Chemoradiation versus chemotherapy after D2 gastrectomy: A meta-analysis including randomized and real-world trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16590-e16590
Author(s):  
Chai Hong Rim ◽  
In-soo Shin ◽  
Hye yoon Lee ◽  
Sunmin Park
Keyword(s):  
Recurrence Rate ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
R0 Resection ◽  
D2 Gastrectomy ◽  
Significant Difference ◽  
Subgroup Analyses

e16590 Background: The ARTIST trial failed to achieve positive result regarding benefit of chemoradiation (CRT) after D2 gastrectomy. In most of clinical guidelines and practices, postoperative CRT has been recommended only for those with R1 resection or lesser extent surgery than D2. Our study is to evaluate oncologic benefit of CRT after D2 gastrectomy, integrating data from randomized clinical trials (RCTs) and real-world studies so far. Methods: Systematic searches for Medline and Embase were performed for controlled trials comparing CRT and chemotherapy (CT) arms after D2 gastrectomy with R0 resection, for gastric cancer. Subgroup analyses were performed including RCTs, and balanced studies without significant difference regarding major clinical indicators. Primary endpoint was disease free survival (DFS), and secondary endpoints included overall survival (OS), locoregional recurrence rate (LRR), distant recurrence rate (DRR), and grade ≥3 complications. Results: A total of 13 studies, comprised of 6 RCTs and 7 non-RCTs, involving 2,603 patients were included. DFS benefit was found in overall pooled analysis [odds ratio (OR): 1.264, p = 0.053, I2= 37.5%], and more evident in subgroup analyses using RCTs (OR: 1.440, p = 0.006, I2= ~0%) and balanced studies (OR: 1.417, p < 0.001, I2= ~0%). OS benefit was not significant. LRR reduction was noted in overall pooled analysis (OR: 0.559, p = 0.012, I2 = 46.1%), and clearer in the subgroup analyses with RCTs (OR: 0.495, p < 0.001, I2= ~0%) and balanced studies (OR 0.472, p < 0.001, I2= 9.2%). Pooled LRR rates were 11.3% (95% confidence interval: 7.5-16.8) and 18.1% (13.1-24.4) in CRT and CT arms. DRR was lower in CRT arms (OR: 0.768, p = 0.023, I2= ~0.0%), but the difference was less significant in subgroup analyses. A grade 5 complication was found in each of the two arms among all studies. Comparison of complications varies and will be shown descriptively in the manuscript. Conclusions: Benefit of DFS and LRR with CRT after D2 gastrectomy was well shown in the present study. Identifying subgroup population mostly benefitable from CRT might yield positive results regarding OS and DRR in future studies.

scholarly journals Real-World Prevalence of Direct Oral Anticoagulant Off-Label Doses in Atrial Fibrillation: An Epidemiological Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan-Nan Shen ◽  
Chi Zhang ◽  
Ying Hang ◽  
Zheng Li ◽  
Ling-Cong Kong ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Real World ◽  
Oral Anticoagulant ◽  
Meta Analysis ◽  
Anticoagulation Therapy ◽  
Direct Oral Anticoagulant ◽  
Prevalence Data ◽  
Off Label ◽  
Significant Difference ◽  
Subgroup Analyses

Background: The use of direct oral anticoagulant (DOAC) off-label doses in atrial fibrillation (AF) patients may result in poor clinical outcomes. However, the true prevalence remains scarce. This study aims at estimating the prevalence of DOAC off-label doses in AF patients.Methods: Databases of MEDLINE, EMBASE, and COCHRANE were searched from inception through February 2020 for real-world studies that reported the off-label definition and prevalence data of AF patients using DOACs. The primacy outcomes were the overall prevalence of DOAC off-label doses and the corresponding underdose and overdose. The random-effects model was used for data synthesis. Variations on individual DOAC and different regions were examined by subgroup analyses.Results: A total of 23 studies involving 162,474 AF patients were finally included. The overall prevalence of DOAC off-label doses was 24% (95% CI, 19–28%), with 18% for dabigatran, 27% for rivaroxaban, 24% for apixaban, and 26% for edoxaban. The prevalence of underdosed DOACs was 20% (95% CI, 16–24%) with significant difference among individual anticoagulants (13% for dabigatran, 22% for rivaroxaban, 22% for apixaban, and 18% for edoxaban; Pinteraction=0.02). The prevalence of overdosed DOACs was 5% (95% CI, 3–7%), with the lowest prevalence observed in apixaban (2%). Subgroup analyses by regions demonstrated that the prevalence of DOAC off-label doses was higher in Asia (32%) than in North America (14%) and in Europe (22%), with underdose being predominant. Regardless of different regions, the prevalence of overdose was relatively low (4–6%).Conclusion: This study provides an estimation of DOAC off-label doses in the real-world setting. The prevalence rate of DOAC off-label doses in AF patients was relatively high, with underdose being predominant. Clinicians in Asia preferred to prescribe underdose of DOACs to AF patients. More evidence about the appropriateness of DOAC off-label doses in AF patients is urgently needed. Education programs concerning the appropriate prescription of DOACs within the drug labels and accepted guidelines are necessary to DOAC prescribers to ensure the safety and effectiveness of anticoagulation therapy for patients with AF.

Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7008-7008 ◽  
Author(s):  
J. P. Pignon ◽  
H. Tribodet ◽  
G. V. Scagliotti ◽  
J. Y. Douillard ◽  
F. A. Shepherd ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Treatment Options ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
Stage I ◽  
Hazard Ratios ◽  
Or Groups

7008 Background: Several recent trials have shown a benefit of adjuvant cisplatin-based chemotherapy on overall survival (OS) in patients with non-small cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation (LACE) is to identify treatment options associated with a higher benefit, or groups of patients benefiting more from adjuvant chemotherapy. Methods: Individual patient data were collected and pooled from the five largest trials (ALPI, ANITA, BLT, IALT and JBR10) of cisplatin-based chemotherapy in completely resected patients, conducted after the NSCLC-meta-analysis (BMJ 1995, update ongoing). The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analysed using hazard ratios (HR) and logrank tests stratified by trial. Results: With a median follow-up of 5.1 years, the overall HR of death was 0.89 (95% confidence interval [CI]: 0.82–0.96; p<0.005) corresponding to a 5-year absolute benefit of 4.2% with chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, p=0.046) with the HR for stage I-A 1.41 [95% CI: 0.96–2.09], stage I-B 0.93 [0.78–1.10], stage II 0.83 [0.73–0.95] and stage III 0.83 [0.73–0.95]. The effect of chemotherapy did not vary significantly (test for interaction, p=0.10) with the associated drugs: vinorelbine (HR=0.80 [0.70–0.91]) etoposide/vinca-alcaloide (0.93 [0.80–1.07]) or other (0.98 [0.84–1.14]). There was no interaction between chemotherapy and sex, age, planned radiotherapy or planned total dose of cisplatin. Conclusions: Adjuvant cisplatin-based chemotherapy improves survival in patients with NSCLC. This benefit depends on stage and is greatest in patients with stages II and III. Our analysis suggests that platinum-based adjuvant chemotherapy may not benefit stage I-A patients. Results of disease-free survival will be presented at the meeting. Supported by PHRC and LNLCC [Table: see text]

scholarly journals Survival benefits from adjuvant transcatheter arterial chemoembolization in patients undergoing liver resection for hepatocellular carcinoma: a systematic review and meta-analysis

2020 ◽  
Vol 13 ◽  
pp. 175628482097769
Author(s):  
Lei Liang ◽  
Chao Li ◽  
Yong-Kang Diao ◽  
Hang-Dong Jia ◽  
Hao Xing ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcatheter Arterial Chemoembolization ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Free Survival ◽  
Subgroup Analyses ◽  
Disease Free ◽  
Arterial Chemoembolization

Background: Although adjuvant transcatheter arterial chemoembolization (TACE) has been used to prevent recurrence after surgery in patients with hepatocellular carcinoma (HCC), the survival benefits from adjuvant TACE remain controversial. We sought to systematically evaluate the data on the effectiveness of adjuvant TACE for HCC, as well as identify patient populations that might benefit from adjuvant TACE. Methods: The PubMed, Embase, Medline and Cochrane library were systematically searched for studies published before July 2019 that compared adjuvant TACE versus surgery alone for HCC. The study endpoints were overall survival (OS) and disease-free survival (DFS). Patients with large HCC (⩾5 cm), multinodular HCC, microvascular invasion (MVI), or portal vein tumor thrombosis (PVTT) were analyzed in subgroup analyses. Results: Twenty-four studies with 6977 patients were included in the analytic cohort. The pooled analysis demonstrated that adjuvant TACE was associated with a better OS and DFS [hazard ratio (HR): 0.67 and 0.67, both p < 0.01]. In subgroup analyses, pooled results revealed that adjuvant TACE was associated with an improved OS and DFS in patients with multinodular HCC (HR: 0.79 and 0.31, both p < 0.01), MVI (HR: 0.62 and 0.67, both p < 0.01), or PVTT (HR: 0.49 and 0.58, both p < 0.01), but not among patients with large HCC (⩾5 cm). Conclusion: Postoperative adjuvant TACE may be effective to improve OS and DFS in patients with multinodular HCC, or HCC with MVI or PVTT. Future randomized controlled trials are needed to better define the benefit of adjuvant TACE in subset patients with HCC.

Laser Influence on Dental Sensitivity Compared to Other Light Sources Used During In-office Dental Bleaching: Systematic Review and Meta-analysis

2020 ◽  
Vol 45 (6) ◽  
pp. 589-597
Author(s):  
BGS Casado ◽  
EP Pellizzer ◽  
JR Souto Maior ◽  
CAA Lemos ◽  
BCE Vasconcelos ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Color Change ◽  
Meta Analysis ◽  
Present Review ◽  
Cochrane Library ◽  
Light Sources ◽  
Eligibility Criteria ◽  
Tooth Color ◽  
Significant Difference ◽  
Meta Analyses

Clinical Relevance The use of laser light during bleaching will not reduce the incidence or severity of sensitivity and will not increase the degree of color change compared with nonlaser light sources. SUMMARY Objective: To evaluate whether the use of laser during in-office bleaching promotes a reduction in dental sensitivity after bleaching compared with other light sources. Methods: The present review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and is registered with PROSPERO (CDR42018096591). Searches were conducted in the PubMed/Medline, Web of Science, and Cochrane Library databases for relevant articles published up to August 2018. Only randomized clinical trials among adults that compared the use of laser during in-office whitening and other light sources were considered eligible. Results: After analysis of the texts retrieved during the database search, six articles met the eligibility criteria and were selected for the present review. For the outcome dental sensitivity, no significant difference was found favoring any type of light either for intensity (mean difference [MD]: −1.60; confidence interval [CI]: −3.42 to 0.22; p=0.09) or incidence (MD: 1.00; CI: 0.755 to 1.33; p=1.00). Regarding change in tooth color, no significant differences were found between the use of the laser and other light sources (MD: −2.22; CI: −6.36 to 1.93; p=0.29). Conclusions: Within the limitations of the present study, laser exerts no influence on tooth sensitivity compared with other light sources when used during in-office bleaching. The included studies demonstrated that laser use during in-office bleaching may have no influence on tooth color change.

scholarly journals Acupuncture for post-stroke depression: a systematic review and meta-analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ran Liu ◽  
Kun Zhang ◽  
Qiu-yu Tong ◽  
Guang-wei Cui ◽  
Wen Ma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Quality Of Evidence ◽  
Post Stroke ◽  
Assessment Development ◽  
Significant Difference ◽  
Post Stroke Depression ◽  
Meta Analyses

Abstract Background Acupuncture for post-stroke depression (PSD) has been evolving, but uncertainty remains. To assess the existing evidence from randomized clinical trials (RCTs) of acupuncture for PSD, we sought to draw conclusions by synthesizing RCTs. Methods An exhaustive literature search was conducted in seven electronic databases from their inception dates to April 19, 2020, to identify systematic reviews (SRs) and meta-analyses (MAs) on this topic. The primary RCTs included in the SRs/MAs were identified. We also conducted a supplementary search for RCTs published from January 1, 2015, to May 12, 2020. Two reviewers extracted data separately and pooled data using RevMan 5.3 software. The quality of evidence was critically appraised with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system. Results A total of 17 RCTs involving 1402 patients were included. Meta-analysis showed that participants who received a combination of acupuncture and conventional treatments exhibited significantly lower scores on the HAM-D17, HAM-D24 and HAM-D (MD, − 5.08 [95% CI, − 6.48 to − 3.67], I2 = 0%), (MD, − 9.72 [95% CI, − 14.54 to − 4.91], I2 = 65%) and (MD, − 2.72 [95% CI, − 3.61 to − 1.82], respectively) than those who received conventional treatment. However, there was no significant difference in acupuncture versus antidepressants in terms of the 17-item, 24-item and HAM-D scales (MD, − 0.43 [95% CI, − 1.61 to 0.75], I2 = 51%), (MD, − 3.09 [95% CI, − 10.81 to 4.63], I2 = 90%) and (MD, − 1.55 [95% CI, − 4.36 to 1.26], I2 = 95%, respectively). For adverse events, acupuncture was associated with fewer adverse events than antidepressants (RR, 0.16 [95% CI, 0.07 to 0.39], I2 = 35%), but there was no significant difference in the occurrence of adverse events between the combination of acupuncture and conventional treatments versus conventional treatments (RR, 0.63 [95% CI, 0.21 to 1.83], I2 = 38%). The quality of evidence was low to very low due to the substantial heterogeneity among the included studies. Conclusions The current review indicates that acupuncture has greater effect on PSD and better safety profile than antidepressants, but high-quality evidence evaluating acupuncture for PSD is still needed.

Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer

2003 ◽  
Vol 13 (4) ◽  
pp. 395-404 ◽  
Author(s):  
B. Winter-Roach ◽  
L. Hooper ◽  
H. Kitchener
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Adjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Early Stage ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Significant Difference ◽  
Well Differentiated ◽  
Platinum Chemotherapy

A systematic review and meta analysis has been undertaken in order to evaluate the effectiveness of adjuvant therapy following surgery for early ovarian cancer. Trials reported since 1990 have been of a higher quality enabling a meta analysis of adjuvant chemotherapy vs adjuvant radiotherapy and a meta analysis of adjuvant chemotherapy vs observation. There was no significant difference between radiotherapy and chemotherapy, though these comprised studies which demonstrated considerable heterogeneity. Chemotherapy did confer significant benefit over observation in terms of both overall and disease free survival. Except for women in whom adequate surgical staging has revealed well differentiated disease confined to one or both ovaries with intact capsule, platinum chemotherapy should be offered to reduce risk of recurrence.

Effectiveness of Single-surface ART Restorations in the Permanent Dentition: A Meta-analysis

2004 ◽  
Vol 83 (2) ◽  
pp. 120-123 ◽  
Author(s):  
J.E. Frencken ◽  
M.A. van ’t Hof ◽  
W.E. van Amerongen ◽  
C.J. Holmgren
Keyword(s):  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Permanent Teeth ◽  
Atraumatic Restorative Treatment ◽  
Restorative Treatment ◽  
The Past ◽  
Significant Difference ◽  
Maximum Period ◽  
Amalgam Restorations ◽  
Late Group

Over the past few years, there has been an increase in the number of studies reporting on various aspects of the Atraumatic Restorative Treatment (ART) approach. Five randomized clinical trials in which ART restorations with glass ionomers were compared with amalgam restorations in permanent teeth for a maximum period of 3 yrs constituted the database. This meta-analysis divided the publications into ‘early’ (1987–1992) and ‘late’ (1995-) studies on the basis of improvements in the approach. The analysis showed that, in the ‘early’ studies, single-surface amalgam restorations survived statistically significantly longer than comparable ART restorations after 1, 2, and 3 yrs. This trend did not continue into the late group of studies; no statistically significant difference between the 2 types of restorations was found. Based on the available data, it appears that there is no difference in survival results between single-surface ART restorations and amalgam restorations in permanent teeth over the first 3 yrs.

scholarly journals Gabapentin as an adjuvant therapy to splinting in carpal tunnel syndrome (CTS): a systematic review and meta-analysis of randomized controlled trials

2020 ◽  
Vol 56 (1) ◽  
Author(s):  
Ahmed M. Ahmed ◽  
Osama G. Hassan ◽  
Ahmed A. Khalifa
Keyword(s):  
Systematic Review ◽  
Carpal Tunnel Syndrome ◽  
Carpal Tunnel ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Pinch Strength ◽  
Symptom Severity Scale ◽  
Significant Difference ◽  
Tunnel Syndrome

Abstract Background Carpal tunnel syndrome (CTS) is a common upper limb entrapment neuropathy; severe cases are treated surgically and mild to moderate can be managed conservatively. The purpose of this systematic review and meta-analysis was to define the efficacy of gabapentin as an adjuvant to splinting in the treatment of mild to moderate CTS. Methods A systematic search through 13 databases, randomized clinical trials (RCTs) reporting the use of gabapentin with splinting in CTS were included and analyzed. Results Three RCTs including 170 patients were eligible. There was no significant difference between gabapentin plus splinting and splinting alone in 5 measured parameters: (1) Symptom Severity Scale (SSS) [MD (95% CI) = − 0.76 (− 2.46–0.93), p = 0.378], (2) Functional Status Scale (FSS) [MD (95% CI) = − 0.23 (− 1.40–0.94), p = 0.701], (3) visual analogue scale (VAS) to assess pain [MD (95% CI) = − 0.6 (− 1.47–0.27), p = 0.174], (4) Grip strength [MD (95% CI) = − 0.11 (− 0.70–0.48), p = 0.718], and (5) pinch strength [MD (95% CI) = 0.72 (− 0.10–1.54), p = 0.083]. Conclusion This review provides low-quality evidence that gabapentin plus nocturnal splinting is not superior to splinting alone. More high-quality trials are needed to determine the role of this drug as an adjuvant in the management of CTS.

Abstract 1122‐000223: Direct to Angiography Suite versus Conventional Imaging in Suspected Large Vessel Occlusion Strokes: A Meta‐Analysis

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Mahmoud H Mohammaden ◽  
Mohamed Elfil ◽  
Mohamed Fahmy Doheim ◽  
Agostinho Camara Pinheiro ◽  
Alhamza R Al‐Bayati ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Functional Independence ◽  
Large Vessel ◽  
Cochrane Library ◽  
Conventional Imaging ◽  
Large Vessel Occlusion ◽  
Vessel Occlusion ◽  
Angiography Suite ◽  
Significant Difference

Introduction : Direct transfer to angiography suite (DTAS) for patients with suspected large vessel occlusion strokes potentially requiring mechanical thrombectomy has been shown to shorten treatment times and improve outcomes compared to conventional imaging (CI) selection. This meta‐analysis compares both approaches to build more concrete evidence. Methods : The potentially relevant studies that were published in four electronic databases/search engines (PubMed, Web of Science, Cochrane Library, and Scopus) till August 2021 were reviewed. Eligible studies were included if they enrolled >10 patients in both groups, were published in English and reported baseline and procedural characteristics and 90‐day outcomes. Relevant data were then extracted and analyzed. Results : Among 4514 searched studies, six qualified for the analysis. Time from door to puncture (MD = ‐26.76minutes, 95 % CI [‐39.48, ‐14.03], P< 0.0001) as well as door to reperfusion (MD = ‐27.21 minutes,95% CI [‐47.42, ‐7.01], P = 0.008) were significantly shorter and the rates of functional independence(mRS0‐2: RR = 1.28, 95% CI [1.03, 1.60], P = 0.03) at 90‐days were significantly higher in the DTAS versus the CI approach. There was no statistically significant difference between DTAS and CI groups in terms of successful reperfusion (modified Thrombolysis In Cerebral Infraction [mTICI] score2B‐3: RR = 0.99, 95% CI [0.93, 1.06], P = 0.86), near complete/ full reperfusion (mTICI 2C‐3: RR = 0.84,95% CI [0.68, 1.04], P = 0.11), or fair outcomes at 90‐days (mRS 0–3: RR = 1.05, 95% CI [0.67, 1.64],P = 0.84). Moreover, there was no difference between groups regarding symptomatic intracranial hemorrhage (RR = 0.81, 95% CI [0.55, 1.17], P = 0.26) or 90 day‐mortality (RR = 0.85, 95% CI [0.59, 1.24],P = 0.41). Conclusions : Our meta‐analysis showed that DTAS significantly improves time metrics and functional outcome with comparable safety to the CI approach. Multicenter randomized clinical trials are ongoing to confirm these results.

scholarly journals Tryptophan Catabolites in Bipolar Disorder: A Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaat Hebbrecht ◽  
Katrien Skorobogatov ◽  
Erik J. Giltay ◽  
Violette Coppens ◽  
Livia De Picker ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Cerebrospinal Fluid ◽  
Methodological Quality ◽  
Meta Analysis ◽  
Random Effect ◽  
Healthy Controls ◽  
Significant Difference ◽  
Subgroup Analyses ◽  
Tryptophan Catabolites

ObjectiveTryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of TRYCAT levels in bipolar disorder (BD) patients compared to healthy controls.MethodsA systematic literature search in seven electronic databases (PubMed, Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier) was conducted on TRYCAT levels in cerebrospinal fluid or peripheral blood according to the PRISMA statement. A minimum of three studies per TRYCAT was required for inclusion. Standardized mean differences (SMD) were computed using random effect models. Subgroup analyses were performed for BD patients in a different mood state (depressed, manic). The methodological quality of the studies was rated using the modified Newcastle-Ottawa Quality assessment Scale.ResultsTwenty-one eligible studies were identified. Peripheral levels of tryptophan (SMD = -0.44; p &lt; 0.001), kynurenine (SMD = - 0.3; p = 0.001) and kynurenic acid (SMD = -.45; p = &lt; 0.001) were lower in BD patients versus healthy controls. In the only three eligible studies investigating TRP in cerebrospinal fluid, tryptophan was not significantly different between BD and healthy controls. The methodological quality of the studies was moderate. Subgroup analyses revealed no significant difference in TRP and KYN values between manic and depressed BD patients, but these results were based on a limited number of studies.ConclusionThe TRYCAT pathway appears to be downregulated in BD patients. There is a need for more and high-quality studies of peripheral and central TRYCAT levels, preferably using longitudinal designs.

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