scholarly journals Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review

Thorax ◽  
2018 ◽  
Vol 74 (3) ◽  
pp. 229-236 ◽  
Author(s):  
Nicola Jane Rowbotham ◽  
Sherie Smith ◽  
Andrew P Prayle ◽  
Karen A Robinson ◽  
Alan Robert Smyth
Keyword(s):  
Cystic Fibrosis ◽  
Systematic Reviews ◽  
Small Sample Size ◽  
Treatment Decisions ◽  
Small Sample ◽  
Multisystem Disorder ◽  
Treatment Interventions ◽  
Registration Number ◽  
Treatment Uncertainties

IntroductionCystic fibrosis (CF) is a multisystem disorder. Treatment is complex and evidence for treatment decisions may be absent. Characterising gaps in the research evidence will highlight treatment uncertainties and help prioritise research questions. We systematically identified the evidence gaps for treatment decisions in CF.MethodsWe searched for systematic reviews and guidelines on treatment interventions in CF. Two researchers identified eligible reviews with arbitration from a third. Using a structured framework, we extracted and characterised evidence gaps.ResultsThere were 73 reviews and 21 guidelines that met our inclusion criteria. From these, we identified 148 evidence gaps across a range of treatment areas. We found 111 evidence gaps through systematic reviews and a further 37 from guidelines. The reason for an evidence gap could only be reliably characterised for systematic reviews. In most cases, there was more than one explanation—most commonly few or no trials (97/111 evidence gaps). Other important factors leading to evidence gaps were small sample size (49/111), inadequate duration of follow-up (38/111) or intervention (37/111) and factors relating to outcomes (35/111). Evidence gaps from both systematic reviews and guidelines fell into the following categories: Respiratory (91); Gastrointestinal (20); PhysiotherapyandExercise (16); Musculoskeletal (6); Endocrine (4); Basic defect of CF (8); Psychosocial (2); Ears, Nose and Throat (1).ConclusionsWe have compiled an up-to-date list of treatment uncertainties in CF and the reasons for these uncertainties. These can be used as a resource to aid researchers and funders when planning future trials.PROSPERO registration numberPre-results; CRD42015030111.

scholarly journals Influenza Virus Detection Following Administration of Live-Attenuated Intranasal Influenza Vaccine in Children With Cystic Fibrosis and Their Healthy Siblings

2016 ◽  
Vol 3 (4) ◽  
Author(s):  
Constantina Boikos ◽  
Lawrence Joseph ◽  
Christine Martineau ◽  
Jesse Papenburg ◽  
David Scheifele ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Sample Size ◽  
Virus Detection ◽  
Credible Interval ◽  
Small Sample ◽  
Influenza Viruses ◽  
Study Cohort ◽  
Rt Pcr ◽  
Rna Detection

Abstract Background.  We aimed to explore the detection profile of influenza viruses following live-attenuated intranasal influenza vaccination (LAIV) in children aged 2–19 years with and without cystic fibrosis (CF). Methods.  Before the 2013–2014 influenza season, flocked nasal swabs were obtained before vaccination and 4 times in the week of follow-up from 76 participants (nCF: 57; nhealthy: 19). Influenza was detected by reverse transcription polymerase chain reaction (RT-PCR) assays. A Bayesian hierarchical logistic regression model was used to estimate the effect of CF status and age on influenza detection. Results.  Overall, 69% of the study cohort shed influenza RNA during follow-up. The mean duration of RT-PCR detection was 2.09 days (95% credible interval [CrI]: 1.73–2.48). The odds of influenza RNA detection on day 1 following vaccination decreased with age in years (odds ratio [OR]: 0.82 per year; 95% CrI: 0.70–0.95), and subjects with CF had higher odds of influenza RNA detection on day 1 of follow-up (OR: 5.09; 95% CrI: 1.02–29.9). Conclusion.  Despite the small sample size, our results indicate that LAIV vaccine strains are detectable during the week after LAIV, mainly in younger individuals and vaccinees with CF. It remains unclear whether recommendations for avoiding contact with severely immunocompromised patients should differ for these groups.

scholarly journals Assessing Biomarkers of Breast Cancer Risk in Underserved Women in a Midwestern County

2021 ◽  
Vol 12 ◽  
pp. 215013272110177
Author(s):  
Marla A. DeWitt ◽  
Ivana T. Croghan ◽  
Celine M. Vachon ◽  
Thomas D. Thacher ◽  
Marcia R. Venegas Pont ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mammographic Density ◽  
Small Sample Size ◽  
Vitamin D Insufficiency ◽  
Screening Mammography ◽  
Small Sample ◽  
Vitamin D Status ◽  
Small Pilot Study ◽  
Unexpected Findings

Objective: The primary aim of this study was to evaluate the feasibility of collecting risk factor information and accessing digitized mammographic data in a medically marginalized population. A secondary aim was to examine the association between vitamin D status and mammographic density. Methods: Breast-screening examinations were provided for age-appropriate patients, and a referral for no-cost screening mammography was offered. Study participants were asked to undergo 25-hydroxyvitamin D testing at mammography and 1-year follow-up. Results: Of 62 women approached, 35 (56%) consented to participate. Of 32 participants who had baseline mammography, the median mammographic density measured by VolparaDensity (Volpara Solutions Limited) was 5.7%. After 1 year, 9 women obtained follow-up mammograms, with a median density of 5.7%. Vitamin D status was measured for 31 participants at baseline and 13 participants in the following year. Insufficient vitamin D status (<30 ng/mL) was noted in 77% at each time point. Mammographic density was not significantly correlated with vitamin D status ( P = .06). Conclusions: On the basis of this small pilot study, vitamin D insufficiency is common in this study population. Owing to the small sample size, an association between vitamin D insufficiency and breast density was not clear. Additional unexpected findings included substantial barriers in initial access to care and longitudinal follow-up in this population. Further study of these issues is needed.

Role of multiparametric MRI in long-term surveillance following focal laser ablation of prostate cancer

2021 ◽  
pp. 20210414
Author(s):  
Mark Paxton ◽  
Eitan Barbalat ◽  
Nathan Perlis ◽  
Ravi J Menezes ◽  
Mark Gertner ◽  
...  
Keyword(s):  
Laser Ablation ◽  
Recurrent Disease ◽  
Small Sample Size ◽  
Focal Therapy ◽  
Outcome Data ◽  
Small Sample ◽  
Restricted Diffusion ◽  
Treatment Site ◽  
Imaging Characteristics

Objective: Determine the multiparametric magnetic resonance imaging (mpMRI) appearance of the prostate following focal laser ablation (FLA) for PCa and to identify imaging characteristics associated with recurrent disease. Methods: Retrospective analysis of patients who underwent FLA for low-intermediate risk PCa between 2010 and 2014 was performed. Early (median 4 months) and late mpMRI (median 49 months) follow-up were qualitatively assessed for T2-weighted, dynamic contrast enhanced (DCE) and diffusion weighted imaging (DWI) appearances and also compared to corresponding PSA values and biopsy results. Results: 55 cancers were treated in 54 men (mean age 61.0 years). Early mpMRI was performed in 30 (54.5%) patients while late follow-up mpMRI in 42 (84%). Ill-defined scarring with and without atrophy at the treatment site were the most common appearances. In patients with paired MRI and biopsy, one of four patients with clinically significant PCa on biopsy (≥GG2 or≥6 mm GG1) showed hyperenhancement or restricted diffusion at early follow-up. At late follow-up, positive biopsies were seen in 5/8 (63%) cases with hyperenhancement and 5/6 (83%) cases with restricted diffusion at the treatment site. PSA change was not associated with biopsy results at either time point. Conclusion: mpMRI is able to document the morphological and temporal changes following focal therapy. It has limited ability to detect recurrent disease in early months following treatment. Late-term mpMRI is sensitive at identifying patients with recurrent disease. Small sample size is, however, a limitation of the study. Advances in knowledge: Implementing MRI in follow-up after FT may be useful in predicting residual or recurrent PCa and therefore provide reliable outcome data.

scholarly journals Prevalence, Symptoms and Duration of Post Acute Effects in SARS-CoV-2 Positive Children – a Nationwide Cohort Study

2021 ◽  
Author(s):  
Luise Borch ◽  
Mette Holm ◽  
Maria Knudsen ◽  
Svend Ellermann-Eriksen ◽  
Soeren Hagstroem
Keyword(s):  
Cohort Study ◽  
Muscle Weakness ◽  
School Children ◽  
Small Sample Size ◽  
Risk Difference ◽  
Small Sample ◽  
Control Group ◽  
Respiratory Problems ◽  
Danish Health ◽  
Registration Number

Abstract Background: Most children have a mild course of acute COVID-19, but only a few mainly non-controlled studies with small sample size, have evaluated the long-term recovery from SARS-CoV-2 infection in children (‘long COVID’).Methods: We conducted a nationwide cohort study of 37,522 children age 0-17 years with RT-PCR verified SARS-CoV-2 infection and a control group of 78,037 randomly selected children. An electronic questionnaire was sent to both groups of children from March 24th until May 9th 2021.Results: Long COVID symptoms were reported by 12-51% of SARS-CoV-2 infected children. Among pre-school children, fatigue Risk Difference (RD) 0.05 (CI 0.04-0.06), loss of smell RD 0.01 (CI 0.01-0.01), loss of taste RD 0.01 (CI 0.01-0.02) and muscle weakness RD 0.01 (CI 0.00-0.01) were statistically significant symptoms of ‘long COVID’.Among school children the most significant symptoms were loss of smell RD 0.12 (CI 0.12-0.13), loss of taste RD 0.10 (CI 0.09-0.10), fatigue RD 0.05 (CI 0.05-0.06), respiratory problems RD 0.03 (CI 0.03-0.04), dizziness RD 0.02 (CI 0.02-0.03), muscle weakness RD 0.02 (CI 0.01-0.02), and chest pain RD 0.01 (CI 0.01-0.01). Children in the control group experienced significantly more concentration difficulties, headache, muscle- and joint pain, cough, nausea, diarrhea and fever than the SARS-CoV-2 infected. In most children ‘long COVID’ symptoms resolved within 1-5 months.Conclusions: This study provides new evidence of ‘long COVID’ symptoms in children.Trial registration number: The study was approved by The Danish Health Data Authority and registered at Central Denmark region (# 1-16-02-621-20).

Utility of chemotherapy given before and/or after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal adenocarcinoma with peritoneal metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16276-e16276
Author(s):  
Tyler Friedrich ◽  
Junxiao Hu ◽  
Robert William Lentz ◽  
Alexis Diane Leal ◽  
Sunnie S. Kim ◽  
...  
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Small Sample Size ◽  
Peritoneal Metastases ◽  
Small Sample ◽  
Histologic Grade ◽  
Low Grade ◽  
Appendiceal Adenocarcinoma

e16276 Background: Appendiceal adenocarcinoma is relatively rare and often diagnosed incidentally during operations for acute appendicitis. It is commonly associated, either at time of initial presentation or upon recurrence, with peritoneal metastases. A typical treatment strategy for patients with peritoneal disease includes cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Extrapolating largely from literature in colorectal cancer, chemotherapy is frequently given before and/or after CRS/HIPEC though high-level evidence to support this is lacking. We sought to evaluate the effect of systemic chemotherapy on survival. Methods: Utilizing a database of CRS/HIPEC procedures at University of Colorado Hospital from 2008 to present we retrospectively reviewed cases of appendiceal adenocarcinoma. Data collected included staging, histologic grade, chemotherapy given, surgical outcomes, and time to disease recurrence. Patients without adequate information regarding treatment, or without at least 1 year of clinical follow-up, were excluded. Associations between administration of chemotherapy or histologic grade and 1-year DFS were analyzed using Fisher’s exact test, and logistic regression was used to assess whether 1-year DFS were different in chemotherapy-treated patients when adjusted for histologic grade. Results: In total, 117 cases reviewed indicated an appendiceal pathology. Of these, 54 cases in a total of 51 patients met the specified criteria for pathology and completeness and length of follow-up information. The average age was 58 years (range 26-81 years). Adenocarcinoma was graded as low in 15 (28%) cases, intermediate in 18 (33%) cases, and high in 21 (39%) cases. 23 (43%) patients received no chemotherapy while 31 (57%) received chemotherapy before and/or after surgery. In the overall population, there was no significant effect of chemotherapy on survival, with 1-year DFS demonstrated in 74.2% of patients receiving some chemotherapy and 70% in patients not receiving chemotherapy (p = 0.765). One-year DFS was achieved in 86% of low-grade cases, 61% of intermediate-grade cases, and 71% of high-grade cases, though this was also not statistically significant (p = 0.254). Furthermore, when 1-year DFS between chemotherapy and non-chemotherapy patients was adjusted for grade, there was again no significant interaction (odds ratio = 0.48, 95% C.I. (0.13-1.64), p = 0.763). Conclusions: In this small, single-institution experience of patients with peritoneal appendiceal adenocarcinoma, there was no significant effect of chemotherapy administration on 1-year DFS. These findings are likely affected by significant confounding with the small sample size and retrospective nature of the data. Further investigation on a larger scale is warranted.

A comparative assessment of orthodontic treatment outcomes using the quantitative light-induced fluorescence (QLF) method between direct bonding and indirect bonding techniques in adolescents: a single-centre, single-blind randomized controlled trial

2019 ◽  
Vol 42 (4) ◽  
pp. 441-453
Author(s):  
Aykan Onur Atilla ◽  
Taner Ozturk ◽  
Mustafa Murat Eruz ◽  
Ahmet Yagci
Keyword(s):  
Orthodontic Treatment ◽  
Small Sample Size ◽  
Controlled Trial ◽  
Small Sample ◽  
White Spot Lesion ◽  
Indirect Bonding ◽  
Signed Rank ◽  
Group 12 ◽  
Registration Number ◽  
Bonding Technique

Summary Introduction The aim of this two-arm parallel trial was to evaluate enamel demineralization in fixed orthodontic treatment using an indirect bonding technique in comparison to a direct bonding technique by the quantitative light-induced fluorescence (QLF) method. Design, settings and participants Fifty-six patients who needed fixed orthodontic treatment were randomly separated into either the direct bonding group or the indirect bonding group. The presence and extent of lesions on the buccal surfaces of all teeth, except the molar teeth, were assessed. The percentage of fluorescence loss (ΔF and ΔFmax), the degree of demineralization (ΔQ) and lesion area (WS area) were determined using the system’s software. The data were analysed with the Wilcoxon signed-rank and Mann–Whitney U-tests (P &lt; 0.05). Interventions Treatment with a direct bonding or an indirect bonding technique. Results This study was completed with 25 patients in the indirect bonding group (12 females, 13 males; mean age: 15.42 ± 1.71 years) and 26 patients in the direct bonding group (12 females, 14 males; mean age: 14.73 ± 1.65 years). In the indirect bonding technique, a few teeth (especially mandibular left canine: 50.45 ± 93.48; 95% confidence interval: −12.35 and 113.26) were found to develop significant white spot lesion (WSL) formation (P &lt; 0.05). However, the number of teeth with demineralization was higher in the direct bonding group (P &lt; 0.05). Conclusion The bonding procedures used in the indirect bonding technique contribute to reducing the degree of WSL formation. Further, the use of flowable composite adhesives in this bonding process is more effective at reducing the appearance of WSLs than in cases where conventional composite adhesives are used. Limitations The limitation of our trial may be the small sample size and the short follow-up time for the patients. Harms No harms were detected during the study. Protocol The protocol was not published before trial commencement. Registration This trial was registered post hoc at ‘Clinical Trials’ (http://www.clinicaltrials.gov), registration number (ID): NCT03738839.

scholarly journals Uterus transplantation: joys and frustrations of becoming a ‘complete’ woman—a qualitative study regarding self-image in the 5-year period after transplantation

2020 ◽  
Vol 35 (8) ◽  
pp. 1855-1863 ◽  
Author(s):  
Stina Järvholm ◽  
Anders Enskog ◽  
Catrina Hammarling ◽  
Pernilla Dahm-Kähler ◽  
Mats Brännström
Keyword(s):  
Small Sample Size ◽  
Small Sample ◽  
Post Transplantation ◽  
Uterus Transplantation ◽  
Self Image ◽  
Registration Number ◽  
Competing Interest ◽  
The Government

Abstract STUDY QUESTION How is a women’s self-image affected by uterus transplantation (UTx)? SUMMARY ANSWER Women experienced receiving a uterus in both positive and negative ways, but in general, their self-image was positively affected; regardless of whether they have given birth to a child or not, recipients describe themselves as being ‘back to normal’ after the hysterectomy to remove the transplanted uterus. WHAT IS KNOWN ALREADY UTx has repeatedly proved to be a successful treatment for absolute uterine factor infertility. However, there has been no previous qualitative long-term research into the self-image of women undergoing UTx. STUDY DESIGN, SIZE, DURATION This complete, prospective cohort study included the nine recipients of the first UTxs performed in Sweden mostly in 2013. Interviews took place in the 5 years following surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS Eight out of the nine recipients had congenital absence of the uterus, a characteristic of Mayer–Rokitansky–Küster–Hauser syndrome, and one recipient lacked a uterus after a radical hysterectomy due to cervical cancer. The mean age of participants was 31.5 years at inclusion and at this time they all lived in stable marital relationships. Post-transplantation, interviews were performed annually for 5 years, comprising a total of 43 interviews. The interview followed a semi-structured guide. All interviews (median duration of around 25 minutes) were recorded, transcribed verbatim and then analysed by thematic approach. MAIN RESULTS AND THE ROLE OF CHANCE The joys and frustrations of becoming a ‘complete’ woman are seen as a master theme, which influences the three underlying subthemes, a changed self-perception, a changed body and a changed sexuality. Each of these subthemes have three underlying categories. LIMITATIONS, REASONS FOR CAUTION The small sample size is a limitation. WIDER IMPLICATIONS OF THE FINDINGS The results provide information that will be helpful in pre-operative screening procedures and in the psychological support offered both to women who experienced successful and unsuccessful outcomes following UTx. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Jane and Dan Olsson Foundation for Science; the Knut and Alice Wallenberg Foundation; an ALF grant from the Swedish state under an agreement between the government and the county councils; the Swedish Research Council; a Ferring Pharmaceuticals scholarship in memory of Robert Edwards; and the Iris Jonzén-Sandblom and Greta Jonzén Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER NCT01844362.

scholarly journals Usefulness of mycophenolate mofetil in Indian patients with C3 glomerulopathy

2018 ◽  
Vol 12 (4) ◽  
pp. 483-487 ◽  
Author(s):  
Joyita Bharati ◽  
Karalanglin Tiewsoh ◽  
Ashwani Kumar ◽  
Ritambhra Nada ◽  
Manish Rathi ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Small Sample Size ◽  
Initial Response ◽  
Immunosuppressive Agent ◽  
Small Sample ◽  
C3 Glomerulopathy ◽  
Standardized Treatment ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background C3 glomerulopathy (C3G) is a heterogeneous disease caused by alternative complement pathway abnormalities without any standardized treatment. An immunosuppressive agent, mycophenolate mofetil (MMF), has been recently shown to be useful in treating C3G, mainly in studies from the west. We report the clinical outcome of 17 Indian C3G patients treated with MMF with or without steroids. Methods The clinical and histology details of the C3G patients treated with MMF for at least 6 months with a follow-up of at least 12 months were retrieved from the medical records of our center. Results The median serum creatinine and proteinuria at presentation were 0.8 mg/dL and 3.7 g/day, respectively, with the majority (88.2%) presenting as nephrotic syndrome. The mean dose of MMF was 1.65 (±0.56) g/day, and the median duration of MMF therapy was 18 months. Two-thirds (64%) of the patients responded to the treatment, with complete remission in 4 (23%) and partial remission in 7 (41%) (median time: 9 months). Three patients progressed to end-stage renal disease (ESRD) on follow-up. Of the three patients, one (33%) had an initial response in proteinuria to MMF but did not respond after a relapse and subsequently progressed to ESRD and two (67%) other patients were nonresponsive to MMF from the start of the therapy. Conclusion Despite a small sample size and lack of a control arm, this study describes the effectiveness of MMF in treating C3G patients from Asia and forms a basis for future randomized trials.

Improved Postoperative Survival for Intraductal- Growth Subtype of Intrahepatic Cholangiocarcinoma

2016 ◽  
Vol 82 (11) ◽  
pp. 1133-1139 ◽  
Author(s):  
Laura L. Dover ◽  
Rojymon Jacob ◽  
Thomas N. Wang ◽  
Joseph H. Richardson ◽  
David T. Redden ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Small Sample Size ◽  
Tumor Stage ◽  
Small Sample ◽  
Postoperative Survival ◽  
Rank Test ◽  
Intraductal Growth ◽  
Kaplan Meier ◽  
Disease Free

Intrahepatic cholangiocarcinoma (ICC) is classified according to the following subtypes: mass-forming (MF), periductal infiltrating (PI), and intraductal growth (IG). The aim of this study is to measure the association between ICC subtypes and patient survival after surgical resection. Data were abstracted on all patients treated with definitive resections of ICC at a single institution between 2000 and 2011 with at least three years follow-up. Survival estimates were quantified using Kaplan-Meier curves and compared using the log-rank test. There were 37 patients with ICC treated with definitive partial hepatectomies with a median survival of 33.5 months. Tumor stage (P < 0.0001), satellitosis (P < 0.001), lymphovascular space invasion (P = 0.003), and macroscopic subtype (P = 0.003) were predictive of postoperative survival. Disease-free survivals for MF, PI, and IG subtypes, respectively, were 30 per cent, 0 per cent, and 57 per cent (P = 0.017). Overall survivals among ICC macroscopic subtypes were as follows: MF 37 per cent, PI 0 per cent, and IG 71 per cent (P = 0.003). Although limited by the small sample size of this rare cancer, this study demonstrates significant differences among macroscopic subtypes of ICC in both disease-free survivals and overall survivals after definitive partial hepatectomy.

Aortic Valve Intervention During Aortic Root Surgery in Children: A Systematic Review

2020 ◽  
Vol 11 (5) ◽  
pp. 611-618
Author(s):  
Maria Rodriguez ◽  
Anahita Malvea ◽  
Dayre McNally ◽  
Vid Bijelic ◽  
Ming Guo ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Root ◽  
Small Sample Size ◽  
Case Series ◽  
Small Sample ◽  
Aortic Root Surgery ◽  
Valve Sparing ◽  
One Year

Background: Pediatric aortic root dilatation is a life-threatening condition that lacks guidelines for surgical management. We aimed to analyze the data on aortic valve interventions during root surgery to guide decision-making. Methods: A search was performed of MEDLINE, Embase, CENTRAL, ClinicalTrials.gov , and WHO ICTRP. Citations were screened in duplicate and independently to identify randomized controlled trials, cohorts, and case series involving populations aged 0 to 18 years, who received valve-sparing and valve-replacing aortic root surgeries between 1999 and 2019. Outcomes considered included mortality (perioperative, one year, five year), reintervention rates. Results: After duplicate removal, 689 citations were screened through abstract and full text review, identifying five eligible studies. All five were observational studies evaluating valve-sparing procedures. There were 81 patients with a mean study age range of 9.9 to 13.9 years. Both reimplantation (74%) and remodeling (26%) subtypes were done. Range of mean duration of follow-up was 1.2 to 4.4 years. There was no mortality reported until the one-year follow-up period. The long-term mortality rate was calculated as 0.02 per patient-year (95% CI: 0.01-0.05). The long-term reintervention rate was 0.08 per patient-year (95% CI: 0.05-0.13). Conclusions: There is limited experience on aortic valve intervention during aortic root surgery in children. Single-arm studies on valve-sparing surgeries show excellent survival up to one year. Mortality and reintervention rates increase in the longer term. The small sample size and lack of controlled studies do not allow for direct comparisons between procedure types.

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