9 research outputs found

    Blinding in randomized control trials: the enigma unraveled.

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    The search for new treatments and testing of new ideas begins in the laboratory and then established in clinical research settings. Studies addressing the same therapeutic problem may produce conflicting results hence Randomised Clinical Trial is regarded as the most valid method for assessing the benefits and harms of healthcare interventions. The next challenge face by the medical community is the validity of such trials as theses tend to deviate from the truth because of various biases. For the avoidance of the same it has been suggested that the validity or quality of primary trials should be assessed under blind conditions. Thus blinding, is a crucial method for reducing bias in randomized clinical trials. Blinding can be defined as withholding information about the assigned interventions from people involved in the trial who may potentially be prejudiced by this knowledge. In this article we make an effort to define blinding, explain its chronology, hierarchy and discuss methods of blinding, its assessment, its possibility, un-blinding and finally the latest guidelines

    Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

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    Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

    Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

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    Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

    Assessment of Folic Acid Supplementation in Pregnant Women by Estimation of Serum Levels of Tetrahydrofolic Acid, Dihydrofolate Reductase, and Homocysteine

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    Background. Status of folic acid use in pregnant women of the hilly regions in North India was little known. This study was carried out to assess the folic acid use and estimate folate metabolites in pregnant women of this region. Materials and Methods. This cross-sectional study is comprised of 76 pregnant women, whose folic acid supplementation was assessed by a questionnaire and serum levels of homocysteine, tetrahydrofolic acid (THFA), and dihydrofolate reductase (DHFR) were estimated using Enzyme Linked Immunoassays. Results. The study data revealed awareness of folic acid use during pregnancy was present in 46.1% and 23.7% were taking folic acid supplements. The study depicted that there was no statistically significant difference between serum levels of THFA and DHFR in pregnant women with and without folic acid supplements (p=0.790). Hyperhomocysteinemia was present in 15.78% of the participants. Conclusion. Less awareness about folic acid supplementation and low use of folic acid by pregnant women were observed in this region. Sufficient dietary ingestion may suffice for the escalated requirements in pregnancy, but since this cannot be ensured, hence folic acid supplementation should be made as an integral part of education and reproductive health programs for its better metabolic use, growth, and development of fetus

    Severity of Vitamin D Deficiency in Children with Nephrotic Syndrome: A Study from Tertiary Care Center in Northern India

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    In nephrotic syndrome (NS) due to podocytopathies, loss of vitamin D binding globulin along with albumin in urine leads to Vitamin D deficient state. We aimed to study the severity of vitamin D deficiency and its clinical correlation in children with NS. We performed a cross-sectional study at a tertiary care hospital in Northern India. Enrolment of children aged 1–18 years was done. Patient's detailed history, numbers of relapse, treatment details, and data regarding various immunomodulatory drugs treatment. Vitamin D level was estimated, and its status was further classified as deficiency <20 ng/mL and insufficiency 20–30 ng/mL as per Global Consensus Recommendations on evaluation, treatment, and prevention of vitamin D deficiency. Continuous variables were compared using tests such as unpaired t-test, Kruskal–Wallis test, and Wilcoxon rank sum test depending on the distribution of parameters. Categorical variables were compared using Chi-squared tests or Fisher's exact test. A total of 96 children with NS were screened, of which 77.1% had vitamin D deficiency. The mean serum vitamin D level was 14.393 ± 8.52 ng/mL. Among the 48 children of the first episode of NS 36 were deficient (36/48 = 75%). Whereas in the relapse category, 30 patients had infrequently relapsing NS (deficient 24/30 = 80%). Eleven children had frequently relapsing NS; among them, 10 were vitamin D deficient (10/11 = 90.9%), and there was a negative correlation between vitamin D level and duration of illness. Vitamin D deficiency is a common comorbidity in children with NS. Given the putative immunomodulatory property of vitamin D, this deficiency should be identified and treated routinely in all cases of NS

    Association Of the Methylene Tetrahydrofolate Reductase (MTHFR) Gene Polymorphism with Susceptibility to Recurrence of Cardiovascular Outcomes Among Ischemic Stroke- A Randomized Controlled Trial

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    Background: Hyperhomocystenemia and genetic variants are factors for causing young age stroke globally. This study aims to identify homocysteine related-MTHFR gene polymorphism that associated with recur-rent cardiovascular outcomes. Methodology: A randomized controlled trial conducted upon 90 hyperhomocysteinemic ischemic stroke patients were taken from the neurology wards of a tertiary care hospital were randomly selected into vita-min B therapy group and control groups (n=45 in each group). Baseline subject details were collected ve-nous blood sample for MTHFR genetic testing via PCR-RFLP technique along with blood homocysteine lev-els, vitamin B12, folic acid levels. Results: The results showed that the frequency of CT genotype polymorphism was 15.5% vs 13.3% for the MTHFR C677T gene without any significant difference between vitamin group and control group respective-ly (p-value >0.05). The reduction in mean homocysteine up to -6.77±4.50 versus -2.08±0.71 µmol/L in the vitamin group as compared to control group respectively, p value 0.001. Conclusion: Considerable amount of MTHFR gene polymorphism found among hyperhomocysteinemic is-chemic stroke of sub-Himalayan region. Nutritional deficiencies including vitamin B 12 & folic acid, and some hidden reasons found, which could lead to the primary cause of hyperhomocysteinemia. Vitamin B therapy is an effective for reducing homocysteine

    Metabolic evaluation of first-time uncomplicated renal stone formers: A prospective study

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    Abstract. Background. Nephrolithiasis is a global health problem. The recurrence rate after the first stone clearance is approximately 50% at 5 years. Metabolic abnormalities are an important factor responsible for stone recurrence. Our prevalidated study aimed to evaluate metabolic abnormalities associated with first-time uncomplicated renal stone formers (FTURSF). Materials and methods. In this prospective, exploratory, time-bound, descriptive study, 30 first-time renal stone formers were evaluated for metabolic abnormalities. High-risk stone formers were excluded from the study. Data were collected in a predefined proforma, transferred to an Excel sheet, and analyzed using the Statistical Package for Social Sciences 20 and Epi Info 7. Fisher exact test, Mann-Whitney U test, paired t test, and Pearson correlation coefficient were used for statistical analyses. Results. The mean age of the participants was 35.57 ± 11.07 years, with a male-to-female ratio of 1.72. The most common abnormality was a 24-hour urine volume of <2.5 L in 73.33% of the participants. One or more metabolic abnormalities were detected in 76.67% of the participants. Other common metabolic abnormalities detected were hypocitraturia (60%), hypercalciuria (16.67%), hyperoxaluria (13.33%), and hyperuricosuria (3.33%). Parathyroid adenoma was detected in one participant (3.33%). Conclusions. Our study documented significant metabolic abnormalities in FTURSF. Therefore, a simplified metabolic evaluation protocol should be adopted while evaluating FTURSF. Detection of an underlying metabolic abnormality would enable the early institution of preventive measures to reduce stone recurrence and related complications

    Genetic Variations in IL-1β, TNF-α, and TGF-β Associated with the Severity of Chronic Cervical Spondylitis in Patients

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    Chronic cervical spondylitis (CCS), a degenerative disorder of the spine, is known for causing disability among old and young people. Single-nucleotide polymorphisms (SNPs) in various cytokine genes have demonstrated an impactful association with several inflammatory disorders. In the present study, we have investigated the SNPs and allelic distribution of the three most prevalent cytokines genes, IL-1β (-511C/T), TNF-α (-308G/A), and TGF-β (-509C/T), along with serum levels of these cytokines in 252 subjects. SNPs were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and digested fragments were separated and visualized using agarose gel electrophoresis and Native Polyacrylamide gel electrophoresis (PAGE). The serum cytokine levels were analyzed with a flow cytometer using a customized multiplex bead-based assay. It was observed that these SNPs did not reflect the susceptibility to CCS but were associated with susceptibility to CCS. We found a significant association between the C/C and G/G genotypes and the C and G alleles of IL-1β and TNF-α, respectively, suggesting a lower risk of CCS. The frequency distribution of risk alleles (-511T) and (-308A) were simultaneously higher in CCS compared to the control, reflecting the susceptibility to CCS. TGF-β showed a significant association with disease susceptibility, along with a significant correlation between age and the chronicity of CCS. The serum cytokine levels were significantly different in CCS and controls

    Exploring the Immunomodulatory Aspect of Mesenchymal Stem Cells for Treatment of Severe Coronavirus Disease 19

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    Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2–14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration
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