最近の精神科の臨床試験におけるプロトコル登録と選択的アウトカム報告：新規抗うつ薬と認知行動療法

京都大学0048新制・課程博士博士(医学)甲第19963号医博第4153号新制||医||1017(附属図書館)33059京都大学大学院医学研究科医学専攻(主査)教授 村井 俊哉, 教授 森田 智視, 教授 佐藤 俊哉学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Discordant Immune Marker Expression Between Preoperatively Biopsied and Matched Surgically Resected Specimens in Patients With Oral Squamous Cell Carcinoma

Programmed cell death ligand 1 (PD-L1) expression and tumor-associated immune cell (TAIC) density can be the biomarkers of survival outcome and for predicting the efficacy of immune checkpoint inhibitors in oral squamous cell carcinoma (OSCC), but whether single biopsy accurately reflects the values of these parameters in resected specimens is unclear. To clarify this, we evaluated the concordance of immune marker expression (PD-L1, PD-1, CD3, CD4, CD8, and CD68) between 39 paired biopsied and surgically resected specimens obtained from patients with OSCC at Kobe City Medical Center General Hospital between July 2011 and January 2016. Immune marker expression was assessed using immunohistochemistry. PD-L1 expression was consistent between the biopsied and surgically resected specimens in only 76.9% of cases. TAIC density was significantly lower in biopsied than in surgically resected specimens. There was considerable discordance in immune marker expression between biopsied and surgically resected specimens. We should take into consideration that PD-L1 positivity and TAIC density would be underestimated by single small biopsies compared to the estimations by surgically resected specimens

Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: A study protocol for a meta-epidemiological investigation

Introduction: Abstracts are the major and often the most important source of information for readers of the medical literature. However, there is mounting criticism that abstracts often exaggerate the positive findings and emphasise the beneficial effects of intervention beyond the actual findings mentioned in the corresponding full texts. In order to examine the magnitude of this problem, we will introduce a systematic approach to detect overstated abstracts and to quantify the extent of their prevalence in published randomised controlled trials (RCTs) in the field of psychiatry. Methods and analysis: We will source RCTs published in 2014 from the Cochrane Register of Controlled Trials (CENTRAL) that claim effectiveness of any intervention for mental disorders. The abstract conclusions will be categorised into three types: superior (only stating significant superiority of intervention to control), limited (suggesting that intervention has limited superiority to control) and equal (claiming equal effectiveness of intervention as control). The full texts will also be classified as one of the following based on the primary outcome results: significant (all primary outcomes were statistically significant in favour of the intervention), mixed (primary outcomes included both significant and non-significant results) or all non-significant results. By comparing the abstract conclusion classification and that of the corresponding full text, we will assess whether each study exhibited overstatements in its abstract conclusion. Ethics and dissemination: This trial requires no ethical approval. We will publish our findings in a peer-reviewed journal. Trial registration number: UMIN000018668; Pre-results

Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan

Background: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan. Results: We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken. Conclusion: This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results. Trial registration: ClinicalTrials.gov: NCT01109693(registered on 21 April 2010)

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder:a systematic review and network meta-analysis

Background Major depressive disorder is one of the most common, burdensome and costly psychiatric disorders worldwide in adults. Both pharmacological and non-pharmacological treatments are available, however, because of lack of resources, antidepressants are used more frequently. Prescription of these agents should be informed by the best available evidence. Consequently, we aimed to update and expand our previous work to compare and rank antidepressants for major depressive disorder in adults. Methods We searched Cochrane CENTRAL, CINAHL, EMBASE, LiLACS, MEDLINE, PSYCINFO, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to January 8th 2016, for the acute treatment of major depressive disorder diagnosed according to standard operationalised criteria. We included placebo-controlled and head-to-head trials of 21 antidepressants in adults. We assessed the certainty of evidence using GRADE. Primary outcomes were efficacy (response rate) and acceptability (discontinuations due to any cause). Secondary outcomes included symptom severity, remission rate and discontinuations due to adverse events. We estimated summary odds ratios (OR) and standardised mean differences (with 95% credibility intervals - 95% CrIs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO (CRD42012002291). Findings We included 522 trials with 116,477 participants. The certainty of evidence was moderate to very low. In terms of efficacy, all antidepressants were more effective than placebo, with OR ranging between 2·13 (95% CrI 1·89 to 2·41) for amitriptyline and 1·38 (95% CrI 1·16 to 1·63) for reboxetine. For acceptability, agomelatine and fluoxetine were associated with fewer dropouts than placebo (OR 0·84, 95% CrI 0·72 to 0·97 and 0·88, 95% CrI 0·80 to 0·96, respectively), while clomipramine was worse than placebo (OR 1.31, 95% CrI 1·01 to 1·68). When all trials were considered, differences in OR between antidepressants ranged from 1·15 (95% CrI 1·04 to 1·27) to 1·55 (95% CrI 1·27 to 1·91) for efficacy and from 0.64 (95% CrI 0·48 to 0·86) to 0.85 (95% CrI 0·75 to 0·96) for acceptability, with wide confidence intervals on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, sertraline, venlafaxine and vortioxetine were more effective than other antidepressants (OR range: 1.12 [95% CrI 1·00 to 1·32] to 1.96 [95% CrI 1·09 to 3·57]), while fluoxetine, reboxetine and trazodone were the least efficacious drugs (OR range: 0.51 [95% CrI 0·72 to 0·97] to 0.89 [95% CrI 0·72 to 0·97]). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were the best drugs (OR range: 0.42 [95% CrI 0·72 to 0·97] to 0.81 [95% CrI 0·72 to 0·97]), while amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine had the highest dropout rates (OR range: 1.23 [95% CrI 1·00 to 1·32] to 2.37 [95% CrI 1·00 to 1·32]). Interpretation All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, while there was more variability in efficacy and rate of drop out in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers and policy-makers on the relative merits of the different antidepressants.</p

Differing Requirements for RAD51 and DMC1 in Meiotic Pairing of Centromeres and Chromosome Arms in Arabidopsis thaliana

During meiosis homologous chromosomes pair, recombine, and synapse, thus ensuring accurate chromosome segregation and the halving of ploidy necessary for gametogenesis. The processes permitting a chromosome to pair only with its homologue are not fully understood, but successful pairing of homologous chromosomes is tightly linked to recombination. In Arabidopsis thaliana, meiotic prophase of rad51, xrcc3, and rad51C mutants appears normal up to the zygotene/pachytene stage, after which the genome fragments, leading to sterility. To better understand the relationship between recombination and chromosome pairing, we have analysed meiotic chromosome pairing in these and in dmc1 mutant lines. Our data show a differing requirement for these proteins in pairing of centromeric regions and chromosome arms. No homologous pairing of mid-arm or distal regions was observed in rad51, xrcc3, and rad51C mutants. However, homologous centromeres do pair in these mutants and we show that this does depend upon recombination, principally on DMC1. This centromere pairing extends well beyond the heterochromatic centromere region and, surprisingly, does not require XRCC3 and RAD51C. In addition to clarifying and bringing the roles of centromeres in meiotic synapsis to the fore, this analysis thus separates the roles in meiotic synapsis of DMC1 and RAD51 and the meiotic RAD51 paralogs, XRCC3 and RAD51C, with respect to different chromosome domains

Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial

Objectives: To investigate whether overstatements in abstract conclusions influence primary care physicians’ evaluations when they read reports of randomised controlled trials (RCTs) Design: CT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis. Participants: Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into ‘without overstatement’ (n=307) and ‘with overstatement’ (n=315) groups. Interventions: We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention. Outcome measures: The primary outcome was the participants’ evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion. Results: There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI −0.28 to 0.42, p=0.69). Participants in the ‘without’ group considered the study conclusion to be more valid than those in the ‘with’ group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001). Conclusion: The overstatements in abstract conclusions did not significantly influence the primary care physicians’ evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported. Trial registration number: UMIN000025317; Pre-results

Neck Dissection for Cervical Lymph Node Metastases from Remote Primary Malignancies

Background and Objectives: Patients with cervical lymph node metastases from remote primary tumours have poor prognoses because of the advanced stage of their cancer. Owing to recent progress in the nonsurgical management of various cancer types, options for surgical treatment to reduce tumour volume are increasing, and may help improve survival rates. For example, neck dissection may be a good option as a definitive therapy for some patients with resectable cervical metastases. We assessed patients who underwent neck dissection with curative intent and discuss the effectiveness of this approach for cervical metastases from remote malignancies. Material and Methods: We retrospectively reviewed the data of 18 patients (10 males and 8 females in an age range of 30&ndash;79 years) who underwent neck dissections for neck lymph node metastases from a remote primary tumour between 2010 and 2019. Patient clinical characteristics, preoperative accuracy of positive node localisation using fluorodeoxyglucose positron emission tomography&ndash;computed tomography (FDG/PET-CT), and patient survival rates were estimated. Results: Primary sites included ten lungs, two mammary glands, one thymus, one thoracic oesophagus, one stomach, one uterine cervix, one ovary, and one testis per patient. There were 19 levels with FDG/PET-CT positive nodes in 17 out of 18 patients. Conversely, there were 28 pathological positive levels out of 50 dissected levels. The sensitivity, specificity, positive and negative predictive values, and accuracy of FDG-PET/CT in predicting positive nodes were 69%, 88%, 95%, 47%, and 74%, respectively. The three-year overall survival (OS) rate for all patients was 70%. The three-year OS rate of the group with zero or one pathological positive nodes was 81%, which was significantly higher than that of the group with more than two positive nodes (51%) (p = 0.03). Conclusions: Neck dissection for cervical lymph node metastases from remote primary malignancies may improve prognoses, especially considering anticancer agents and radiotherapy advancements