The effect of lavender aroma for anxiety disorder: a study protocol for a multicenter, double-masked, randomized, placebo-controlled clinical trial.

BACKGROUND: Anxiety disorder is the most prevalent psychiatric disorder. Benzodiazepines, which are often used for anxiety in patients with anxiety disorder, have various side effects. Lavender, one of the most commonly used essential oils in aromatherapy, has the potential to reduce benzodiazepine use for anxiety disorders. METHODS: This study is a multicenter, double-masked, randomized, placebo-controlled clinical trial. The study will recruit patients aged 20-59 years old with generalized anxiety disorder and panic disorder among anxiety disorders. The bottle containing the test solution (lavender aroma essential oil or distilled water) will be given to the patients. Patients will carry the bottles with them in their daily life and use the drops on tissue paper when anxious. The primary endpoint is the number of times anxiolytics used in 28 days. DISCUSSION: If the use of benzodiazepines could be reduced by sniffing lavender aroma, which is inexpensive and safe, it would contribute not only to the risks associated with benzodiazepine use but also to the health care economy and could even be added as a standard treatment. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), ID: UMIN000034422 Registered 17 January 2019.

Should an R&D manager refer to distant technical fields? The effectiveness of new combinations with knowledge from different technical fields through the quantitative analysis of patent data related to NetZero.

This study showcases a technique to categorize NetZero-related patent applications into three technical fields according to the degree of proximity between claimed inventions and cited inventions by comparing technological classifications between the patent applications and cited applications thereof. In this technique, the author first describes the existing methods used in previous studies. The technique proposed in this article is different from those of previous studies in that it is characterized by comparing the technical fields of not only the primary classification but also the subsequent classifications. This is made possible by using two patent classifications without having a specific classification corresponding to the middle hierarchy in between, rather than using three patent classifications with different hierarchies. This technique reduces the possibility that two applications, even if they are the same in their subsequent classification, will be judged as applications in different technical fields because they are in different classes in the primary classification. Using the proposed technique, the author examined the impact on the subsequent patent application of NetZero-related patent applications filed in Japan. As a result of the analysis, the author found that approximately 33% of subject applications, whose technical field differs from the backward citations when comparing the primary classification only, match one of the subsequent classifications when comparing them in consideration of the subsequent classifications as well. The author then found that these 33% of subject applications had a greater impact on subsequent patent applications than the remaining applications.

The Effect of Mindfulness Yoga in Children With School Refusal: A Study Protocol for an Exploratory, Cluster-Randomized, Open, Standard Care-Controlled, Multicenter Clinical Trial.

Background: School refusal occurs in about 1-2% of young people. Anxiety and depression are considered to be the most common emotional difficulties for children who do not attend school. However, at present, no definitive treatment has been established for school refusal, although interventions such as cognitive behavioral therapy have been used. This paper reports a protocol for a cluster-randomized controlled trial of a mindfulness yoga intervention for children with school refusal. Methods: This study is a multicenter, exploratory, open cluster-randomized controlled trial. This study will recruit children aged 10-15 years with school refusal. After a 2-week baseline, participants for each cluster will be randomly assigned to one of two groups: with or without mindfulness yoga for 4 weeks. Mindfulness yoga will be created for schoolchildren for this protocol and distributed to the participants on DVD. The primary outcome is anxiety among children with school refusal using the Spence Children's Anxiety Scale-Children. Discussion: For this study, we developed a mindfulness yoga program and protocol, and examine whether mindfulness yoga can improve anxiety in children with school refusal. Our mindfulness yoga program was developed based on the opinions of children of the same age, and is a program that children can continue to do every day without getting bored. In this way, we believe that we can contribute to the smooth implementation of support to reduce the anxiety of children with school refusal, and to the reduction of the number of children who refuse to go to school.

Recurrence of Overdose Suicide Attempt index: a novel scoring system for predicting the recurrence of intentional overdose.

Repeated suicide attempts through intentional overdose are not infrequent, but little is known about the risk factors associated with intentional overdose. We investigated these risk factors within 1 year of discharge from hospital and developed an index predicting recurrence. This retrospective observational study included 419 patients admitted to our hospital between 2011 and 2018 due to intentional overdose. Of these, 43 (10.0%) repeated an overdose within 1 year of discharge. The risk factors with the highest odds ratios from multivariate logistic regression analyses were used to develop an index assessing Recurrence of Overdose Suicide Attempt. The following variables were significantly associated with recurrence and were included in the index: anxiety and/or insomnia at discharge; use of five or more psychotropic medications; diagnosis of an ICD-F4 anxiety disorders; and female sex (odds ratios: 4.24; 5.52; 2.41; and 3.41, respectively). The area under the receiver operating characteristic curve of the index was 0.797. Sensitivity, specificity, and positive and negative predictive values for Recurrence of Overdose Suicide Attempt >4 points (out of 6) were 72.1%, 75.8%, 25.4%, and 96.0%, respectively. Our novel index predicted the recurrence of intentional overdose with a good negative predictive value and may therefore be a useful screening tool for this high-risk population.

How long do tympanostomy ventilation tubes last in pediatric patients with otitis media with effusion or adhesion? A study using Kaplan-Meier survival analysis.

OBJECTIVE: The purpose of this study was to evaluate the functional duration and survival rate of tympanostomy ventilation tubes and the complications associated with their use in pediatric patients who underwent tube insertion for otitis media with effusion (OME). Complications were analyzed including recurrence and tympanic membrane perforation after the tube removal or extrusion. METHODS: Altogether, 447 ears from 234 pediatric patients younger than 15 years of age were studied retrospectively. All patients had undergone long-term tympanostomy ventilation tube: the Goode T-tube insertion for OME at the Osaka Women's and Children's Hospital, which is the pediatrics specialty hospital between April 2014 and March 2016. They were typically followed up every 3-4 months or more frequently if necessary due to otorrhea or tube infection. Subsequently, the tube duration, survival rates of the tube especially at 22 months after insertion defined as "full-term placement", and the rates of recurrence and perforation were calculated and statistically evaluated. RESULTS: Of 447 ears, 335 ears from 184 patients underwent their first tube insertion, and 112 ears from 64 patients underwent their second or subsequent tube insertion within the targeted period. Two hundred ears from 106 patients were associated with a cleft palate. The survival rate at full-term placement was 51.7%. The recurrence rate was 56.3%, and the rate of the tympanic perforation was 8.5%. CONCLUSIONS: Approximately half of the tubes survived for 22 months. The perforation rate was relatively low; however, recurrence of OME was seen in more than half the ears.

[Acute Drug Poisoning among Adolescents Using Over-the-counter Drugs: Current Status].

We discuss the current status of, and possible countermeasures for, acute drug poisoning among adolescents using OTC drugs. In the last 10 years, 36 patients aged <20 years who overdosed on OTC drugs were examined for the type of drug ingested, its active ingredients in cases of lethal dose intake, and the relevant place of purchase. Patients aged <20 years accounted for 30% of all the cases. The ingestion of multi-ingredient common-cold medication was the highest at 23%, and no ingestion of any first-class OTC drugs was observed. Caffeine accounted for 54% of the cases of lethal dose intake. At 80%, the most common method of drug purchase was from drugstores and other OTC vendors. In recent years, the number of adolescents patients who take lethal doses of OTC drugs has been increasing, and new measures are needed to avoid such cases. School pharmacists and vendors play a major role in reducing the incidences of drug poisoning. As drugs can be easily purchased over the counter, increasing the vendors' awareness of the problem throughout society may be the quickest way to reduce the incidences of acute drug poisoning among adolescents.

Predicting the Potential Applicability to Other Technical Fields Through the Linkage Between Backward and Forward Citations.

This article is a modest attempt to shed some light on the question of linkages between backward and forward citations in technical fields posed by Trajtenberg et al. (1997). They found interesting similarities and high correlations between equivalent measures looking forward and backward. They also implied the linkage between distant backward and distant forward citations. There are several questions to be posed in applying their insights to Japanese patent applications, however, due to the differences in the patent classification system and the subject of citation, i.e., citations by the applicant or examiner, between the US and Japan. In addition, and most importantly, the possibility that subsequent classifications may match, even if the first classification is different, is unavoidable with existing measurement methods of technical distance. In order to investigate these research questions, the author proposes a new measurement method for the technological proximity between examiner's citations and their originating patents using IPC-based patent classifications. Using such a proposed method, the author created two hypotheses and tested them for about 14,000 examined patent applications filed in 2008 with the JPO. As a result of testing Hypothesis I, the author confirmed that Trajtenberg et al.'s insights can be applied to Japanese patent applications using citations by the examiners and IPC-based patent classifications. In other words, it was confirmed that patent applications citing backward citations categorized in a technical field distant from the invention are more likely to be cited by forward citations categorized in a technical field distant from the invention. As a result of the verification of Hypothesis Ⅱ, it was further confirmed in some technical fields that the backward citations categorized in a technical field distant from the invention are more likely to be in the same technical field as the forward citations categorized in a technical field distant from the invention. The author believes that these verified results indicate the possibilities of using backward citations as a starting point from which we can find patent applications for inventions at an early stage with potential applicability to other technical fields.

Lung-to-finger circulation time can be measured stably with high reproducibility by simple breath holding method in cardiac patients.

Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or < 75 years group, respectively), 0.81 and 0.84 (N = 26, ≥ or < 2.2 L/min/M2). These results show that our new method to measure LFCT is highly stable and feasible for any type of heart failure patients.

Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity.

INTRODUCTION: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP. METHODS AND ANALYSIS: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints. ETHICS AND DISSEMINATION: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT04621136 and jRCT2071200047.

Local temperature control improves the accuracy of cardiac output estimation using lung-to-finger circulation time after breath holding.

As timely measurement of the cardiac index (CI) is one of the key elements in heart failure management, a noninvasive, simple, and inexpensive method of estimating CI is keenly needed. We attempted to develop a new device that can estimate CI from the data of lung-to-finger circulation time (LFCT) obtained after a brief breath hold in the awake state. First, we attempted to estimate CI from the LFCT value by utilizing the correlation between 1/LFCT and CI estimated with MRI. Although we could obtain LFCT from 45 of 53 patients with cardiovascular diseases, we could not find the anticipated relation between 1/LFCT and CI. However, we realized that when we adopted only LFCT from patients with a finger temperature of ≥31°C, we could obtain a consistent and clear correlation with CI (correlation coefficient, r = .81). Thus, we next measured LFCT before and after warming the forearm. We found that LFCT decreased after the local temperature increased (from 27.5 ± 13.6 to 18.4 ± 5.3 s, p < 0.01). The correlation between the inverse of LFCT and CI improved after warming (1/LFCT vs. CI, from r = .69 to r = .82). The final Bland-Altman analysis between the measured and estimated CI values revealed that the bias and precision were -0.05 and 0.37 L min-1  m-2 , respectively, and the percentage error was 34.3%. This study clarified that estimating CI using a simple measurement of LFCT is feasible in most patients and a low fingertip temperature strongly affects the CI-1/LFCT relationship, causing an error that can be corrected by proper local warming.

Clinical outcomes of ex utero intrapartum treatment for fetal airway obstruction.

PURPOSE: The aim of this study was to evaluate the indications and the clinical outcomes of the fetuses managed with ex utero intrapartum treatment (EXIT) procedures. METHODS: We retrospectively reviewed the medical records of all fetuses who underwent EXIT procedures between 2003 and 2018. RESULTS: EXIT procedures were performed in nine cases. The prenatal diagnosis of the neonates was congenital high airway obstruction syndrome in four cases, the neck masse in five cases. Although the airway management under the EXIT procedure was successful in eight cases, the airway management failed in one case. During the EXIT procedures, the airway was managed by endotracheal intubation in two cases, whereas six cases underwent tracheostomy. Six cases with fetal airway obstruction survived to discharge, whereas three cases died due to airway management failure or complications of the underlying disease. A case with a cervical teratoma underwent tumor resection the day after birth due to rapid enlargement of the neck mass. Long-term survival was achieved in five cases. CONCLUSIONS: We concluded that the EXIT procedure was effective and could be performed safely in the airway management of fetuses with suspected airway obstruction. The treatment strategy for the neck masses should be planned before birth.

A Case of Skull Base Osteomyelitis with Multiple Cerebral Infarction.

Skull base osteomyelitis is classically documented as an extension of malignant otitis externa. Initial presentation commonly includes aural symptoms and cranial nerve dysfunctions. Here we present a case that emerged with multiple infarctions in the right cerebrum. A male in his 70s with diabetes mellitus and chronic renal failure presented with left hemiparesis. Imaging studies showed that blood flow in the carotid artery remained at the day of onset but was totally occluded 7 days later. However, collateral blood supply prevented severe infarction. These findings suggest that artery-to-artery embolization from the petrous and/or cavernous portion of the carotid artery caused the multiple infarctions observed on initial presentation. Osteomyelitis of the central skull base was diagnosed on the basis of the following findings taken together: laboratory results showing high levels of inflammation, presence of Pseudomonas aeruginosa in the otorrhea and blood culture, multiple cranial nerve palsies that appeared later, the bony erosion observed on CT, and the mass lesion on MRI. Osteomyelitis was treated successfully by long-term antibiotic therapy; however, the patient experienced cefepime-induced neurotoxicity during therapy. The potential involvement of the internal carotid artery in this rare and life-threatening disease is of particular interest in this case.

Health insurance status and survival among patients with head and neck cancer in Japan.

BACKGROUND: Healthcare systems vary among countries, and in many countries, insurance and economic statuses significantly impact the mortality associated with head and neck squamous cell carcinoma (HNSCC). Japan prides itself on its unique healthcare and health insurance system, which provides equal coverage and healthcare access with low individual payments to most citizens. Additionally, citizens in poverty are covered by insurance for the poor (public assistance) and receive medical and other types of assistance. Hence, they have no barriers to healthcare services. This study aimed to determine the impact of health insurance status on mortality in Japanese patients with HNSCC. METHODS: We reviewed 409 patients with HNSCC, using the Kaplan-Meier method to estimate overall survival. The association between insurance status and disease stage at diagnosis was analyzed via logistic regression. Cox and Fine-Gray proportional hazard models were employed to investigate the impact of insurance status on survival. RESULTS: The public assistance and other insurances groups did not significantly differ in clinical stage distribution. The 5-year overall survival, cumulative incidence of HNSCC death, and cumulative incidence of other death rates were 63.3 and 59.1 %, 27.0 and 31.8 %, and 10.3 and 9.7 % for the public assistance and other insurances groups, respectively. The adjusted subdistribution hazard ratio for the association between public assistance and HNSCC death was 0.73 (95 % confidence interval 0.44-1.21). CONCLUSIONS: The demonstrated non-inferiority of public assistance regarding HNSCC-specific mortality indicates the equality of healthcare in Japan, irrespective of the insurance status, and the superiority of the Japanese healthcare system.

Risk factors associated with competing mortality among patients with head and neck cancer in Japan.

Conclusions This study demonstrated a high incidence of competing mortality in patients with head and neck cancer (HNC). It identified age to be an independent prognostic factor for non-cancer mortality. These findings contribute to the appropriate treatment selection in clinical settings and study design in clinical trials. Objectives To investigate the incidences of second primary cancer (SPC) and non-cancer mortalities among patients with HNC and reveal the determinant factors for these mortalities. Methods This study reviewed the records of 334 patients with HNC between 2006-2012. The cumulative incidences of HNC, non-cancer, and SPC mortalities were estimated. A Fine and Gray regression model was used to investigate factors associated with cancer and non-cancer mortalities. Results The 5-year cumulative incidences of HNC, SPC, and non-cancer mortalities were 28.0%, 2.5%, and 6.5%, respectively. In univariate analysis, the factors associated with SPC mortality were tumor site and comorbidity, whereas those associated with non-cancer mortality were age, gender, and comorbidity. In multivariate analysis, age (sub-distribution hazard ratio = 2.59) was the independent risk factor for non-cancer mortality.

[A Case of Hereditary Medullary Thyroid Cancer (MEN2A/FMTC) Diagnosed at the Time of Recurrence].

We report a 42-year-old man with hereditary medullary thyroid cancer (multiple endocrine neoplasia, MEN2A/familial medullary thyroid carcinoma, FMTC), which was diagnosed at the time of tumor recurrence. He had a past history of a left thyroidectomy with neck dissection 7 years previously. A RET gene analysis revealed a point mutation (codon 618), and we diagnosed him as having hereditary medullary thyroid cancer. We resected the recurrent tumor in the right thyroid lobe together with performing a right lateral and central neck dissection. A RET gene analysis should be performed for patients with medullary thyroid cancer. When a RET gene mutation is present, a total thyroidectomy must be performed for the medullary thyroid cancer.

Effects of cooling the pharyngeal mucosa after bipolar scissors tonsillectomy on postoperative pain.

CONCLUSION: Bipolar scissors tonsillectomy followed by cooling down the pharyngeal mucosa has advantages in terms of postoperative pain and intraoperative blood loss compared with cold dissection. OBJECTIVES: The purpose of this study was to compare the postoperative pain between bipolar scissors tonsillectomy followed by cooling the pharyngeal mucosa and a traditional cold dissection. METHODS: A total of 189 patients aged more than 16 years were operated due to habitual tonsillitis, obstructive sleep apnea syndrome, and IgA nephropathy. Of these, 79 patients were operated using bipolar scissors followed by cooling the pharyngeal mucosa with 4°C saline for 10 min just after the removal of tonsils. The other 110 patients underwent cold dissection tonsillectomy. Outcome measures were intraoperative blood loss, operative time, postoperative pain evaluated on a visual analog scale, and postoperative secondary hemorrhage. RESULTS: Significantly lower levels of intraoperative blood loss and less postoperative pain were obtained in bipolar scissors tonsillectomy followed by cooling the pharyngeal mucosa compared with cold dissection. Postoperative hemorrhage needing hemostatic surgery occurred in 2 of 79 patients who underwent bipolar scissors tonsillectomy with cooling, while it occurred in 1 of 110 patients after cold dissection. However, the difference was not statistically significant.

Phosphorylation and recruitment of Syk by immunoreceptor tyrosine-based activation motif-based phosphorylation of tamalin.

Tamalin is a scaffold protein that forms a multiple protein assembly including metabotropic glutamate receptors (mGluRs) and several postsynaptic and protein-trafficking scaffold proteins in distinct mode of protein-protein association. In the present investigation, we report that tamalin possesses a typical immunoreceptor tyrosine-based activation motif (ITAM), which enables Syk kinase to be recruited and phosphorylated by the Src family kinases. Coimmunoprecipitation analysis of rat brain membrane fractions showed that tamalin is present in a multimolecular protein assembly comprising not only mGluR1 but also c-Src, Fyn, and a protein phosphatase, SHP-2. The protein association of both tamalin and c-Src, as determined by truncation analysis of mGluR1 in COS-7 cells, occurred at the carboxyl-terminal tail of mGluR1. Mutation analysis of tyrosine with phenylalanine in COS-7 cells revealed that paired tyrosines at the ITAM sequence of tamalin are phosphorylated preferentially by c-Src and Fyn, and this phosphorylation can recruit Syk kinase and enables it to be phosphorylated by the Src family kinases. The phosphorylated tyrosines at the ITAM sequence of tamalin were highly susceptible to dephosphorylation by protein-tyrosine phosphatases in COS-7 cells. Importantly, tamalin was endogenously phosphorylated and associated with Syk in retinoic acid-treated P19 embryonal carcinoma cells that undergo neuron-like differentiation. The present investigation demonstrates that tamalin is a novel signaling molecule that possesses a PDZ domain and a PDZ binding motif and mediates Syk signaling in an ITAM-based fashion.