Development and validation of prediction models for papillary thyroid cancer structural recurrence using machine learning approaches.

BACKGROUND: Although papillary thyroid cancer (PTC) patients are known to have an excellent prognosis, up to 30% of patients experience disease recurrence after initial treatment. Accurately predicting disease prognosis remains a challenge given that the predictive value of several predictors remains controversial. Thus, we investigated whether machine learning (ML) approaches based on comprehensive predictors can predict the risk of structural recurrence for PTC patients. METHODS: A total of 2244 patients treated with thyroid surgery and radioiodine were included. Twenty-nine perioperative variables consisting of four dimensions (demographic characteristics and comorbidities, tumor-related variables, lymph node (LN)-related variables, and metabolic and inflammatory markers) were analyzed. We applied five ML algorithms-logistic regression (LR), support vector machine (SVM), extreme gradient boosting (XGBoost), random forest (RF), and neural network (NN)-to develop the models. The area under the receiver operating characteristic (AUC-ROC) curve, calibration curve, and variable importance were used to evaluate the models' performance. RESULTS: During a median follow-up of 45.5 months, 179 patients (8.0%) experienced structural recurrence. The non-stimulated thyroglobulin, LN dissection, number of LNs dissected, lymph node metastasis ratio, N stage, comorbidity of hypertension, comorbidity of diabetes, body mass index, and low-density lipoprotein were used to develop the models. All models showed a greater AUC (AUC = 0.738 to 0.767) than did the ATA risk stratification (AUC = 0.620, DeLong test: P < 0.01). The SVM, XGBoost, and RF model showed greater sensitivity (0.568, 0.595, 0.676), specificity (0.903, 0.857, 0.784), accuracy (0.875, 0.835, 0.775), positive predictive value (PPV) (0.344, 0.272, 0.219), negative predictive value (NPV) (0.959, 0.959, 0.964), and F1 score (0.429, 0.373, 0.331) than did the ATA risk stratification (sensitivity = 0.432, specificity = 0.770, accuracy = 0.742, PPV = 0.144, NPV = 0.938, F1 score = 0.216). The RF model had generally consistent calibration compared with the other models. The Tg and the LNR were the top 2 important variables in all the models, the N stage was the top 5 important variables in all the models. CONCLUSIONS: The RF model achieved the expected prediction performance with generally good discrimination, calibration and interpretability in this study. This study sheds light on the potential of ML approaches for improving the accuracy of risk stratification for PTC patients. TRIAL REGISTRATION: Retrospectively registered at www.chictr.org.cn (trial registration number: ChiCTR2300075574, date of registration: 2023-09-08).

A polydopamine coating enabling the stable cycling of MnO2 cathode materials in aqueous zinc batteries.

MnO2 is a desired cathode candidate for aqueous zinc batteries. However, their cycling stability is seriously limited by active material dissolution, and pre-addition of Mn2+ salts in electrolytes is widely required to shift the dissolution equilibrium. Herein, we synthesize a polydopamine (PDA) coated MnO2 composite material (MnO2/PDA) to realize stable cycling in zinc cells without relying on pre-added Mn2+. The functional groups on PDA exhibit strong coordination ability with the Mn active material. It not only confines dissolved species within the cathode during discharge, but also enhances their deposition back to the cathode during charge to retrieve the active material. Thanks to this effect, the cathode achieves 81.1% capacity retention after 2000 cycles at 1 A g-1 in the 1 M ZnSO4 electrolyte, superior to 37.3% with the regular MnO2 cathode. This work presents an effective strategy to realize the stable cycling of manganese oxide cathode materials in aqueous zinc batteries.

Handling time-varying treatments in observational studies: A scoping review and recommendations.

OBJECTIVE: Time-varying treatments are common in observational studies. However, when assessing treatment effects, the methodological framework has not been systematically established for handling time-varying treatments. This study aimed to examine the current methods for dealing with time-varying treatments in observational studies and developed practical recommendations. METHODS: We searched PubMed from 2000 to 2021 for methodological articles about time-varying treatments, and qualitatively summarized the current methods for handling time-varying treatments. Subsequently, we developed practical recommendations through interactive internal group discussions and consensus by a panel of external experts. RESULTS: Of the 36 eligible reports (22 methodological reviews, 10 original studies, 2 tutorials and 2 commentaries), most examined statistical methods for time-varying treatments, and only a few discussed the overarching methodological process. Generally, there were three methodological components to handle time-varying treatments. These included the specification of treatment which may be categorized as three scenarios (i.e., time-independent treatment, static treatment regime, or dynamic treatment regime); definition of treatment status which could involve three approaches (i.e., intention-to-treat, per-protocol, or as-treated approach); and selection of analytic methods. Based on the review results, a methodological workflow and a set of practical recommendations were proposed through two consensus meetings. CONCLUSIONS: There is no consensus process for assessing treatment effects in observational studies with time-varying treatments. Previous efforts were dedicated to developing statistical methods. Our study proposed a stepwise workflow with practical recommendations to assist the practice.

A low concentration electrolyte additive for constructing solid-electrolyte interphase on a Zn metal anode for aqueous batteries.

Zn metal anodes in aqueous batteries experience inhomogeneous deposition and corrosion issues. Herein, we introduced, at a low concentration, dioxane (DX) as an electrolyte additive to stabilize a Zn anode. The oxygen sites of DX endowed it with a strong affinity for Zn and Zn2+, resulting in its adsorption onto the Zn electrode surface and its coordination with Zn2+ locally. The Zn2+-DX species exhibited a decreased lowest unoccupied molecular orbital energy level relative to those of water-involved components. The DX additive not only inhibited side reactions but also generated a stable solid-electrolyte interphase on the Zn electrode, ensuring a uniform Zn deposition. As a result of including the additive, the cycle life of the Zn symmetric cell was extended from 99 h to 2100 h, and the coulombic efficiency in Zn//Cu cell reached 99.5%.

Sample size calculations for randomized controlled trials with repeatedly measured continuous variables as primary outcomes need improvements: a cross-sectional study.

OBJECTIVES: Randomized controlled trials (RCTs) with repeatedly measured continuous variables as primary outcomes are common. Although statistical methodologies for calculating sample sizes in such trials have been extensively investigated, their practical application remains unclear. This study aims to provide an overview of sample size calculation methods for different research questions (e.g., key time point treatment effect, treatment effect change over time) and evaluate the adequacy of current practices in trial design. STUDY DESIGN AND SETTING: We conducted a comprehensive search of PubMed to identify RCTs published in core journals in 2019 that utilized repeatedly measured continuous variables as their primary outcomes. Data were extracted using a predefined questionnaire including general study characteristics, primary outcomes, detailed sample size calculation methods, and methods for analyzing the primary outcome. We re-estimated the sample size for trials that provided all relevant parameters. RESULTS: A total of 168 RCTs were included, with a median of four repeated measurements (interquartile range 3-6) per outcome. In 48 (28.6%) trials, the primary outcome used for sample size calculation differed from the one used in defining the primary outcomes. There were 90 (53.6%) trials exhibited inconsistencies between the hypotheses specified for sample size calculation and those specified for primary analysis. The statistical methods used for sample size calculation in 158 (94.0%) trials did not align with those used for primary analysis. Additionally, only 6 (3.6%) trials accounted for the number of repeated measurements, and 7 (4.2%) trials considered the correlation among these measurements when calculating the sample size. Furthermore, of the 128 (76.2%) trials that considered loss to follow-up, 33 (25.8%) used an incorrect formula (i.e., N∗(1+lose rate) for sample size adjustment. In 53 (49.5%) out of 107 trials, the re-estimated sample size was larger than the reported sample size. CONCLUSION: The practice of sample size calculation for RCTs with repeatedly measured continuous variables as primary outcomes displayed significant deficiencies, with a notable proportion of trials failed to report essential parameters about repeated measurement required for sample size calculation. Our findings highlight the urgent need to use optimal sample size methods that align with the research hypothesis, primary analysis method, and the form of the primary outcome.

Reporting, handling, and interpretation of time-varying drug treatments in observational studies using routinely collected healthcare data.

BACKGROUND: Time-varying drug treatments are common in studies using routinely collected health data (RCD) for assessing treatment effects. This study aimed to examine how these studies reported, handled, and interpreted time-varying drug treatments. METHODS: A systematic search was conducted on PubMed from 2018 to 2020. Eligible studies were those used RCD to explore drug treatment effects. We summarized the reporting characteristics and methods employed for handling time-varying treatments. Logistic regressions were performed to investigate the association between study characteristics and the reporting of time-varying treatments. RESULTS: Two hundred and fifty-six studies were included, and 225 (87.9%) studies involved time-varying treatments. Of these, 24 (10.7%) reported the proportion of time-varying treatments and 105 (46.7%) reported methods used to handle time-varying treatments. Multivariable logistic regression showed that medical studies, prespecified protocol, and involvement of methodologists were associated with a higher likelihood of reporting the methods applied to handle time-varying treatments. Among the 105 studies that reported methods, as-treated analyses were the most commonly used analysis sets, which were employed in 73.9%, 75.3% and 88.2% of studies that reported approaches for treatment discontinuation, treatment switching and treatment add-on. Among the 225 studies involved time-varying treatments, 27 (12.0%) acknowledged the potential bias introduced by treatment change, of which 14 (51.9%) suggested that potential biases may impact acceptance or rejection of the null hypothesis. CONCLUSIONS: Among observational studies using RCD, the underreporting about the presence and methods for handling time-varying treatments was largely common. The potential biases due to time-varying treatments have frequently been disregarded. Collaborative endeavors are strongly needed to enhance the prevailing practices.

Interface regulation of the Zn anode by using a low concentration electrolyte additive for aqueous Zn batteries.

The Zn metal anode in aqueous Zn batteries faces a number of challenges including instable deposition and corrosion issues. Here, we present an interface environment regulation for a Zn electrode with a low concentration electrolyte additive of 0.1 m 3-aminobenzenesulfonic acid (ASA). ASA prefers to adsorb on the Zn surface over water and creates an ASA-rich interface. It further enters the Zn2+ solvation sheath locally, which shifts the lowest unoccupied molecular orbital from solvated water to ASA. The hydrogen evolution reaction from solvated water reduction is inhibited, and the reduction of solvated ASA generates a stable solid-electrolyte interphase composed of the ion conductor ZnS covered by organic-inorganic mixed components. With the resulting homogenized Zn deposition, continuous Zn stripping in symmetric cells reaches 99.7% depth of discharge (DOD) at a current density of 2 mA cm-2, whereas cell short-circuit takes place at 11.4% DOD in the ASA free ZnSO4 electrolyte. The repeated stripping/plating also realizes 1100 h cycle life at 2 mA cm-2, and a 99.54% stabilized coulombic efficiency is obtained for 500 cycles at 10 mA cm-2.

Stable and Highly Luminescent Silver Nanoclusters in the 13X Zeolite Enabled by Mg2+ Doping and Their Luminescence Tuning by Heating Temperature.

Zeolite-confined silver nanoclusters (Ag-zeolite) have aroused vast interest due to their remarkable luminescence. The countercations within a zeolite play critical roles in determining the luminescent properties of the resulting Ag-zeolite. We observed, in this work, that introducing Mg2+ enabled the Ag-13X zeolite a stable and bright yellow emission with a high PLQY of 94.6%, the first report on the luminescence enhancement of the Ag-13X zeolite by Mg2+, to the best of our knowledge. The formation of specific internal electric fields inside 13X and the structural contraction of the zeolite framework due to the high charge density and the small ionic radius of Mg2+ are believed to be responsible for the enhanced stable and bright yellow emission. The stabilization effect of Mg2+ is removed by increasing the heating temperature above 700 °C, which leads to the variation of silver nanoclusters as a result of the framework collapse of the zeolite. The Ag-zeolite synthesized by us, featured with a broad emission band, a high PLQY of 94.6%, and good thermal stability, can be considered a suitable candidate to replace the traditional commercial yellow-emitting phosphor YAG:Ce3+ for light-based applications. This work contributes to a valuable reference for the rational design of silver nanoclusters confined in zeolites with promising new functionalities and stimulates potential applications as novel phosphors for near-ultraviolet light-emitting diodes (NUV-LEDs).

Quality and consistency of clinical practice guideline recommendations for PET/CT and PET: a systematic appraisal.

OBJECTIVES: To systematically appraise the methodologies used for guidelines for positron emission tomography (PET) imaging and to compare the consistency of these recommendations. METHODS: We searched PubMed, EMBASE, four guideline databases, and Google Scholar to identify evidence-based clinical practice guidelines pertaining to the use of PET, PET/computed tomography (CT), or PET/magnetic resonance in routine practice. We assessed the quality of each guideline using the Appraisal of Guidelines for Research and Evaluation II instrument and compared recommendations regarding indications for 18F-fluorodeoxyglucose (FDG) PET/CT. RESULTS: Thirty-five guidelines for PET imaging, published between 2008 and 2021, were included. These guidelines performed well in the domains of scope and purpose (median 80.6%, inter-quartile range [IQR] 77.8-83.3%) and clarity of presentation (median 75%, IQR 69.4-83.3%), but poorly in applicability (median 27.1%, IQR 22.9-37.5%). Recommendations for 48 indications in 13 cancers were compared. Considerable inconsistencies in the direction of whether to support the use of FDG PET/CT were observed in 10 (20.1%) indications pertaining to 8 cancer types: head and neck cancer (treatment response assessment), colorectal cancer (staging in patients with stages I-III disease), esophageal cancer (staging), breast cancer (restaging and treatment response assessment), cervical cancer (staging in patients with stage < IB2 disease and treatment response assessment), ovarian cancer (restaging), pancreatic cancer (diagnosis), and sarcoma (treatment response assessment). CONCLUSIONS: Current guidelines for PET imaging vary in methodological quality and provided considerably inconsistent recommendations. Efforts are needed to improve adherence to guideline development methodologies, to synthesis high-quality evidence, and to adopt standard terminologies. PROTOCOL REGISTRATION NUMBER: PROSPERO CRD42020184965. CLINICAL RELEVANCE STATEMENT: Guidelines for PET imaging provide considerably inconsistent recommendations and vary in methodological quality. It is suggested that clinicians be critical of these recommendations when applying them in practice, that guideline developers adopt more rigorous development methodologies, and that researchers prioritize research gaps identified by current guidelines. KEY POINTS: • PET guidelines vary in methodological quality and provided inconsistent recommendations. Efforts are needed to improve methodologies, synthesize high-quality evidence, and standardize terminologies. • Among six domains of methodological quality assessed by the AGREE II tool, guidelines for PET imaging performed well in scope and purpose (median 80.6%, inter-quartile range 77.8-83.3%) and clarity of presentation (75%, 69.4-83.3%), but poorly in applicability (27.1%, 22.9-37.5%). • Among the 48 recommendations (for 13 cancer types) compared, conflicts in the direction of whether to support FDG PET/CT use were observed in 10 (20.1%), for 8 cancer types (i.e., head and neck, colorectal, esophageal, breast, cervical, ovarian, pancreatic, and sarcoma).

An organic-inorganic solid-electrolyte interface generated from dichloroisocyanurate electrolyte additive for a stable Zn metal anode in aqueous Zn batteries.

Dendrite growth and side reactions of the Zn metal anode limit the cycle life of aqueous Zn batteries. Herein, we propose a sodium dichloroisocyanurate electrolyte additive with a low concentration of 0.1 M to modify the Zn interface environment and construct a stable organic-inorganic solid-electrolyte interface on the Zn electrode. It suppresses corrosion reactions and directs uniform Zn deposition. The cycle life of the Zn electrode in symmetric cells extends to 1100 h at 2 mA cm-2 and 2 mA h cm-2, and the Zn plating/stripping coulombic efficiency reaches 99.5% for more than 450 cycles.

Acupuncture for treatment of knee osteoarthritis: A clinical practice guideline.

CLINICAL QUESTION: Is acupuncture effective in treating knee osteoarthritis (KOA)? CURRENT PRACTICE: Although increasingly used in the clinical setting, acupuncture is not mentioned or weakly recommended in guidelines for the treatment of KOA. RECOMMENDATIONS: We suggest acupuncture rather than no treatment in adult KOA (weak recommendation, moderate certainty evidence), and acupuncture combined with nonsteroidal anti-inflammatory drugs (NSAIDs) rather than acupuncture alone when KOA symptoms are severe (weak recommendation, moderate certainty evidence), with duration of acupuncture for 4-8 weeks depending on KOA severity and treatment response (weak recommendation, moderate certainty evidence), and discussing with patients in shared decision-making. HOW THIS GUIDELINE WAS CREATED: This rapid recommendation was developed following the Making GRADE the Irresistible Choice (MAGIC) methodological framework. First, the clinical specialist identified the topic of recommendation and demand for evidence. Then the independent evidence synthesis group performed a systematic review to summarize available evidence and evaluate the evidence using the GRADE approach. Finally, the clinical specialist group produced recommendations for practice through a consensus procedure. THE EVIDENCE: The linked systematic review and meta-analysis included 9422 KOA patients, 61.1% of whom were women. The median mean age was 61.8 years. Compared with no treatment, acupuncture had beneficial effect on KOA in improving the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (moderate certainty evidence), and WOMAC pain (very low certainty evidence), WOMAC stiffness (low certainty evidence), and WOMAC function (low certainty evidence) subscale scores. Compared with usual care, acupuncture improved WOMAC stiffness subscale score (moderate certainty evidence). Subgroup analyses showed different effects in the improvement of WOMAC total scores by different durations of acupuncture and whether acupuncture combined with NSAIDs, but no difference between manual acupuncture and electroacupuncture was found. UNDERSTANDING THE RECOMMENDATIONS: Compared with no treatment, acupuncture is suggested to reduce pain, stiffness, and disfunction in KOA patients, ultimately improving the patient's health status. Acupuncture can be used as an alternative therapy when usual care is ineffective or there are adverse reactions so that patients can no longer continue the treatment. Manual acupuncture or electroacupuncture is suggested for 4-8 weeks to improve the health status of KOA. The patient's values and preferences should be considered when selecting acupuncture for KOA treatment.

Tunable Luminescence of Silver Nanoclusters Confined in SOD/FAU Zeolites and Selective Sensing for Organic Amine.

A series of Ag-zeolite luminescent composites are prepared based on SOD and FAUY zeolites, and the effect of zeolite host particle size on their dynamic luminescent emission properties was discussed for the first time. The relationship between zeolite particle size and the nucleation of silver nanoclusters (AgNCs) is revealed. With the increase of zeolite particle size from nanometers to microns, the luminescent color of both Ag-SOD and Ag-Y composites shows significant blue shift. The observed tunable luminescence can be accounted for the slower nucleation rate of AgNCs in micron-scale zeolites with longer channels, resulting in smaller nuclearity of AgNCs within large-size zeolites, through the characterization of extended X-ray absorption fine structure, implying the important roles played by the zeolite themselves in determining the luminescence properties. Moreover, the composites prepared by us feature simple signal transduction, fast response (30 s), and excellent selectivity and sensitivity for discriminative luminescence detection of triethylamine and ethylamine, and they have good reversible luminescence response after sensing HAc gas, which might imply the potential applications in the volatile organic amine detection and information encryption field.

Unprecedented toughness in transparent, luminescent, self-healing polymers enabled via hierarchical rigid domain design.

The preparation of luminescent self-healing materials simultaneously featuring superior integrated mechanical properties is still a great challenge because the relationship between self-healing ability and mechanical capacities is conflicted. Here, transparent luminescent materials with balanced self-healing behavior, extreme toughness, and fast elastic recovery are prepared via hierarchical rigid domain design by coordinating lanthanide (Ln3+) to terpyridine (TPy) moieties linked to the polymer chains formed through polymerization of tolylene-2,4-diisocyanate-terminated polypropylene glycol (PPG-NCO) and 1,6-hexanediamine (HDA). The hierarchical rigid domain containing lanthanide-terpyridine (Ln3+-TPy) coordination interactions and H-bonds formed by urea and urethane leads to a tough network that features unprecedented toughness of 133.35 MJ m-3, which reaches 83% of that of typical spider silk (≈ 160 MJ m-3) and is also dynamic for fast self-healing at ambient temperature. Besides, the multi-color emission, ranging from red through orange and yellow to green, can be achieved via adjusting the molar ratio of Eu3+/Tb3+. We believe that the strategy applied in this work provides some insights for the preparation of high mechanical strength luminescence materials with self-healing properties.

Factors associated with concurrent malignancy risk among patients with incidental solitary pulmonary nodule: A systematic review taskforce for developing rapid recommendations.

OBJECTIVE: To assess the association between prespecified factors and the malignancy risk of solitary pulmonary nodules (SPNs) to support the development of rapid recommendations for daily use in the Chinese setting. METHODS: The expert panel for the rapid recommendations voted for 12 candidate factors based on published guidelines, selected publications, and clinical experiences. We then searched Medline, Embase, and Web of Science up to October 17, 2021, for studies investigating the association between these factors and the diagnosis of malignant SPNs in patients with CT-identified SPNs through multivariable regression analysis. The risk of bias was assessed using the Agency for Healthcare Research and Quality (AHRQ) Checklist. We pooled adjusted odds ratios (aOR) between candidate factors and the diagnosis of the malignant SPNs. RESULTS: A total of 32 cross-sectional studies were included. Nine factors were statistically associated with malignant SPNs: age (aOR 1.06, 95% confidence interval [CI]: 1.05-1.07), smoking history (2.83, 1.84-4.36), history of extrathoracic malignancy (5.66, 2.80-11.46), history of malignancy (4.64, 3.37-6.39), family history of malignancy (3.11, 1.66-5.83), nodule diameter (1.23, 1.17-1.31), spiculation (3.41, 2.64-4.41), lobulation (3.85, 2.47-6.01), and mixed ground-glass opacity (mGGO) density of the nodule (5.56, 2.47-12.52). No statistical association was found between family history of lung cancer, emphysema, nodule border, and malignant SPNs. CONCLUSION: Nine prespecified factors were associated with the concurrent malignancy risk among patients with SPNs. Risk stratification for SPNs is warranted in clinical practice.

Malignancy risk stratification for solitary pulmonary nodule: A clinical practice guideline.

CLINICAL QUESTION: The detection rate of the solitary pulmonary nodule (SPN) is increasing with the popularization of CT scanning. Malignancy risk stratification for SPN is a major clinical difficulty. CURRENT PRACTICE: There have been several guidelines for SPN assessment. Inconsistency of these guidelines makes the clinical application difficult and confusing. RECOMMENDATIONS: In this Rapid Recommendation, solid and subsolid SPNs are recommended to be evaluated respectively. Six factors, namely the combination of age with sex, smoking history, history of malignancy, family history of malignancy, and nodule size, are recommended for malignancy risk stratification for both kinds of SPNs; the border of nodules (spiculation and lobulation) is recommended for evaluating solid SPNs and the density of nodules (pure or mixed ground-glass nodule) is recommended for subsolid nodules. Among them, smoking history and radiologic features (nodule diameter, border, and density) are of relatively higher importance. A scoring system was proposed to assist malignancy risk stratification of SPNs, with a total score ranging from six points to 15 points (if solid) or 17 points (if subsolid). For each SPN, regardless of solid or subsolid in nature, a total score of ≤ 7 points suggested a low risk of being malignant, while 7 to 9 points suggested medium risk, and ≥ 9 points suggested high risk. HOW THIS GUIDELINE WAS CREATED: This rapid recommendation was developed using the MAGIC (Making GRADE the Irresistible Choice) methodological framework. First, a clinical subcommittee identified the topic of recommendation and requested evidence. Then, an independent evidence synthesis subcommittee performed a comprehensive literature review and evaluated the evidence. Finally, based on findings from the systematic review and use of real-world data, the clinical subcommittee formulated recommendations, including the scoring system, through a consensus procedure. THE EVIDENCE: A total of 13857 patients with SPNs were included in the meta-analysis and the association between 12 candidate factors and the risk of SPNs being malignant was studied. Eventually, seven factors were recommended for SPNs evaluation, and a scoring system was proposed. UNDERSTANDING THE RECOMMENDATION: The parameters included are objective. Therefore, this recommendation is feasible in clinical practice. However, there are several uncertainties, such as a lack of further verification. It might be misclassified by the scoring system. Clinicians could choose the most suitable scheme according to the recommendation, along with their own experience in specific situations.

Missing data were poorly reported and handled in randomized controlled trials with repeatedly measured continuous outcomes: a cross-sectional survey.

BACKGROUND AND OBJECTIVES: Missing data are common in randomized controlled trials (RCTs) involving repeatedly measured continuous outcomes. Evidence on the reporting and handling of such outcome data is lacking, which has prevented further improvement in methods and reporting of RCTs. METHODS: We searched PubMed to identify RCTs published in the Core Clinical Journals in 2019 that reported a continuous primary outcome with repeated measures. A team of investigators conducted a study screening and collected data using pilot-tested, standardized questionnaires from a random sample of eligible RCTs. We thoroughly collected information about the reporting of missing data for the repeatedly measured continuous outcome and the methods used to handle the missing data. RESULTS: We included 200 eligible trials, whose mean number of repeated measures for the continuous primary outcomes was 5.46 (SD = 3.4). Sixty-one (30.5%) trials explicitly reported missing data at both participant and outcome levels, 116 (58.0%) at the participant level only, and 2 (1.0%) at the outcome level only. Sixty (30.0%) trials reported missing data at the participant level by group and by time point, and 53 (26.5%) at the outcome level by group and by time point. Among 179 trials having reported missing data, 162 (90.5%) did not assess the balance of baseline characteristics, 143 (79.9%) did not assume missing mechanism; 65 (36.3%) used suboptimal methods for handling missing data (e.g., complete case analysis); 41 (22.9%) conducted sensitivity analyses, and 5 (11.9%) assumed alternative missing mechanisms for sensitivity analyses. CONCLUSION: The reporting of missing data for repeatedly measured continuous outcomes were inadequate and the use of statistical methods for handling missing data was far from optimal. Substantial efforts are warranted to improve the reporting and statistical handling of these outcome data.

Quantifying the contribution of 18F-FDG PET to the diagnostic assessment of pediatric patients with fever of unknown origin: a systematic review and meta-analysis.

BACKGROUND: The value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic assessment of pediatric fever of unknown origin is not known, and evidence from adults is not applicable. OBJECTIVE: To quantify the contribution of 18F-FDG PET to pediatric fever of unknown origin, considering its diagnostic limitations. MATERIALS AND METHODS: We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials up to Feb. 18, 2021. We included studies on patients with pediatric fever of unknown origin presenting sufficient data to calculate the likelihood of achieving definite diagnosis (based on pathology or clinical follow-up) between those with abnormal PET findings versus those with normal PET findings. We assessed the risk of bias using a modified Newcastle-Ottawa quality assessment scale and quantified the value of PET by pooling the likelihood of achieving definite diagnosis using a random-effects model. RESULTS: We included 6 studies and found that pediatric patients with abnormal PET findings were about 17 times more likely to achieve definite diagnoses than those with normal PET findings (odds ratio [OR]: 16.75, 95% confidence interval [CI] 8.0-35, P < 0.00001). Sensitivity analyses using a fixed-effect model (OR 16.91, 95% CI 8.1-35, P < 0.0001) or removing one study at a time (OR 12-20, 95% CI lower bound 3.8-8.6, 95% CI upper bound 33-45, P < 0.0001) did not significantly alter the results. Sample size (interaction P = 0.75), imaging modality (interaction P = 0.29), length of follow-up (interaction P = 0.37), fever of unknown origin subclasses (interaction P = 0.89) and geographical areas (interaction P = 0.74) of studies showed no statistically significant influence on the results. CONCLUSION: 18F-FDG PET is a promising approach in the diagnostic work-up of pediatric fever of unknown origin. Further studies are warranted to support routine use in clinical care.

Analyses of repeatedly measured continuous outcomes in randomized controlled trials needed substantial improvements.

OBJECTIVES: Systematic understanding is lacking regarding how current trials handle repeated measure data and the extent to which appropriate statistical methods are used for such data set. This study investigated the current practice of analyzing the repeated measure data among randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: We searched the Core Clinical Journals indexed in PubMed for RCTs published in 2019 and included a continuous primary outcome with repeated measures. We randomly sampled RCTs from the eligible trials. Team of methods trained investigators screened studies for eligibility and collected data using the pilot-tested, standardized questionnaires. We thoroughly documented statistical analyses of the continuous primary outcome with repeated measures and particularly recorded how statistically advanced methods were used to handle these repeated measures. RESULTS: In total, 200 trials were included. Of these trials, the mean number of repeated measures for the continuous primary outcome was 5.46 (SD = 3.4); 58 (29.0%) trials did not specify the time point of primary outcome in the method; 113 (56.5%) trials did not use statistically advanced methods for handling repeated measure data in the primary analyses. Among187 trials included the baseline values, 88 (47.1%) trials did not adjust for outcome value at baseline. Among 87 trials using statistically advanced methods, 49 (56.3%) did not specify correlation structure for model. CONCLUSIONS: The statistical analyses of repeatedly measured continuous outcomes in RCTs need substantial improvements. Careful planning of the primary outcome and the use of statistically advanced methods for analyzing data are warranted.