Disinformation about COVID-19 Preventions and Treatments: Analysis of USFDA Warning Letters.

COVID-19 poses a challenge beyond the virus itself, in that lockdown has been associated increased use of the internet and social media. Disinformation about prevention and treatment strategies for COVID-19 can have lethal consequences. The United States Food and Drug Administration (USFDA) is currently monitoring the compliance of manufacturing firms as well as medicinal product advertisers to the Federal Food, Drug, and Cosmetic Act, 21 USC § 321(h) regulations. In the event of noncompliance in the form of advertising products without prior USFDA approval for specific indications, doses, or route of administration, warning letters (WLs) are issued. WLs are intended to address the concerns identified by USFDA and encourage the recipient to take corrective steps to avoid similar instances in the future. We analyzed 182 WLs that were issued for noncompliance with drugs/devices related to either treatment, prevention, or testing of COVID-19 infections. The medicinal product website was identified as the major source of disinformation, followed by disseminated information on Facebook, Twitter, and Instagram. Nearly four-fifths were related to drugs, followed by devices and biologicals. Several biologicals, as well as allopathic, herbal, and non-herbal drugs were identified in the WLs. We observed that noncompliance with the USFDA regulations in terms of advertising a variety of products for prevention and treatment of COVID-19 infection was widely prevalent. More efforts are required by the respective national drug regulatory authorities to initiate or continue their monitoring of disinformation that may have lethal consequences.

Comparative assessment of interventions for treating cutaneous leishmaniasis: A network meta-analysis of randomized clinical trials.

INTRODUCTION: Various interventions including laser therapy, heat therapy, and several drugs have been trialed in patients with cutaneous leishmaniasis. Due to the lack of an evidence-based comparison of all these interventions, we carried out the present network meta-analysis. METHODS: Electronic databases were searched for randomized clinical trials evaluating the efficacy and safety of any interventions in patients with cutaneous leishmaniasis. The proportion of patients with complete cure was the primary outcome. The proportion of lesions cured at the end of treatment, the proportion of lesions with minimal/no response to treatment, and proportion of wounds with minimal/no change were the secondary outcomes. Random-effects modeling was used for generating pooled estimates. Rankogram plot was used for identifying the 'best intervention'. For interventions containing a combination of treatments, backslash (/) has been used for depicting the same. RESULTS: One-hundred and thirty-one studies were included. Intralesional meglumine, topical paromomycin/gentamicin, topical paromomycin, parenteral sodium stibogluconate, topical honey/intralesional meglumine, topical liposomal amphotericin B, oral zinc sulphate, oral miltefosine, parenteral meglumine, heat therapy, topical liposomal azithromycin, intralesional meglumine/silver dressing, intralesional sodium stibogluconate, parenteral meglumine/intralesional meglumine, oral allopurinol/parenteral meglumine, topical trichloroacetic acid/heat therapy, oral zinc sulphate/oral ketoconazole, topical imiquimod/cryotherapy, intralesional meglumine/cryotherapy, topical herbal extract of Z-HE, parenteral pentamidine, topical trichloroacetic acid/intralesional meglumine, carbon-dioxide laser, topical recombinant granulocyte-macrophage colony-stimulating factor/parenteral meglumine, intralesional dapsone, carbon-dioxide laser/intralesional meglumine, moist wet dressing with sodium hypochlorite, parenteral sodium stibogluconate/intralesional recombinant granulocyte-macrophage colony-stimulating factor, oral dapsone, intralesional sodium stibogluconate/oral ketoconazole, intralesional sodium stibogluconate/parenteral sodium stibogluconate and electrocautery/moist wet dressing with sodium hypochlorite were observed with significantly greater proportion of patients with complete cure compared to placebo/untreated controls. Rankogram analysis revealed that parenteral pentamidine has the highest statistical probability of being the best in the pool. CONCLUSION: We observed several interventions to be effective for treating cutaneous leishmaniasis. However, greater caution is required in interpreting the results as the estimates are likely to change with the advent of results from future studies.

Adjuvant interventions with opioids for vaso-occlusive crisis in sickle cell disease: A mixed treatment network meta-analysis of randomized controlled clinical trials.

OBJECTIVE: Vaso-occlusive crisis is the most common clinical feature requiring opioid analgesics in patients with sickle cell disease. We conducted a network meta-analysis to compare the drugs that can be used as add-on with opioids for vaso-occlusive crisis. DESIGN: Network meta-analysis of randomized clinical trials. PATIENTS: Sickle cell disease patients with vaso-occlusive crisis receiving adjuvants to opioids for pain management. MAIN OUTCOME MEASURES: A number of patients with complete pain relief and pain scores assessed either by visual ana-log or by a numerical rating scale were the primary outcomes. Adverse events and dose of opioids (in morphine equiva-lents) for pain alleviation between the treatment arms were the secondary outcome measures. RESULTS: Eleven studies evaluating the addition of ketorolac, magnesium sulfate, ketoprofen, ibuprofen, methadone, inhalational nitric oxide, methylprednisolone, and arginine with morphine were obtained. The pooled analysis showed a favorable effect in the pain reduction for the additions of arginine {-2 [-3.39, -0.61]} and ibuprofen {-1.7 [-3.26, -0.14]} with morphine. Arginine has high probability of being the "best" in the pool followed by ibuprofen. No significant differ-ences were observed in the risk of adverse events {ketoprofen-0.84 [0.42, 1.65]; magnesium sulfate-1.81 [0.64, 5.81]; and arginine-2.08 [0.18, 24.31]}. A significant lower dose of opioid was required when given adjunctive to argin-ine, inhalational nitric oxide, and methylprednisolone. CONCLUSION: We observed that arginine and ibuprofen could produce additional analgesic effects when combined with morphine in vaso-occlusive crisis.

Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials.

Background: Several interventions were explored in clinical trials for treating hyperemesis gravidarum (HG). The present study is a network meta-analysis of such interventions.Methods: Electronic databases were searched for appropriate randomized clinical trials comparing interventions for treatment of patients with HG. Control of HG symptoms was the primary outcome and emetic episodes, hospital stay, nausea scores, patients requiring rescue antiemetics, hospital readmission, adverse events, and adverse pregnancy outcomes were the secondary outcome measures. Random-effects model was used and odds ratio (OR) [95% confidence interval (CI)] was the effect estimate for categorical outcomes and weighted mean difference (WMD) [95% confidence interval] for numerical outcomes.Results: Twenty studies were included in the systematic review and 18 in the meta-analysis. Acupuncture (OR: 18.9; 95% CI: 2.1, 168), acupressure (OR: 26.7; 95% CI: 2.5, 283.1) and methylprednisolone (OR: 6.7; 95% CI: 1.1, 38.8) were associated with better control of HG symptoms than standard of care. Acupressure decreases the requirement of rescue antiemetics (OR: 0.06; 95% CI: 0.01, 0.44); ondansetron with reduced hospital stay (WMD: -0.2; 95% CI: -0.31, -0.01) and diazepam with reduced risk of hospital admission (OR: 0.11; 95% CI: 0.01, 0.95). The quality of evidence is very low.Conclusion: Acupuncture, acupressure, and methylprednisolone were observed with better therapeutic benefits than other interventions for treating HG. However, the pooled estimates may change with the advent of results from future head-to-head clinical trials.

Interventions for treating nausea and vomiting in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials.

INTRODUCTION: Several drugs were explored for their utility in treating nausea and vomiting in pregnancy (NVP). The present study is a network meta-analysis of such drugs. METHODS: Electronic databases were searched for randomized clinical trials that have compared active interventions (with placebo or other active interventions) for treating NVP. Nausea scores were the primary outcome and changes in nausea scores, emetic episodes, adverse events, and vomiting control were the key secondary outcomes. Weighted mean difference was the effect estimate for continuous variable and odds ratio for the numerical variable. Random-effects model was used and the strength of the evidence was graded. RESULTS: Fifty studies were included in the systematic review and 42 in the meta-analysis. Acupuncture, chamomile, dimenhydrinate, doxylamine/vitamin B6, ginger, quince, metoclopramide, and vitamin B6 were associated with reduced nausea scores compared to placebo. Of these interventions, ginger and vitamin B6 were also associated with better vomiting control and less incidence of adverse events. Adequate evidence supporting the use exists only for ginger and the quality of evidence for this comparison is moderate. Strength of evidence for all other comparisons is very low. CONCLUSION: Present evidence is conclusive on the therapeutic benefits of ginger in treating NVP. Although favorable results were obtained for several other interventions, the strength of evidence is very low. The results of this network meta-analysis should be interpreted with extreme caution as it might change with the advent of data from future head-to-head clinical trials.

Interventions for Improving Bone Mineral Density and Reducing Fracture Risk in Osteogenesis Imperfecta: A Mixed Treatment Comparison Network Meta-analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Osteogenesis imperfecta is a rare metabolic disorder associated with reduced mineralization of bone and corresponds to increased fracture risk. We carried out the present network meta-analysis comparing all the medical interventions for osteogenesis imperfecta. METHOD: Electronic databases were searched for randomized controlled clinical trials evaluating the use of drugs in patients with osteogenesis imperfecta. Percent change in BMD was the primary and fracture risk reduction and adverse events were the secondary outcome measures. The weighted mean difference was the pooled estimate for primary outcome and odds ratio with 95% confidence interval for the secondary outcome measures. Direct and mixed treatment comparisons between the interventions were carried out by inverse heterogeneity model. Sub-group analyses were carried out on children, adults and within bisphosphonate groups. The trial sequential analysis was carried out for the comparison of oral bisphosphonates with placebo. RESULTS: A total of 16 studies were included evaluating oral and intravenous bisphosphonates, teriparatide, anti-sclerostin antibody, high dose vitamin D and recombinant growth hormone (rGH) combined with intravenous bisphosphonates. Oral bisphosphonates and teriparatide were observed with a statistically significant increase in BMD compared to placebo. Also, only oral bisphosphonates were associated with significant reduction in the fracture risk but when the alpha error was adjusted for the information accrued till date as well as when the results of a trial were excluded, no significant difference was observed. Either low or very low quality was observed for pooled estimates of the key comparisons. CONCLUSION: Oral bisphosphonates and teriparatide significantly increase BMD but are not associated with fracture risk reduction. Of the available interventions, oral bisphosphonates could perform better than others in osteogenesis imperfecta. This evidence should be considered preliminary and may change with future head-to-head clinical trials.

Efficacy and safety of iron chelators in thalassemia and sickle cell disease: a multiple treatment comparison network meta-analysis and trial sequential analysis.

BACKGROUND: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis. METHODS: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy. RESULTS: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons. CONCLUSION: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.

Pharmacological interventions for preventing acute mountain sickness: a network meta-analysis and trial sequential analysis of randomized clinical trials.

BACKGROUND: Individuals ascending to high altitude are at a risk of getting acute mountain sickness (AMS). The present study is a network meta-analysis comparing all the interventions available to prevent AMS. METHODS: Electronic databases were searched for randomized clinical trials evaluating the use of drugs to prevent AMS. Incidence of AMS was the primary outcome and incidence of severe AMS, paraesthesia (as side effect of acetazolamide use), headache and severe headache, and oxygen saturation were the secondary outcomes. Odds ratio [95% confidence interval] was the effect estimate for categorical outcomes and weighted mean difference for oxygen saturation. Random effects model was used to derive the direct and mixed treatment comparison pooled estimates. Trial sequential analysis and grading of the evidence for key comparisons were carried out. RESULTS: A total of 24 studies were included. Acetazolamide at 125, 250 and 375 mg twice daily, dexamethasone and ibuprofen had statistically significant lower incidence of AMS compared to placebo. All the above agents except ibuprofen were also observed to significantly reduce the incidence of severe AMS. Acetazolamide alone or in combination with Ginkgo biloba were associated with lower incidence of headache, but higher risk of paraesthesia. Acetazolamide at 125 mg and 375 mg twice daily significantly reduce the incidence of severe headache as like ibuprofen. Trial sequential analysis indicates that the current evidence is adequate for the incidence of AMS only for acetazolamide 125 and 250 mg twice daily. Similarly, the strength of evidence for acetazolamide 125 and 250 mg twice daily was moderate while it was either low or very low for all other comparisons. CONCLUSIONS: Acetazolamide at 125, 250 and 375 mg twice daily, ibuprofen and dexamethasone significantly reduce the incidence of AMS of which adequate evidence exists only for acetazolamide 125 and 250 mg twice daily therapy. Acetazolamide 125 mg twice daily could be the best in the pool considering the presence of enough evidence for preventing AMS and associated with lower incidence of paraesthesia. Key messages Acetazolamide 125, 250 and 375 mg twice daily, dexamethasone and ibuprofen reduce the incidence of AMS in high altitudes. Adequate evidence exists supporting the use of acetazolamide 125 mg and 250 mg twice daily for preventing AMS of which acetazolamide 125 mg twice daily could be the best.

Effect of clonidine on the efficacy of lignocaine local anesthesia in dentistry: A systematic review and meta-analysis of randomized, controlled trials.

Alternatives to adrenaline with lignocaine local anesthesia, such as clonidine, have been trialed in various randomized, controlled trials. Therefore, the aim of the present systematic review was to compile the available evidence on using clonidine with lignocaine for dental anesthesia. Electronic databases were searched for eligible studies. A data-extraction form was created, extracted data were analyzed using non-Cochrane mode in RevMan 5.3 software. Heterogeneity between the studies were assessed using the forest plot, I2 statistics (where >50% was considered to have moderate-to-severe heterogeneity), and χ2 -test. Random-effects models were used because of moderate heterogeneity. Five studies were included for the final review. While clonidine was found to significantly shorten the onset of local anesthesia when measured subjectively, no significant difference was observed objectively. No significant difference was observed in the duration and postoperative analgesia. Stable hemodynamic parameters within the safe range were observed postoperatively when clonidine was used. Clonidine could be considered as an alternative to adrenaline in cases of contraindications to adrenaline, such as like cardiac abnormalities, hypertension, and diabetes.

Electrical nerve stimulation for xerostomia: A meta-analysis of randomised controlled trials.

BACKGROUND: Xerostomia leads to caries, infection and overall psychological discomfort. Salivary substitutes and pharmacological agents have been tried only with temporary relief. The use of transcutaneous electrical nerve stimulation (TENS) has been contemplated on by various researchers for treatment of xerostomia. We carried out the present review as a systematic compilation and quantitative synthesis of the existing evidence related to the utility of TENS in patients with xerostomia. METHODOLOGY: Six randomized controlled trials were identified from databases for inclusion and analysed using non-Cochrane mode in RevMan 5.0 software. The heterogeneity between the studies were assessed using Forest plot, I2 statistics wherein more than 50% was considered to have moderate to severe heterogeneity and Chi-square test with a statistical P-value of less than 0.10 to indicate statistical significance. RESULTS: Results show that the effect of TENS on salivary flow rate in 369 participants with SMD [95% CI] was 0.63 [-0.03, 1.29] and was not statistically significant. CONCLUSION: To conclude, the current evidence does not support the use of TENS in patients with xerostomia and may be considered as a salivary substitute for symptomatic improvement. However the type, frequency and amplitude of current used needs to be studied in detail. High quality randomized controlled trials with adequate power are required, either to support or refute the use of TENS in xerostomia.

Therapies for Meibomian Gland Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Meibomian Gland Dysfunction (MGD) is a common, often overlooked, chronic condition affecting eyes for which various therapies are being evaluated. Considering the absence of a systematic review and meta-analysis, the present review was carried out. METHODS: An appropriate search strategy eligibility criteria were framed and electronic databases were scrutinized for appropriate literature. Randomized Controlled Trials (RCTs) enrolling patients diagnosed with MGD were included. Outcome measures were Tear Break Up Time (TBUT), Schirmer's test, Meibomian Gland (MG) secretion score, MG plugging score, OSDI and SPEED. Cochrane's tool was used to assess the risk of bias and Forest plot were generated either with fixed or random effects model, with Standardized Mean Difference (SMD). RESULTS: TBUTs, Schirmer's test and OSDI scores for systemic antimicrobials with placebo were 1.58 [1.33, 1.83], 2.93 [0.78, 5.09] and -3.58 [-4.28, -2.89] respectively. No quantitative synthesis was attempted for either mebiomian plugging or meibomian secretion scores and no significant changes were observed with any other outcome parameter. CONCLUSION: Only the systemic antimicrobials were found to improve the clinical features of meibomian gland dysfunction. Varying effects of different therapeutic agents (heat therapies, omega-3-fatty acids and castor oil) were identified for MGD but the risk of bias pertaining to randomization and allocation concealment was found to be associated with most of the current RCTs. More high quality evidence is required to confirm the findings of the present review.

Therapeutic clowns in pediatrics: a systematic review and meta-analysis of randomized controlled trials.

UNLABELLED: Children and/or their parents are in fear and anxiety when admitted to hospitals or undergo invasive surgeries or investigations. Clown therapy has been shown as an effective measure in reducing this hospital fear and anxiety. Hence, we carried out a systematic compilation of the existing evidence on the clinical utility of hospital clowns in pediatric population. Electronic databases were searched with an appropriate search strategy, and only randomized controlled trials comparing the effect of clown therapy with standard care in children were included. The key outcome measures were as follows: extent of anxiety and pain felt by children and extent of state and trait parental anxiety. Random effect model was applied when moderate to severe heterogeneity was observed. Forest plot, I(2) statistics and risk of bias were evaluated using RevMan 5.3 software. A total of 19 studies were found eligible to be included in the systematic review and 16 for meta-analysis. The pooled SMD [95 % CI] for child anxiety score was -0.83 [-1.16, -0.51] favoring clown therapy. Similarly, a statistically significant reduction {SMD [95 % CI] -0.46 [-0.7, -0.21]} in the state anxiety was observed amongst parents. CONCLUSION: We found that hospital clowns play a significant role in reducing stress and anxiety levels in children admitted to hospitals as well as their parents. WHAT IS KNOWN: • Trials with clown doctors in pediatric population have shown conflicting results in allaying anxiety amongst children undergoing either hospitalization or invasive procedures What is new: • This is the first systematic review and meta-analysis on hospital clowns • We found out that hospital clowns reduce anxiety amongst children before undergoing either hospitalization or invasive procedures.

Clinical trials in Ayurveda: Analysis of clinical trial registry of India.

Ayurveda is one of the complementary and alternative systems of medicine requiring generation of high quality evidence for rational practice. Evidence can be generated from study designs and the present study is an attempt to critically assess the registered studies in the field of Ayurveda from clinical trial registry of India. We found low number of trials conducted with more focus required on the quality of these studies to contribute to high quality evidence.