The Fragility of Statistically Significant Results in Randomized Clinical Trials for COVID-19

[Importance] Interpreting results from randomized clinical trials (RCTs) for COVID-19, which have been published rapidly and in vast numbers, is challenging during a pandemic. [Objective] To evaluate the robustness of statistically significant findings from RCTs for COVID-19 using the fragility index. [Design, Setting, and Participants] This cross-sectional study included COVID-19 trial articles that randomly assigned patients 1:1 into 2 parallel groups and reported at least 1 binary outcome as significant in the abstract. A systematic search was conducted using PubMed to identify RCTs on COVID-19 published until August 7, 2021. [Exposures] Trial characteristics, such as type of intervention (treatment drug, vaccine, or others), number of outcome events, and sample size. [Main Outcomes and Measures] Fragility index. [Results] Of the 47 RCTs for COVID-19 included, 36 (77%) were studies of the effects of treatment drugs, 5 (11%) were studies of vaccines, and 6 (13%) were of other interventions. A total of 138 235 participants were included in these trials. The median (IQR) fragility index of the included trials was 4 (1-11). The medians (IQRs) of the fragility indexes of RCTs of treatment drugs, vaccines, and other interventions were 2.5 (1-6), 119 (61-139), and 4.5 (1-18), respectively. The fragility index among more than half of the studies was less than 1% of each sample size, although the fragility index as a proportion of events needing to change would be much higher. [Conclusions and Relevance] This cross-sectional study found a relatively small number of events (a median of 4) would be required to change the results of COVID-19 RCTs from statistically significant to not significant. These findings suggest that health care professionals and policy makers should not rely heavily on individual results of RCTs for COVID-19

Readministration of gefitinib in a responder after treatment discontinuation due to gefinitib-related interstitial lung disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gefitinib is a new molecular-targeted agent for the treatment of patients with advanced non-small cell lung cancer that fail to respond to conventional chemotherapy. Gefitinib is considered to be well tolerated and less toxic compared with conventional cytotoxic drugs. However, interstitial lung disease (ILD) has been reported as a serious adverse effect. The precise management of a gefitinib responder having severe adverse events remains unknown.</p> <p>Case Presentation</p> <p>We report the case of gefitinib readministration in a patient with lung adenocarcinoma who had once responded but in whom treatment had to be discontinued owing to gefinitib-related ILD. A dramatic response was achieved both at the time of initial treatment (250 mg/day) and at readministration of gefitinib (125 mg/day). The effectiveness of gefitinib therapy in our patient could be explained in part by the presence of an activating mutation of epidermal growth factor receptor (<it>EGFR</it>) gene, L858R in exon 21, which was identified in the primary tumor.</p> <p>Conclusion</p> <p>A reduced dose of gefitinib might be sufficient for patients having tumors with <it>EGFR </it>gene mutations, and that the currently approved dose may be excessively potent in some of these patients, thus resulting in the onset of adverse events.</p

血液透析患者における施設レベルのリン管理ガイドラインへの遵守と死亡との関連：前向きコホート研究

京都大学新制・課程博士博士(社会健康医学)甲第23820号社医博第120号新制||社医||12(附属図書館)京都大学大学院医学研究科社会健康医学系専攻(主査)教授 中山 健夫, 教授 小杉 眞司, 教授 柳田 素子学位規則第4条第1項該当Doctor of Public HealthKyoto UniversityDFA

Predicting Smoking Prevalence in Japan Using Search Volumes in an Internet Search Engine: Infodemiology Study

BackgroundTobacco smoking is an important public health issue and a core indicator of public health policy worldwide. However, global pandemics and natural disasters have prevented surveys from being conducted. ObjectiveThe purpose of this study was to predict smoking prevalence by prefecture and sex in Japan using Internet search trends. MethodsThis study used the infodemiology approach. The outcome variable was smoking prevalence by prefecture, obtained from national surveys. The predictor variables were the search volumes on Yahoo! Japan Search. We collected the search volumes for queries related to terms from the thesaurus of the Japanese medical article database Ichu-shi. Predictor variables were converted to per capita values and standardized as z scores. For smoking prevalence, the values for 2016 and 2019 were used, and for search volume, the values for the April 1 to March 31 fiscal year (FY) 1 year prior to the survey (ie, FY 2015 and FY 2018) were used. Partial correlation coefficients, adjusted for data year, were calculated between smoking prevalence and search volume, and a regression analysis using a generalized linear mixed model with random effects was conducted for each prefecture. Several models were tested, including a model that included all search queries, a variable reduction method, and one that excluded cigarette product names. The best model was selected with the Akaike information criterion corrected (AICC) for small sample size and the Bayesian information criterion (BIC). We compared the predicted and actual smoking prevalence in 2016 and 2019 based on the best model and predicted the smoking prevalence in 2022. ResultsThe partial correlation coefficients for men showed that 9 search queries had significant correlations with smoking prevalence, including cigarette (r=–0.417, P<.001), cigar in kanji (r=–0.412, P<.001), and cigar in katakana (r=-0.399, P<.001). For women, five search queries had significant correlations, including vape (r=0.335, P=.001), quitting smoking (r=0.288, P=.005), and cigar (r=0.286, P=.006). The models with all search queries were the best models for both AICC and BIC scores. Scatter plots of actual and estimated smoking prevalence in 2016 and 2019 confirmed a relatively high degree of agreement. The average estimated smoking prevalence in 2022 in the 47 prefectures for the total sample was 23.492% (95% CI 21.617%-25.367%), showing an increasing trend, with an average of 29.024% (95% CI 27.218%-30.830%) for men and 8.793% (95% CI 7.531%-10.054%) for women. ConclusionsThis study suggests that the search volume of tobacco-related queries in internet search engines can predict smoking prevalence by prefecture and sex in Japan. These findings will enable the development of low-cost, timely, and crisis-resistant health indicators that will enable the evaluation of health measures and contribute to improved public health

Association between facility-level adherence to phosphorus management guidelines and mortality in haemodialysis patients: a prospective cohort study

[Objectives] To examine the association between facility-level adherence to phosphorus management guidelines and mortality among patients with haemodialysis, and to explore the facility-related factors associated with facility-level guideline adherence. [Design] Prospective cohort study. [Setting] The Dialysis Outcomes and Practice Pattern Study, which included 57 representative dialysis facilities in Japan between 2012 and 2015. [Participants] A total of 2054 adult patients who received maintenance haemodialysis were included. We defined exposure according to the following four categories, depending on whether facility-level target ranges of serum phosphorus concentration adhered to the Japanese clinical practice guidelines: adherence group (lower limit ≥3.5 mg/dL and upper limit ≤6.0 mg/dL), low-target group (lower limit 6.0) and high-target group (lower limit ≥3.5 and upper limit >6.0). [Primary outcome measure] The primary outcome was the patient all-cause mortality rate. [Results] The mortality rate among the patients was 7.3 per 100 person-years; 27 facilities (47%) set targets according to the guidelines. HRs for mortality with reference to the adherence group were 1.04 (95% CI 0.76 to 1.43) in the low-target group, 1.11 (95% CI 0.68 to 1.81) in the wide-target group and 1.95 (95% CI 1.12 to 3.38) in the high-target group. Involvement of dieticians in dialysis treatment was associated with facility-level guideline adherence (OR 4.51; 95% CI 1.15 to 17.7). [Conclusions] A higher facility-level target range for phosphorus was associated with increased patient mortality. Among facilities that set the target according to the guidelines, dieticians tended to be involved in dialysis care. These findings suggest the importance of reviewing facilities’ treatment policies in relation to updated guidelines and the need to work with relevant professionals

The differential cellular uptake of curcuminoids in vitro depends dominantly on albumin interaction

Curcuminoids, mainly present in the plant rhizomes of turmeric (Curcuma longa), consist of mainly three forms (curcumin (CUR), bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC)). It has been reported that different forms of curcuminoids possess different biological activities. However, the mechanisms associated with these differences are not well-understood. Recently, our laboratory found differences in the cellular uptake of these curcuminoids. Therefore, it has been inferred that these differences contribute to the different biological activities. In this study, we investigated the mechanisms of differential cellular uptake of these curcuminoids. Based on our previous study, we hypothesized the differential cellular uptake is caused by (I) polarity, (II) transporters, (III) metabolism rate of curcuminoids and (IV) medium components. These four hypotheses were each investigated by (I) neutralizing the polarities of curcuminoids by encapsulation into poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs), (II) inhibition of polyphenol-related absorption transporters, (III) analysis of the cellular curcuminoids and their metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and (IV) use of different mediums in cell study. The differential cellular uptake was not affected by (I-III). However, when investigating (IV), not only CUR but also BDMC and DMC were incorporated into cells when serum free media was used. Furthermore, when we used the serum free medium containing bovine serum albumin (BSA), only CUR was taken up but BDMC and DMC were not. Therefore, we identified that the differential cellular uptake of curcuminoids is caused by the medium components, especially BSA. Also, the fluorescence quenching study suggested that differential cellular uptake is due to the different interaction between BSA and each curcuminoid. The differential cellular uptake of curcuminoids was caused by the different interaction between curcuminoids and BSA. The results from this study might give clues on the mechanisms by which curcuminoids exhibit different physiological activities. [Display omitted