Altered Functional Connectivity during Mild Transient Respiratory Impairment Induced by a Resistive Load.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.

[Tips and Outcomes of Safe Laparoscopic Rectal Resection with Adequate Lymph Node Dissection in Patients with Obesity].

BACKGROUND: This study aimed to describe the surgical procedures involved in laparoscopic rectal resection in patients with obesity and report the short-term outcomes. MATERIALS AND METHODS: A total of 194 consecutive patients who underwent laparoscopic rectal resection in our department from 2013 to 2018 were divided into non-obese(body mass index[BMI] <25 kg/m2; n=161)and obese groups(BMI≥25 kg/m2; n=33)and subsequently analyzed. RESULTS: The operative time was significantly longer in the obese group(225 vs 266 min; p=0.003)than in the non-obese group. No conversions to laparotomy occurred in either group, and no discernible differences in blood loss(1 vs 5 mL; p=0.582), number of harvested lymph nodes(20 vs 17; p=0.356), and postoperative complication rates(9.3 vs 6.1%; p=0.547)were observed. CONCLUSION: Establishing an appropriate operative field, clarifying landmarks, and standardizing the procedure are important to assure safe laparoscopic rectal resection with adequate lymph node dissection in patients with obesity.

Novel Repair Technique for Oral and Anal Side Stoma Prolapse of a Loop Colostomy With the Stapled Modified Altemeier Method Using Indocyanine Green Fluorescence Imaging.

BACKGROUND/AIM: Stoma prolapse is a common complication in the late phase after stoma creation. With advances in chemotherapy, a double-orifice colostomy or ileostomy and chemotherapy are used to treat primary unresectable colorectal cancer. Preoperative therapy with a double-orifice colostomy or ileostomy is performed to aid primary colorectal cancer miniaturization. Therefore, the number of stoma prolapses will likely increase in the future. Previous reports on the repair of stoma prolapse focused on unilateral stoma prolapse of loop colostomy, and there are no reports about the bilateral stoma prolapse of loop colostomy or ileostomy. CASE REPORT: We report a novel repair technique for oral and anal side (bilateral) stoma prolapse of a loop colostomy with the stapled modified Altemeier method using indocyanine green (ICG) fluorescence imaging considering the distribution of marginal artery in preventing marginal artery injury which has considerable clinical significance. CONCLUSION: Our novel technique for the oral and anal side prolapse of a loop colostomy is considered effective and safe.

IL-18 receptor-α signalling pathway contributes to autoantibody-induced arthritis via neutrophil recruitment and mast cell activation.

OBJECTIVES: The interleukin (IL)-18 signalling pathway is involved in animal models of collagen-induced arthritis, but the role of this pathway in autoantibody-induced arthritis is poorly understood. An autoantibody-induced arthritis model, K/BxN serum transfer arthritis, reflects the effector phase of arthritis and is important in innate immunity including neutrophils and mast cells. This study aimed to investigate the role of the IL-18 signalling pathway in autoantibody-induced arthritis using IL-18 receptor (IL-18R) α-deficient mice. METHODS: K/BxN serum transfer arthritis was induced in IL-18Rα-/- and wild-type B6 (controls) mice. The severity of arthritis was graded, and histological and immunohistochemical examinations were performed on paraffin-embedded ankle sections. Total Ribonucleic acid (RNA) isolated from mouse ankle joints was analysed by real-time reverse transcriptase-polymerase chain reaction. RESULTS: IL-18 Rα-/- mice had significantly lower arthritis clinical scores, neutrophil infiltration, and numbers of activated, degranulated mast cells in the arthritic synovium than in controls. IL-1ß, which is indispensable for the progression of arthritis, was significantly downregulated in inflamed ankle tissue in IL-18 Rα-/- mice. CONCLUSIONS: IL-18/IL-18Rα signalling contributes to the development of autoantibody-induced arthritis by enhancing synovial tissue expression of IL-1ß and inducing neutrophil recruitment and mast cell activation. Therefore, inhibition of the IL-18Rα signalling pathway might be a new therapeutic strategy for rheumatoid arthritis.

Three cases of open surgical procedures on ileal conduits for the repair of benign ureteroenteric anastomotic strictures after total pelvic exenteration of rectal tumors.

Ureteroenteric anastomotic strictures (UEAS) are typical complications after creating an ileal conduit for total pelvic exenteration (TPE) of rectal tumors. We report the ileal conduit for reconstruction in three patients, in the age-range of 47-73 years. Case 1 was when a left-sided UEAS had sufficient length of ureter for anastomosis, Case 2 was a right-sided UEAS with sufficient length of ureter for anastomosis, and Case 3 was a left-sided UEAS with insufficient length of ureter for anastomosis. There were no complications after operation and no recurrence of UEAS. It is important to learn the open surgical procedures for repair of a benign UEAS after TPE of rectal cancers. This has fewer complications and is safe in the long term.

Endobronchial cryptococcosis with bronchial stenosis in a patient with severe asthma treated with inhaled corticosteroids: A case report.

Cryptococcosis typically manifests as pulmonary lesions, with endobronchial lesions occurring rarely. Inhaled corticosteroids (ICS) may be a risk factor for cryptococcosis of the larynx but not of the bronchi. Here, we report a case involving a 73-year-old Japanese man who developed endobronchial cryptococcosis during ICS treatment for asthma. Chest computed tomography showed right mainstem bronchial stenosis and asthma control worsening when he received adequate asthma treatments. Bronchoscopy revealed multiple elevated lesions with white slough from the trachea to the right mainstem bronchus and the right mainstem bronchus lumen entrance narrowing. Bronchial lavage culture revealed Cryptococcus neoformans. Combination treatment with the antifungal agent, mepolizumab, and bronchodilation surgery successfully controlled cryptococcosis and asthma. Attention should be paid to central airway lesions during ICS treatment for uncontrolled asthma.

Effects of Compression Intervention on the Thigh Using Elastic Bandage on Lateral Femoral Pain After Trochanteric Fractures: A Multicenter Randomized Controlled Trial.

A trochanteric fracture is one type of hip fracture. Management of postoperative pain after trochanteric fracture that is caused by decreased gliding between tissues in the lateral thigh is not established. The aim of this study was to examine the effect of compression of the thigh using an elastic bandage on trochanteric fracture after surgery. Multicenter randomized controlled trial was conducted in collaboration with the Comprehensive Rehabilitation Unit (sub-acute rehabilitation Unit) in two hospitals. Eligible volunteers (n = 34) with trochanteric fractures after surgery were randomly assigned to two groups. In the treatment group, participants practiced standing and walking under compression of the thigh with an elastic bandage. The control group was blinded to the intervention and practiced standing and walking under non-compression of the thigh with an elastic bandage. Both groups underwent a standard physical therapy program 2 times a day, daily. Two-way repeated measures of ANOVA showed significant main effect between the groups for gliding between tissue (p < .001), lateral femoral pain (p < .001), subcutaneous tissue thickness (p = .044). Compression of the thigh with an elastic bandage significantly improved subcutaneous tissue thickness, gliding between tissues, lateral thigh pain. Gait velocity improved with these functional improvements.

How many times can patients tolerate reoperation for the local recurrence of colorectal cancer in terms of complications?

The frequency of resection for the recurrence of colorectal cancer has not been investigated in previous studies. Likewise, the related postoperative complications and the limit for indicating surgical resection has not been reported. Herein, we reported the complications of a highly frequent surgical approach for rectal cancer recurrence, i.e., exceeding three reoperations, based on our clinical experience. We included 15 cases exceeding two operations for the local recurrence of colorectal cancer from 2014 to 2019. We examined the postoperative complications classified as Clavien?Dindo IIIb. The positive rates of the complications were 0 (0.0%), 0 (0.0%), 2 (13.3%), 3 (37.5%), and 0 (0.0%) for the primary, 1st recurrent, 2nd recurrent, 3rd recurrent, and 4th recurrent operation group (p=0.027), respectively. It is important to exercise caution in handling cases exceeding two reoperations (exceeding three reoperations including the primary operation). J. Med. Invest. 70 : 369-376, August, 2023.

Novel Ureteral Stent Catheterization Technique for Treating Hyperchloremic Metabolic Acidosis After Total Pelvic Exenteration.

BACKGROUND/AIM: Hyperchloremic metabolic acidosis after total pelvic exenteration (TPE) is relatively rare. Urinary diversion of the ileal conduit during TPE can result in increased urine reabsorption leading to hyperchloremic metabolic acidosis. We developed a new technique for the retrograde catheterization of a ureteral stent into an ileal conduit to treat hyperchloremic metabolic acidosis. CASE REPORT: A 70-year-old man underwent TPE for locally recurrent rectal cancer. Multiple episodes of complications, such as hyperchloremia and metabolic acidosis, occurred. Effective drainage of urine from the ileal conduit is crucial. With collaboration between an endoscopist and a radiologist, we developed a novel method for retrograde catheterization of the ureteral stent into an ileal conduit for hyperchloremic metabolic acidosis after TPE. The patient's condition quickly improved after the procedure. CONCLUSION: Our novel technique of retrograde catheterization of a ureteral stent into an ileal conduit for hyperchloremic metabolic acidosis could be adopted worldwide, as it is effective and safe.

Clinical Impact of Radical Resection of Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer.

BACKGROUND: According to some case series, patients with colorectal cancer (CRC) who underwent radical resection of synchronous peritoneal metastases (PM) with the primary tumor had better survival than patients who underwent non-surgical treatment. However, little evidence exists regarding the significance of radical resection for metachronous PM. OBJECTIVE: This study aimed to evaluate the clinical significance of surgical intervention for isolated PM from CRC, with a particular focus on time to PM. METHODS: A total of 74 consecutive patients with isolated PM from CRC, including 40 and 34 patients with synchronous and metachronous PM, respectively, treated between 2007 and 2018 were retrospectively analyzed. The primary outcome measure was overall survival (OS) from diagnosis, and the OS was compared between radical resection and palliative chemotherapy. RESULTS: Five-year OS was 39.7% for all patients. Patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy (62.8% vs. 11.0%; p < 0.0001). According to time to PM, patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy for both synchronous PM (47.6% vs. 0%; p = 0.019) and metachronous PM (77.2% vs. 15.2%; p < 0.0001). Multivariable analysis stratified by time to PM revealed that surgical intervention is a significant favorable prognostic factor only in patients with metachronous PM (hazard ratio 0.117, 95% confidence interval 0.020-0.678; p = 0.017). CONCLUSIONS: Patients with radical resection of PM had good survival compared with those with chemotherapy alone, especially for metachronous PM. Surgical intervention should be considered for isolated metachronous PM when radical resection is feasible.

Usefulness of a 4-Grade Novel Mouthpiece Device for Increased Mouth Pressure Reproducing Artificial Difficulty in Breathing.

OBJECTIVE: The use of a novel 4-grade mouthpiece device to reproduce difficulty in breathing was assessed in healthy individuals. METHODS: A double-blind, randomized, crossover-controlled trial was conducted to investigate the efficacy and safety of the device with increasing mouth pressure. The modified Borg (mBorg) scale values, respiratory system resistance at 5 Hz (R5), and forced expiratory volume in one second (FEV1) were assessed while using the device. MATERIALS: The four grades of breathing difficulty device were tested in 32 healthy participants. RESULTS: The 4-grade device linearly worsened the mBorg scale with increasing mouth pressure. The mean R5 (± standard deviation [SD]) with grade I, II, III, and IV devices were 5.6 ± 0.1, 10.3 ± 0.3, 21.5 ± 0.7, and 54.8 ± 2.0 kPa/L/s, respectively. The mean %FEV1 predicted (± SD) were 83.6 ± 15.9% with grade I, 55.3 ± 11.8% with grade II, 32.0 ± 6.1% with grade III, and 15.3 ± 3.2% with the grade IV device. The mBorg scale was positively correlated with R5 (r = 0.79, p < 0.0001) and negatively with %FEV1 predicted (r = -0.81, p < 0.0001). No severe adverse events were reported during the trial. CONCLUSION: We demonstrated that the novel device could effectively reproduce the semi-quantitative artificial difficulty in breathing safely and easily in healthy individuals. These devices could be helpful to understand the mechanisms of difficulty in breathing.

Efficacy and safety of once-daily single-inhaler triple therapy for mild-to-moderate chronic obstructive pulmonary disease: a study protocol for a randomised and interventional study.

INTRODUCTION: Bronchodilators, including long-acting muscarinic antagonists (LAMA) and long-acting beta 2 agonists (LABA), are the main treatments for chronic obstructive pulmonary disease (COPD). The efficacy of triple therapy (inhaled corticosteroids/LAMA/LABA) has also been reported. However, the effect of triple therapy on patients with mild-to-moderate COPD has not yet been clarified. This study aims to investigate the safety and efficacy of triple therapy, compared with LAMA/LABA combination therapy, for lung function and health-related quality of life in patients with mild-to-moderate COPD and identify baseline characteristics and biomarkers to predict responders and non-responders to triple therapy. METHODS AND ANALYSIS: This is a multicentre, prospective, open-label, randomised, parallel-group study. Mild-to-moderate patients with COPD will be randomised to receive fluticasone furoate/umeclidinium/vilanterol or umeclidinium/vilanterol for 24 weeks. A total of 668 patients will be enrolled from March 2022 to September 2023 from 38 sites in Japan. The primary endpoint is the change in the trough forced expiration volume in 1 s after 12 weeks of treatment. Secondary endpoints are responder rates based on the COPD assessment test score and the St. George's Respiratory Questionnaire total score after 24 weeks of treatment. The safety endpoint is the occurrence of any adverse events. We will also investigate safety in terms of changes in microbial colonisation in sputum and antimycobacterium avium complex antibodies. ETHICS AND DISSEMINATION: The study protocol and informed consent documents were approved by the Saga University Clinical Research Review Board (approval number: CRB7180010). Written informed consent will be obtained from all patients. Recruitment of the patients began in March 2022. The results will be disseminated through scientific peer-reviewed publications and domestic and international medical conferences. TRIAL REGISTRATION NUMBERS: UMIN000046812 and jRCTs031190008.

Clinical Relevance of Lateral Pelvic Lymph Node Dissection for Enlarged Lateral Nodes in Locally Advanced Low Rectal Cancer without Preoperative Treatment.

Objectives: The present study aimed to investigate the clinical relevance of lateral pelvic lymph node dissection (LPLND) in low rectal cancer without preoperative treatment, with a focus on the presence of LPLN enlargement in preoperative imaging. Methods: Consecutive patients with cT3 to T4 low rectal cancer who underwent mesorectal excision and LPLND without preoperative treatment between 2007 and 2018 at a single dedicated cancer center were included. LPLN short-axis diameter (SAD) measured using preoperative multi-detector row computed tomography (MDCT) was evaluated retrospectively. Results: A total of 195 consecutive patients were analyzed. Overall, 101 (51.8%) and 94 (48.2%) patients had visible and no visible LPLNs in preoperative imaging, including 56 (28.7%), 28 (14.4%), and 17 (8.7%) patients had SADs of <5 mm, 5-7 mm, and ≥7 mm, respectively. Incidence of pathologically confirmed LPLN metastasis were 18.1%, 21.4%, 28.6%, and 52.9%, respectively. Overall, thirteen (6.7%) patients developed local recurrence (LR), including one patient who developed lateral recurrence, yielding a 5-year cumulative risk for LR of 7.4%. Five-year RFS and OS for all patients were 69.7% and 85.7%, respectively. No differences were observed in the cumulative risk for LR and OS between any pairs of groups. Conclusions: No significant difference was observed in the cumulative risk for LR and OS regardless of LPLN SAD, implying the good impact of LPLND on the prevention of lateral recurrence, as well as the difficulty of predicting LPLN metastasis using only LPLN SAD in preoperative imaging.

The Efficacy and Safety of First-Line Single-Inhaler Triple versus Dual Therapy in Controller-Naïve and Symptomatic Adults with Asthma: A Preliminary Retrospective Cohort Study.

Purpose: The efficacy and safety of first-line triple and dual therapy remain unclear because the stepwise strategy is a worldwide standard in controller-naïve asthma. A preliminary retrospective cohort study was conducted to investigate the efficacy and safety of first-line triple and dual therapy for managing controller-naïve and symptomatic adult patients with asthma. Patients and Methods: Patients with asthma who received first-line single-inhaler triple therapy (SITT) or dual therapy (SIDT) for at least 8 weeks were selected between December 1, 2020, and May 31, 2021, in Fujiki Medical and Surgical Clinic, Miyazaki, Japan. Data on daytime and nighttime visual analog scale (VAS) scores, lung function tests, fractional exhaled nitrogen oxide (FENO), and adverse events were compared between SITT and SIDT pre- and post-treatment. Results: The SITT significantly improved the nighttime, but not daytime, VAS scores better than the SIDT 2 weeks post-treatment (P = 0.0026), whereas SITT and SIDT significantly improved daytime and nighttime VAS scores after treatment compared to baseline. Both therapies also significantly improved lung functions and FENO post-treatment. The proportion of patients achieving complete control in the nighttime VAS scores after SITT was significantly higher than that four (P = 0.0186) and 8 weeks (P = 0.0061) after SIDT. Only patients with SITT experienced dry mouth. Conclusion: Our study demonstrated that first-line SITT and SIDT were effective, and SITT improved disease control faster than SIDT in controller-naïve and symptomatic adult patients with asthma. The first-line SITT may contribute to faster and better control levels in symptomatic patients with asthma.

Proton Beam Therapy as a Curative Treatment for a Young Case of Unresectable Tracheal Adenoid Cystic Carcinoma.

Primary tracheal adenoid cystic carcinoma (TACC) is a rare malignancy without an established treatment. Central airway obstruction due to TACC often decreases the quality of life and has life-threatening consequences. A 19-year-old man with unresectable TACC and central airway obstruction suffered from progressive cough and dyspnea after exercise. Proton beam therapy (PBT) was selected as the preferred treatment over systemic anti-cancer chemotherapy for TACC. PBT led to complete remission of TACC and the almost complete disappearance of the respiratory symptoms without adverse events. PBT is a useful and safe treatment for unresectable primary TACC.

Lateral pelvic lymph node metastasis in T2 low rectal cancer: is TME alone sufficient for cure?

BACKGROUND: Some patients with even T2 low rectal cancer are known to develop lateral pelvic lymph node metastasis. This study aimed to investigate real-world evidence regarding lateral nodal metastasis on T2 low rectal cancer treatment. METHODS: Consecutive patients with pathological T2 low rectal adenocarcinoma who underwent curative-intent surgery between January 2007 and December 2015 at two Japanese cancer centres dedicated to lateral pelvic lymph node dissection were identified and included in the analysis. Lateral pelvic lymph node metastasis was defined as pathologically confirmed metastatic lateral pelvic lymph node or lateral-local recurrence after primary surgery. RESULTS: A total of 215 consecutive patients, including 101 and 114 patients who did and did not undergo bilateral lateral pelvic lymph node dissection, were included in the analysis. Overall, 19 (8.8%) patients had lateral pelvic lymph node metastasis, including 13 with pathologically confirmed metastatic lateral pelvic lymph node and six with lateral-local recurrence. A total of 10 (4.7%) patients had local recurrence, including six with lateral-local recurrence, two with central-local recurrence and two with anastomotic recurrence. Five/7-year cumulative risks of lateral-local recurrence in patients with and without lateral pelvic lymph node dissection were 1.1/1.1% and 3.9/5.2%, respectively. CONCLUSION: The problem of the relatively high rate of lateral local recurrence remains in treating T2 low rectal cancer with only total mesorectal excision. The selection of high-risk patients of lateral pelvic lymph node metastasis and the indication of additional treatment in T2 low rectal cancer should be discussed further.

A Cluster of Paragonimiasis with Delayed Diagnosis Due to Difficulty Distinguishing Symptoms from Post-COVID-19 Respiratory Symptoms: A Report of Five Cases.

Paragonimiasis caused by trematodes belonging to the genus Paragonimus is often accompanied by chronic respiratory symptoms such as cough, the accumulation of sputum, hemoptysis, and chest pain. Prolonged symptoms, including respiratory symptoms, after coronavirus disease 2019 infection (COVID-19) are collectively called post-COVID-19 conditions. Paragonimiasis and COVID-19 may cause similar respiratory symptoms. We encountered five cases of paragonimiasis in patients in Japan for whom diagnoses were delayed due to the initial characterization of the respiratory symptoms as a post-COVID-19 condition. The patients had consumed homemade drunken freshwater crabs together. One to three weeks after consuming the crabs, four of the five patients were diagnosed with probable COVID-19. The major symptoms reported included cough, dyspnea, and chest pain. The major imaging findings were pleural effusion, pneumothorax, and nodular lesions of the lung. All the patients were diagnosed with paragonimiasis based on a serum antibody test and peripheral blood eosinophilia (560-15,610 cells/µL) and were treated successfully with 75 mg/kg/day praziquantel for 3 days. Before diagnosing a post-COVID-19 condition, it is necessary to consider whether other diseases, including paragonimiasis, may explain the symptoms. Further, chest radiographic or blood tests should be performed in patients with persistent respiratory symptoms after being infected with COVID-19 to avoid overlooking the possibility of infection.

Total Pelvic Exenteration Combined With Sacral Resection for Rectal Cancer.

BACKGROUND: This retrospective study aimed to demonstrate surgical operative approach of total pelvic exenteration combined with sacral resection with rectal cancer and elucidate the relationships between the level of sacral resection and short-term outcomes. METHODS: Twenty cases were selected. Data regarding sex, age, body mass index, neoadjuvant therapy, location of sacral resection ("Upper" or "Lower" relative to the level between the 3rd and 4th sacral segment), operative time, bleeding, and curability (R0/R1) were collected and compared to determine their association with complications exhibiting a Clavien-Dindo grade III. RESULTS: The complication rate was significantly higher for recurrent cancers (n = 10, 76.9%) than for primary cancers (n = 1, 14.3%) (P = .007), and for "Upper" resection (n = 8, 72.7%) than for "Lower" resection (n = 3, 33.3%) (P = .078). Significant differences were observed when complication rates for "Lower" and primary cancer resection (n = 3, .0%) were compared between "Upper" and recurrent cancers (n = 8, 100.0%) (P = .007). CONCLUSION: In patients with recurrent rectal cancer, "Upper" sacral resection during total pelvic exenteration is associated with a high complication rate, highlighting the need for careful monitoring.

Daytime and Nighttime Visual Analog Scales May Be Useful in Assessing Asthma Control Levels Before and After Treatment.

Purpose: Few questionnaires evaluate daytime and nighttime symptoms separately, although these assessments could contribute to the improvement of disease control levels and prevention of future risks in asthma. The purpose of this retrospective study was to investigate whether daytime and nighttime visual analog scales (VAS) are useful in measuring the perception of symptoms, assessing disease control levels, and evaluating the treatment effects in asthma. Patients and Methods: Self-reporting asthma control tests (ACT) before and after treatment are standardized tests used to determine disease control levels. A multiple regression analysis was performed to determine the correlation between daytime and nighttime VAS and the characteristics of patients before treatment, as well as the changes in VAS and lung functions and fractional exhaled nitrogen oxide after treatment in 55 treatment-naïve symptomatic adult patients with asthma. Results: Both daytime (r = -0.57, P < 0.0001) and nighttime (r = -0.46, P < 0.0001) VAS correlated well with ACT scores, and there was a correlation between daytime and nighttime VAS (r = 0.33, P = 0.0148) before treatment. In addition, the changes in daytime (r = -0.65, P < 0.0001) and nighttime (r = -0.44, P < 0.0001) VAS were significantly associated with changes in the ACT scores. The multiple regression analysis (ß [95% confidence interval]) revealed that improvements in the daytime (-2.33 [-4.55 to -0.11], P = 0.0405) and nighttime (-3.09 [-6.25 to 0.07], P = 0.0505) VAS were associated with an increased forced vital capacity after treatment, although there was no correlation between the VAS and characteristics before treatment. Conclusion: Our study demonstrated that daytime and nighttime VAS were useful in assessing disease control levels and evaluating the treatment effects in asthma.

MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway.

The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR­874 targets. Next-generation sequencing analysis revealed a significant miR-874-mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874-induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.