair. The mean length of hospitalization was 8.6±7.2 days. Complications not requiring reintervention occurred in 3.9% (12/306) of patients through 30-days and 12.4% (38/306) through 1-year. Endoleak occurred in 2.9% (9/306) of patients at 30 days and 9.5% (29/306) at 1 year. Coil migration and aneurysm rupture were not reported for any patient. Aneurysm-related mortalities occurred in 0.0% (0/305) at 30 days and 0.3% (1/303) at 1 year. All-cause mortalities occurred in 0.7% (2/306) at 30 days and 3.3% (10/304) at 1 year., Conclusions: This study demonstrated that the use of Cerenovus coils yielded a high rate of 30-day-reintervention-free survival and low rates of type II endoleak occurrence and recurrence at the target vessel through 30 days and 1 year in patients following EVAR of an AAA with coil embolization, either for prophylactic endoleak prevention during EVAR or as a reintervention to repair an endoleak., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To compare the characteristics and prognosis of patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) with pleuroparenchymal fibroelastosis (PPFE) with those of patients with nodular/bronchiectatic (NB) and fibrocavitary (FC) NTM-PD., Methods: This multicenter, retrospective, observational study enrolled 32 patients with NTM-PPFE (median age: 70.5 years, 15 females) from six institutions in Japan from January 2003 to December 2018. Their clinical characteristics and response to therapy were compared with age- and sex-matched cohorts of patients with noncavitary NB and cavitary NB/FC NTM-PD., Results: Patients with NTM-PPFE had a lower body mass index and a higher standard NTM-PD therapy initiation rate than patients with other NTM-PD types. Sputum culture conversion rates were comparable between groups; however, patients with NTM-PPFE had a higher incidence of treatment-related adverse events, including optic neuropathy associated with high-dose ethambutol therapy, lower percent predicted forced vital capacity values, higher serum Krebs von den Lungen-6 (KL-6) levels, and poorer treatment outcomes than the other groups. Cox regression revealed that NTM-PPFE was an independent risk factor for death/pneumothorax (adjusted hazard ratio: 35.3, 95% confidence interval: 3.90-4692)., Conclusion: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes., Competing Interests: Declarations 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 article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Standard care for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) involves chemoradiotherapy followed by durvalumab. The clinical significance of durvalumab after chemoradiotherapy in patients with LA-NSCLC having a performance status of 2 or aged ≥75 years, however, remains unclear. Therefore, we investigated the clinical benefit of durvalumab after daily carboplatin plus thoracic concurrent radiotherapy., Patients and Methods: In this prospective phase II study, daily low-dose carboplatin (30 mg/m 2 ) was administered before radiotherapy for the first 20 fractions and concurrent radiotherapy (60 Gy) followed by durvalumab. The primary endpoint was 12 months progression-free survival (PFS) rate from durvalumab initiation. The secondary endpoints included rate of therapeutic completion, PFS, overall survival, objective response rate, and safety., Results: Of 86 patients who underwent chemoradiotherapy with daily carboplatin from September 2019 to October 2021, 61 (70.9%) received durvalumab consolidation. The performance status was 0, 1, and 2 in 28 (45.9%), 26 (42.6%), and 7 (11.5%) patients, respectively. The rate of therapeutic completion for durvalumab was 26.2% (16/61). The PFS rate of 12 months after durvalumab initiation was 51.0%, indicating that the primary endpoint was achieved because the expected value of 35% calculated from previous studies was exceeded. The objective response rate after chemoradiotherapy and durvalumab was 47.0% and 57.4%, respectively. The median PFS and overall survival were 12.3 and 28.1 months, respectively. The most common adverse event in grades 3 or 4 was pneumonitis (8.2%). One patient died because of interstitial pneumonitis., Conclusions: Durvalumab consolidation after daily carboplatin with radiotherapy was effective and tolerable for LA-NSCLC vulnerable patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Clot waveform analysis (CWA) reportedly enhances the interpretation of clotting time measurement. This study aimed to compare CWA between prothrombin time (PT) and activated partial thromboplastin time (APTT) assays for better understanding how to apply CWA for assessing effects of direct oral anticoagulants (DOACs)., Methods: Samples were prepared by spiking plasma with rivaroxaban, apixaban, edoxaban, or dabigatran. To compensate the influence of fibrinogen, CWA parameters were adjusted by unifying maximum changes in transmittance in clotting reaction curves detected by the optical system., Results: Non-adjusted PT-CWA parameters unexpectedly rose at low drug concentrations but declined at high drug concentrations while adjusted PT-CWA parameters exhibited dose-dependent decrease. Both non-adjusted and adjusted APTT-CWA parameters showed dose-dependent decrease. Adjusted CWA parameters were applicable to Hill plot analysis. All DOACs exhibited Hill coefficients indicating positively cooperative effects regarding most adjusted PT-CWA parameters. Regarding adjusted APTT-CWA parameters, rivaroxaban, apixaban, and edoxaban exhibited Hill coefficients indicating no or negatively cooperative effects. The observed differences between PT-CWA and APTT-CWA suggested the implication of thrombin positive feedback in DOAC effects., Conclusion: The results revealed distinct features of DOAC effects in extrinsic and intrinsic pathways. To ascertain the clinical implication, further studies using clinical samples are needed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This multicenter study aimed to analyze the risk factors for fluoroquinolone (FQ) resistance and to clarify the clinical characteristics of acute bacterial prostatitis (ABP) in Japan., Methods: A total of 124 patients clinically diagnosed with ABP at 13 medical institutions participating in the Japanese Research Group for Urinary Tract Infection between January and December 2017 were retrospectively reviewed., Results: Of the 124 patients included in this study, 37 were outpatients, and 87 were inpatients. The main underlying medical conditions before the onset of ABP were severe dysuria, urinary retention, transurethral manipulation, indwelling urinary catheter, and transrectal prostate biopsy (TRBx). The main symptoms were fever (≥37.5 °C), prostate tenderness, dysuria, micturition pain, urinary retention, and macrohematuria. Bacteremia was observed in 14 patients. Prostatic abscess was observed in three patients. Escherichia coli was the predominant organism, accounting for 48 % (51/106). FQ-resistant E. coli was detected in 33 % (17/51), and extended-spectrum beta-lactamase-producing E. coli in 12 % (6/51). TRBx (odds ratio [OR] = 48.60, 95 % confidence interval [CI]: 5.49-430.00, p < 0.001) and inpatient status (OR = 29.00, 95 % CI: 1.95-430.00, p = 0.014) were risk factors for the detection of FQ-resistant bacteria., Conclusions: The detection rate of FQ-resistant bacteria was significantly higher with TRBx ABP and inpatient status. These findings have important implications for the management of ABP and antimicrobial treatment, especially for TRBx ABP, which should be considered a separate category., Competing Interests: Declaration of Competing interest The authors declare no conflicts of interest., (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.)

Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests 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 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC., 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 B.V. All rights reserved.)

Introduction: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species., Materials and Methods: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan., Results: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 μg/mL) decreased from 14.7% to 7.7%., Discussion: Bacterial strains that produced extended-spectrum β-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years., Competing Interests: Declaration of competing interest Satoshi Takahashi received speaker honoraria from Fujirebio Inc. and research funding from Shino-Test Corporation, Roche Diagnostic K. K., Fujirebio Inc., and Abbott Japan Co., Ltd. Koichiro Wada received speaker honoraria from Janssen Pharmaceutical K.K., and MSD K.K. Shingo Yamamoto received speaker honoraria from MSD K.K., Fuso Pharmaceutical Industries, Ltd., Daiichi Sankyo Co., Ltd. and scholarship donations from Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. and research funding from Takeda Pharmaceutical Co., Ltd. Tetsuya Matsumoto received speaker honoraria from MSD K.K., Pfizer Japan Inc., and Kyorin Pharmaceutical Co., Ltd., and research funding from Kewpie Corporation., Biofermin Pharmaceutical Co., Ltd. Kazumasa Matsumoto received research funding from Sysmex Corporation. Tohru Nakagawa received speaker honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K., (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.)

Purpose: The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas., Methods: Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines., Results: The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5'-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected., Conclusion: These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

This prospective cohort study aimed to investigate the impact of medication-related osteonecrosis of the jaw (MRONJ) on health-related quality of life (HRQOL) and oral health-related QOL (OHRQOL) and the association between the downstaging of MRONJ and OHRQOL. The HRQOL and OHRQOL of 44 patients with MRONJ were assessed using the SF-36v2 and the General Oral Health Assessment Index (GOHAI), respectively. Treatment was performed in accordance with the AAOMS position paper (2014). The SF-36v2 and GOHAI scores at the beginning of the survey were used to evaluate the impact of MRONJ on QOL. Potential confounders affecting the association between downstaging and QOL improvement were selected using directed acyclic graphs. Multiple regression analysis was performed to evaluate causal inferences. HRQOL scale scores declined below the national average. The three-component summary score (3CS), comprising the physical component summary (PCS), mental component summary (MCS), and role/social component summary (RCS), revealed that performance status and primary disease significantly affected the PCS and RCS (P = 0.005 and P < 0.001, respectively) and PCS and MCS (P = 0.024 and P = 0.003, respectively). The MRONJ stage did not influence the 3CS; however, OHRQOL declined in a stage-dependent manner (P = 0.005). Downstaging of MRONJ was independently associated with the improvement rate of the total GOHAI scores after adjusting for variables (P = 0.045). The HRQOL of patients with MRONJ declined; however, this may depend on the underlying disease status rather than the MRONJ stage. Improvement of the disease status can potentially predict an improvement in OHRQOL, regardless of the treatment modality., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate the association between the number of teeth, food intake, and cognitive function in Japanese community-dwelling older adults., Methods: This 9-year longitudinal study included a total of 293 analyzable participants who participated in baseline and follow-up surveys. Dental status (number of teeth and periodontal pocket depth), dietary assessment using the brief-type self-administered diet history questionnaire, cognitive function, and the following confounding factors were evaluated: educational level, financial satisfaction, living situation, smoking and drinking habits, history of chronic diseases, apolipoprotein E-ε4 carrier, body mass index, handgrip strength, instrumental activities of daily living, and depressive symptomatology. The Japanese version of the Montreal Cognitive Assessment was used to evaluate cognitive function. A multinomial logistic regression analysis for the intake level of each food categorized into three groups (low, moderate, high), and a generalized estimating equation (GEE) for cognitive function over nine years were performed., Results: After controlling for confounding factors, the number of teeth was shown to be associated with the intake of green-yellow vegetables and meat. Furthermore, the GEE indicated that the lowest quartile of intake of green-yellow vegetables significantly associated with lower cognitive function (unstandardized regression coefficient [B] = -0.96, 95 % confidence interval [CI]: -1.72 to -0.20), and the lowest quartile of intake of meat significantly associated with lower cognitive function (B = -1.42, 95 % CI: -2.27 to -0.58)., Conclusions: The intake of green and yellow vegetables and meat, which is influenced by the number of teeth, was associated with cognitive function in Japanese community-dwelling older adults., Clinical Significance: There are few studies that have examined the association between oral health, food intake, and cognitive function. This 9-year longitudinal study suggests that it is important to maintain natural teeth to enable the functional means to consume green-yellow vegetables and meat, and thereby help maintain cognitive function., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paula Moynihan reports a relationship with GSK Consumer Healthcare that includes: consulting or advisory. Paula Moynihan reports a relationship with Haleon Oral Health Strategic Advisory Council that includes: consulting or advisory. If there are other authors, they 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Globally, mental health conditions pose a substantial burden of disease. Despite the availability of evidence-based pharmacological and psychological treatments, the symptoms of a substantial subgroup of patients do not respond to these interventions, and only a minority of patients have access to them. This study aimed to assess the efficacy of ImPuls, a 6-month transdiagnostic group exercise intervention, plus treatment-as-usual, compared with treatment-as-usual alone in outpatients with various mental disorders., Methods: In this pragmatic, two-arm, multisite, randomised controlled trial in Germany, ten outpatient rehabilitative and medical care facilities were involved as study sites. Participants were outpatients diagnosed according to ICD-10 with one or more of the following disorders based on structured clinical interviews: moderate or severe depression, primary insomnia, post-traumatic stress disorder (PTSD), panic disorder, or agoraphobia. Participants were required to be aged between 18 years and 65 years, insured by the health insurers Allgemeine Ortskrankenkasse Baden-Württemberg or Techniker Krankenkasse, fluent in German, and without medical contraindications for exercise. Blocks of six participants were randomly allocated to ImPuls plus treatment-as-usual or treatment-as-usual alone (allocation ratio: 1:1), stratified by study site. The randomisation sequence was generated by an external data manager. The team responsible for data collection and management was masked to the randomisation sequence. The ImPuls intervention comprised evidence-based outdoor exercises lasting 30 min, and aimed at achieving at least moderate intensity. It also incorporated behavioural change techniques targeting motivational and volitional determinants of exercise behaviour. Treatment-as-usual was representative of typical outpatient health care in Germany, allowing patients access to any standard treatments. The primary outcome was global symptom severity at 6 months after randomisation, measured using self-report on the Brief Symptom Inventory (BSI-18) and analysed in the intention-to-treat sample. No individuals with lived experience of mental illness were involved in conducting the study or writing the final publication. Safety was assessed in all participants. The trial was registered with the German Clinical Trials Register (DRKS00024152) with a completion date of June 30, 2024., Findings: 600 patients provided informed consent, were recruited to the study, and underwent a diagnostic interview between Jan 1, 2021, and May 31, 2022. Following this, 199 were excluded on the basis of inclusion and exclusion criteria and one withdrew consent during the baseline assessment. Of the 400 eligible participants, 284 (71%) self-identified as female, 106 (27%) self-identified as male, and nine (2%) self-identified as other. The mean age was 42·20 years (SD 13·23; range 19-65). Ethnicity data were not assessed. 287 (72%) participants met the criteria for moderate or severe depression, 81 (20%) for primary insomnia, 37 (9%) for agoraphobia, 46 (12%) for panic disorder, and 72 (18%) for PTSD. 199 participants were allocated to the intervention group of ImPuls plus treatment-as-usual and 201 to the control group of treatment-as-usual alone. 38 (19%) participants did not receive the minimum ImPuls intervention dose. ImPuls plus treatment-as-usual demonstrated superior efficacy to treatment-as-usual alone in reducing global symptom severity, with an adjusted difference on BSI-18 of 4·11 (95% CI 1·74-6·48; d=0·35 [95% CI 0·14-0·56]; p=0·0007) at 6 months. There were no significant differences in the total number of adverse events or serious adverse events between the two groups. There was one serious adverse event (male, torn ligament) related to the intervention., Interpretation: ImPuls is an efficacious transdiagnostic adjunctive treatment in outpatient mental health care. Our findings suggest that exercise therapy should be implemented in outpatient mental health care as an adjunctive transdiagnostic treatment for mental disorders such as depression, insomnia, panic disorder, agoraphobia, and PTSD. Transdiagnostic group exercise interventions might ameliorate the existing disparity in care provision between the many individuals in need of evidence-based treatment and the few who are receiving it., Funding: The German Innovation Fund of the Federal Joint Committee of Germany., Competing Interests: Declaration of interests SP declares that the German Association for Health-Enhancing Physical Activity and Exercise Therapy maintains a training programme for psychiatry, psychosomatics, and addiction. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD + decreases with age in certain tissues, and age-related NAD + depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD + precursor significantly elevates NAD + levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD + in animal studies, the efficacy of NAD + precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD + precursor treatment efficiently increases NAD + levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD + precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD + intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD + metabolism. Also, the reduced form of NAD + precursor shows their potential to raise NAD + , though preclinical studies have yet to discover their efficacy. This review sheds light on NAD + therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD + metabolism., Competing Interests: Declaration of competing interest No financial and commercial conflict of interest was disclosed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT., Methods: Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6., Results: Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported., Conclusions: The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation., Clinical Trial Registration: NCT02344004., Competing Interests: Declaration of competing interest Kozo Morimoto received an educational grant from Insmed G.K. to NTM-JRC, serves as a consultant to Nippon Boehringer Ingelheim Co. Ltd. and Insmed G.K., received honoraria for writing promotional material from Insmed G.K. and Nippon Boehringer Ingelheim Co. Ltd.; Mizu Nonaka received lecture fees from Insmed G.K.; Taku Nakagawa received lecture fees from Insmed Inc. and was a member of the advisory board of Insmed Inc.; Kazunari Tsuyuguchi serves as a consultant to Insmed Inc. and Asahi Kasei Pharma and received honoraria for writing promotional material from Insmed Inc., Janssen Pharmaceutical K.K., Eiken Chemical Co. Ltd., AstraZeneca K.K., Kyorin Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and Oxford Immunotec K.K; Zhanna Jumadilova was a former employee of Insmed Inc. and received grants or contracts from Insmed Inc.; Dayton W. Yuen is an employee of Insmed Inc. and reports stock or stock options in Insmed Inc.; Monika Ciesielska is an employee of Insmed Inc. and reports stock or stock options in Insmed Inc.; Naoki Hasegawa serves as a consultant to Insmed Inc.; Yoshitaka Yamazaki, Jin Takasaki, and Seigo Kitada have no conflicts of interest., (Copyright © 2024 [The Author/The Authors]. Published by Elsevier B.V. All rights reserved.)

Background: Intramedullary nailing (IMN) is considered the gold-standard treatment for femoral shaft fractures. The post operative fracture gap is commonly recognized as a risk factor for nonunion. However, no evaluation standard for measuring the fracture gap size has yet been established. In addition, the clinical implications of the fracture gap size have also not been determined so far. This study aims to clarify how we should evaluate fracture gaps when assessing simple femoral shaft fractures with radiographs and to determine the acceptable cut-off value of the fracture gap size in simple femoral shaft fractures., Method: A retrospective observational study with a consecutive cohort was conducted at the trauma center of a university hospital. We investigated the fracture gap using postoperative radiography and the postoperative bone union of transverse and short oblique femoral shaft fractures fixed by IMN. The receiver operating characteristic curve analysis was conducted to obtain the fracture gap's mean, minimum, and maximum cut-off values. Fisher's exact test was used at the cut-off value of the most accurate parameter., Results: In the four nonunions among the 30 cases, the analysis using ROC curves revealed that the maximum value had the highest accuracy among the maximum, minimum, and mean values of fracture-gap size. The cut-off value was determined to be 4.14 mm with high accuracy. Fisher's exact test showed that the incidence of nonunion was higher in the group with a maximum fracture gap of 4.14 mm or greater (risk ratio = not applicable, risk difference = 0.57, P = 0.001)., Conclusion: In simple transverse and short oblique femoral shaft fractures fixed with IMN, the fracture gap on radiographs should be evaluated by the maximum gap in the AP and lateral views. The remaining maximum fracture gap of ≥4.14 mm would be a risk factor for nonunion., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: This study compares the clinical and microbiological efficacy of ceftolozane/tazobactam (CTLZ/TAZ) and piperacillin/tazobactam (PIPC/TAZ) for treating complicated cystitis or acute pyelonephritis., Methods: Patients who had been treated with empiric antibiotics, CTLZ/TAZ (52 cases) or PIPC/TAZ (47 cases), due to urinary tract infections (UTIs) were eligible for this study. Patients' demographic backgrounds, types of UTIs, and causative microorganisms isolated from urine or blood bacterial cultures were collected. Short-term clinical efficacy at the end of the initial empiric therapy, long-term clinical efficacy including sequential antibiotic treatments (nonrecurrence rate within 1 month after the initial empiric therapy), and microbiological efficacy were retrospectively compared in both CTLZ/TAZ and PIPC/TAZ groups., Results: Complicated UTIs were present in most eligible patients, and no significant difference in the patients' background was observed between the two groups. Escherichia coli and Enterococcus faecalis were the most common microorganisms isolated from urine culture in both groups. The short-term clinical effective rate of CTLZ/TAZ and PIPC/TAZ was 80.8% and 87.2%, respectively. For long-term clinical efficacy, the nonrecurrence rate of UTIs was present in 95.1% and 89.7% of patients with CTLZ/TAZ and PIPC/TAZ, respectively. No significant difference was observed in the short- and long-term effects between the two groups. The microbiological efficacy of the CTLZ/TAZ and PIPC/TAZ groups was 72.7% and 86.0%, respectively. No significant difference in microbiological effects was also observed between the two groups., Conclusions: This study demonstrated the noninferiority of CTLZ/TAZ to PIPC/TAZ, suggesting that CTLZ/TAZ is an alternative antibiotic used as empiric therapy for UTIs., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: While skeletal muscle index (SMI) is the most widely used indicator of low muscle mass (or sarcopenia) in oncology, optimal cut-offs (or definitions) to better predict survival are not standardized., Methods: We compared five major definitions of SMI-based low muscle mass using an Asian patient cohort with gastrointestinal or genitourinary cancers. We analyzed 2015 patients with surgically-treated gastrointestinal (n = 1382) or genitourinary (n = 633) cancer with pre-surgical computed tomography images. We assessed the associations of clinical parameters, including low muscle mass by each definition, with cancer-specific survival (CSS) and overall survival (OS)., Results: During a median follow-up period of 61 months, 303 (15%) died of cancer, and 147 died of other causes. An Asian-based definition diagnosed 17.8% of patients as having low muscle mass, while the other Caucasian-based ones classified most (>70%) patients as such. All definitions significantly discriminated both CSS and OS between patients with low or normal muscle mass. Low muscle mass using any definition but one predicted a lower CSS on multivariate Cox regression analyses. All definitions were independent predictors of lower OS. The original multivariate model without incorporating low muscle mass had c-indices of 0.63 for CSS and 0.66 for OS, which increased to 0.64-0.67 for CSS and 0.67-0.70 for OS when low muscle mass was considered. The model with an Asian-based definition had the highest c-indices (0.67 for CSS and 0.70 for OS)., Conclusions: The Asian-specific definition had the best predictive ability for mortality in this Asian patient cohort., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Bone marrow derived cells (BMDCs) migrate into the hypothalamus, where those cells give rise to microglia to regulate food intake. Given the fact that diabetes functionally impairs BMDCs, we hypothesized that diabetic microglia would fail to exhibit physiological function, accounting for hyperphagia in diabetes. To examine the role of BMDCs, total bone marrow cells from GFP transgenic mice were transplanted into wild type mice in which diabetes was induced by streptozotocin. We first confirmed that bone marrow transplantation could be utilized to examine BMDCs in the brain parenchyma as GFP positive cells could engraft the brain parenchyma and give rise to microglia even when the BBB was intact in the recipient mice. While diabetic mice manifested hyperphagia, BMDCs were in smaller number in the hypothalamus with less response to fasting in the brain parenchyma compared to nondiabetic mice. This finding was also confirmed by examining nondiabetic chimera mice in which BMDCs were diabetic. Those mice also exhibited less response of BMDCs in response to fasting. In conclusion, diabetic BMDCs had less response of microglia to fasting, perhaps accounting for diabetic hyperphagia., 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 works reported in this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD + biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD + concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD + concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis., 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.)

Background: In distal humerus fracture surgery, postoperative ulnar neuropathy is a common complication. The present study assessed the utility of the modified paratricipital approach for preventing ulnar neuropathy. This approach preserved the continuity of the attachment of the triceps with the ulnar nerve and allowed anterior subluxation of the ulnar nerve onto the hardware to be avoided., Methods: From December 2018 to March 2020, 13 patients who underwent surgery for distal humerus fracture through the modified paratricipital approach at our hospital were prospectively enrolled in the study. Ulnar neuropathy, Mayo Elbow Performance Score (MEPS), and Range of motion (ROM) were evaluated., Results: No postoperative ulnar neuropathy was observed. At the final follow-up, the mean Mayo Elbow Performance score was 97.7 (range, 85-100). The mean arc motion was 132.7° (range, 115°-145°) with a mean flexion contracture of 4.2° (range, 0°-10°) and mean flexion of 136.2° (range, 120°-145°). Hardware breakage leading to a loss of reduction occurred in one case, but the other fractures united., Conclusions: Our results demonstrated the effectiveness of the modified paratricipital approach for preventing postoperative ulnar neuropathy. The modified paratricipital approach is a safe and reliable method of performing distal humerus fracture surgery., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objective: This study aims to elucidate the trajectory of quality of life (QoL) over a two-year period after radiotherapy and/or chemotherapy for head and neck cancer (HNC), addressing the gap in long-term QoL information., Methods: Employing a prospective longitudinal observational design, we tracked 58 HNC patients who underwent radiotherapy and/or chemotherapy, analyzing their QoL using Short-Form 36-Item Health Survey version 2 (SF36v2), the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30), and the European Organization for Research and Treatment of Cancer quality of life head and neck-35 (EORTC-QLQ-H&N35) questionnaires for two years post-discharge. The data underwent repeated measures analysis of variance., Results: Over the two-year follow-up, 10 patients (17.2%) succumbed, and 8 (13.8%) dropped out. SF36v2 physical and role-social component summary scores declined during treatment, requiring 1-2 years for recovery. The mental component summary score remained stable. EORTC-QLQ-30 revealed global health status recovery within one year post-discharge. EORTC-QLQ-H&N35 items like "swallowing," "senses problems," "trouble with social eating," "dry mouth," "sticky saliva," "coughing," and "felt ill" worsened pre-discharge. "Trouble with social contact" improved within a year, while "pain," "swallowing," "senses problems," "trouble with social eating," and "coughing" improved within two years. "Dry mouth" and "sticky saliva" persisted throughout the two-year follow-up, common symptoms of HNC and treatment side effects., Conclusions: Recovery of specific QoL aspects in HNC patients treated with radiotherapy and/or chemotherapy may require up to two years. Prolonged monitoring and management of oral symptoms could enhance QoL. Future research should extend follow-up beyond two years for comprehensive interventions enhancing patient QoL., (© 2023 The Author(s).)

Introduction: The Geriatric 8 (G8) and Vulnerable Elders Survey-13 (VES-13) are established screening tools for assessing vulnerability in older patients. Here we investigated their usefulness as predictors of length of hospital stay and postoperative complications in Japanese patients undergoing urological surgery., Materials and Methods: This study included 643 patients who underwent urological surgery (74% were for malignancy) at our institute from 2017 to 2020. G8 and VES-13 scores were routinely recorded upon admission. These indices and other clinical data were obtained through chart review. The correlation between G8 group (high, >14; intermediate, 11-14; low, <11) or VES-13 group (normal, <3; high, ≥3) and length of total hospital stay (LOS), postoperative hospital stay (pLOS), and postoperative complications including delirium were analyzed., Results: The median patient age was 69 years. A total of 44%, 45%, and 11% of patients were classified into high, intermediate, and low G8 groups, respectively, while 77% and 23% were classified into normal and high VES-13 groups, respectively. Univariate analyses revealed that low G8 scores were associated with prolonged LOS (vs. intermediate, odds ratio [OR] 2.87, P < 0.001; vs. high, OR 3.87, P < 0.001), prolonged pLOS (vs. intermediate, OR 2.37, P = 0.005; vs. high, OR 3.06, P < 0.001), and delirium (vs. intermediate, OR 3.23, P = 0.007; vs. high, OR 5.38, P < 0.001), and high VES-13 scores were associated with prolonged LOS (OR 2.85, P < 0.001), prolonged pLOS (OR 2.97, P < 0.001), and Clavien-Dindo grade ≥ 2 complications (OR 1.74, P = 0.044), and delirium (OR 3.18, P = 0.001). Furthermore, multivariate analyses revealed that low G8 and high VES-13 scores were independent factors which predicted prolonged LOS (low G8; vs. intermediate, OR 2.96, P < 0.001; vs. high, OR 3.94, P < 0.001; high VES-13; OR 2.98, P < 0.001) and prolonged pLOS (low G8; vs. intermediate, OR 2.41, P = 0.008; vs. high, OR 3.18, P = 0.002; high VES-13; OR 3.47, P < 0.001), respectively., Discussion: The G8 and VES-13 may be effective tools for predicting prolonged LOS/pLOS and postoperative complications in Japanese patients who undergo urological surgery., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: We aimed to use two indices, amniotic fluid interleukin-6 (IL-6) concentration at diagnosis and diagnosis-to-delivery interval, to clarify the frequencies of maternal inflammatory response (MIR) and fetal inflammatory response (FIR) in the placenta of patients with intra-amniotic infection and intra-amniotic inflammation (IAI)., Methods: This is a single-center retrospective cohort study. From August 2014 to April 2020, participants were diagnosed with IAI with or without microbial invasion of the amniotic cavity (MIAC) using amniocentesis. IAI was defined as concentrations of amniotic IL-6 ≥ 2.6 ng/mL. MIAC was defined as a positive amniotic fluid culture. IAI with MIAC was defined as an intra-amniotic infection. We calculated the cut-off values for IL-6 concentration in the amniotic fluid at diagnosis and the diagnosis-to-delivery interval for MIR-positive cases among those with intra-amniotic infection., Results: The amniotic fluid IL-6 concentration at diagnosis and diagnosis-to-delivery interval were 15.8 ng/mL and 12 h, respectively. Among cases with intra-amniotic infection, MIR was 98% (52/53) positive, i.e., when either of the two cut-off values was exceeded. There were no significant differences between the frequencies of MIR and FIR. In cases with IAI but no MIAC, the frequencies of MIR and FIR were significantly lower than those with intra-amniotic infection, except when neither of the two cut-off values was exceeded., Discussion: We clarified the MIR- and FIR-positive cases in intra-amniotic infection and cases with IAI but no MIAC according to condition, including the diagnosis-to-delivery interval., 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 Ltd. All rights reserved.)

Alzheimer's disease (AD) causes neurodegeneration, leading to cognitive impairment and memory loss. Our previous studies have demonstrated that the induction of growth arrest and DNA damage-inducible gene 34 (GADD34) by quercetin can affect eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-activated transcription factor 4 (ATF4) signaling. However, the relationship between GADD34 expression and cognitive function has not been clarified. In this study, we determined the direct effect of GADD34 on memory. To achieve this, truncated GADD34 (GADD34.5) was injected into the mouse brain to suppress eIF2α phosphorylation and evaluate memory. The injection of GADD34.5 into the hippocampus in AD-model mice did not improve novel object recognition but improved novel object location. The injection of GADD34.5 into the amygdala also resulted in the maintenance of contextual fear memory based on the fear condition test. These results suggest that GADD34 is effective in improving memory for spatial cognition and contextual fear conditioning in AD by inhibiting eIF2α phosphorylation. In summary, GADD34 suppresses eIF2α phosphorylation in the brain and prevents memory loss. As quercetin feeding increases GADD34 expression, it might be used in preventative applications for AD., 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.)

The epigenetic regulation for gene expression determines cell plasticity. Oral squamous cell carcinoma (SCC) exhibits bidirectional cell plasticity, i.e. epithelial differentiation and epithelial to mesenchymal transition (EMT). The epigenetic regulator LSD1 is a histone H3-specific demethylase to which chemical inhibitors for its activity had been developed as an anti-cancer therapeutics. The bidirectional plasticity of the oral SCC cell line OM-1 had been characterized, but it remained unclear how chemical LSD1 inhibitors affect cell plasticity. Here we reported an adverse effect against cancer therapeutics, which was EMT induction in vitro by the chemical LSD1 inhibitor. The LSD1 inhibitor caused EMT-TF ZEB1 in OM-1 to undergo EMT. Furthermore, an additional EMT-TF Snail-dependent partial EMT phenotype in OM-1 progressed to complete EMT in conjunction with LSD1 inhibitor-dependent ZEB1 induction. The promotor activity of ZEB1 was up-regulated under LSD1 inhibition. The regulatory chromatin regions of ZEB1 accumulated histone H3 methylation under the chemical inhibition of LSD1. The LSD1 inhibitor also upregulates epithelial gene expression in vitro; however, the bidirectional effect of LSD1 inhibitor should be considered in cancer therapeutics., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression., 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 © 2022 Elsevier B.V. All rights reserved.)

Malaria is an infectious disease caused by Plasmodium parasites and has high mortality rates, especially among children in African and Southeast Asian countries. Patients with hemolytic anemia are suggested to adapt protective measures against malarial infection. Nicotinamide adenine dinucleotide (NAD + ) is a crucial cofactor associated with numerous biological processes that maintain homeostasis in all living organisms. In a previous study, we had demonstrated that the deficiency of nicotinamide mononucleotide adenylyltransferase 3 (Nmnat3), an enzyme catalyzing NAD + synthesis, causes hemolytic anemia accompanied by a drastic decline in the NAD + levels in the erythrocytes. It is well known that hemolytic anemia is linked to a reduced risk of malarial infections. In the present study, we investigated whether hemolytic anemia caused by Nmnat3 deficiency is beneficial against malarial infections. We found that Nmnat3 deficiency exacerbated malarial infection and subsequently caused death. Moreover, we demonstrated that the NAD +  levels in malaria-infected Nmnat3 red blood cells significantly increased and the glycolytic flow was largely enhanced to support the rapid growth of malarial parasites. Our results revealed that hemolytic anemia induced by the deletion of Nmnat3 was harmful rather than protective against malaria., 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 © 2022 Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ), a biological molecule integral to redox reactions involved in multiple cellular processes, has the potential to treat nonalcoholic fatty liver diseases (NAFLDs) and nonalcoholic steatohepatitis (NASH). Nicotinamide mononucleotide adenylyltransferase (Nmnat1), one of the NAD + biosynthesizing enzymes, plays a central role in all NAD + metabolic pathways and it is vital to embryonic development. However, the function of Nmnat1 in metabolic pathology and, specifically, in the development and progression of NAFLD and NASH remains unexplored. First, we generated hepatic Nmnat1 knockout (H-Nmnat1 -/- ) mice to investigate the physiological function of Nmnat1 and found that NAD + levels were significantly lower in H-Nmnat1 -/- mice than control mice. However, H-Nmnat1 -/- mice appeared normal with comparable metabolic activity. Next, we used three different diet-induced NASH models to assess the pathophysiological role of Nmant1 in metabolic disorders and discovered that hepatic loos of Nmnat1 decreased 35%-40% of total NAD + in an obese state. Nevertheless, our analysis of phenotypic variations found comparable body composition, gene expression, and liver histology in all NASH models in H-Nmnat1 -/- mice. We also found that aged H-Nmnat1 -/- mice exhibited comparable liver phenotypes with control mice. These findings suggest that Nmnat1 has a redundancy to the pathophysiology of obesity-induced hepatic disorders., 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 © 2022 Elsevier Inc. All rights reserved.)

Plasma membrane (PM) H + -ATPase contributes to nutrient uptake and stomatal opening by creating proton gradient across the membrane. Previous studies report that a dominant mutation in the OPEN STOMATA2 locus (OST2-2D) constitutively activates Arabidopsis PM H + -ATPase 1 (AHA1), which enlarges proton motive force for root nutrient uptake. However, the stomatal opening is also constitutively enhanced in the ost2-2D, causing drought hypersensitivity. To develop plants with improved nutrient acquisition and normal stomatal movement, we generated grafted plants (scion/rootstock: Col-0 (WT)/ost2-2D), and compared their growth, nutrient element content, and transcriptomes with those of control plants (WT/WT) under nutrient-rich or nutrient-poor conditions. WT/ost2-2D shoots had larger weights, rosette diameter, leaf blade area, and content of C, N, K, Ca, S, P, Mg, Na, Mn, B, Co, and Mo under nutrient-poor conditions compared with WT/WT shoots. The root weights and primary root length were greater in WT/ost2-2D plants than in WT/WT plants under both nutrient conditions. Root expression of the high-affinity nitrate transporter NRT2.1, potassium transporter HAK5, and divalent cation transporter IRT1 was higher in WT/ost2-2D plants than in WT/WT plants under nutrient-poor conditions. These results suggest that root-specific activation of PM H + -ATPase enhances plant growth by increasing root uptake of nutrient elements under nutrient-poor conditions. Our study presents a novel approach to improving nutrient uptake efficiency in crops for low-input sustainable agriculture., Competing Interests: Declaration of competing interest The authors declare that this study was conducted in the absence of any commercial relationships that could lead to any potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Oropharyngeal swallowing is centrally mediated by a swallowing central pattern generator (Sw-CPG) in the medulla oblongata. The activity of the Sw-CPG depends on the sensory inputs determined by physical and chemical bolus properties. Here we investigate the sensory-motor integration during swallowing arising from different sensory sources. To do so we electrically stimulated the superior laryngeal nerve and we triggered swallowing with oral injections of distilled water or capsaicin solution and extracellularly recorded from swallowing interneurons in arterially perfused brainstem preparations of rats. We recorded the activities of 40 neurons, while monitoring the motor activities of the phrenic, vagal and hypoglossal nerves. Eighteen neurons responded to electrical stimulation of the ipsilateral superior laryngeal nerve, and 6 neurons were excited by oral fluid injection, while 16 non-respiratory neurons did not receive afferent inputs to either electrical or physiological stimuli. The cellular activities displayed by swallowing interneurons during electrical and physiological stimulation of pharyngeal and laryngeal afferent input reveal complex adaptations of the timing of firing patterns and frequencies. The modulation of neuronal activity is likely to contribute to the coordination of efficient bolus transfer during the pharyngeal stage of swallowing., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)