Double-blind Randomized Control Trial Research Articles

Efficacy and safety of topical capsaicin in the treatment of osteoarthritis pain: A systematic review and meta-analysis.

Osteoarthritis (OA) affects hundreds of millions of people worldwide. The objective was to critically appraise the efficacy and safety of topical capsaicin in reducing pain in OA. MEDLINE (PubMed) and Embase (Ebsco) were searched from inceptions until February 2023. The eligibility criteria included randomized controlled trials (RCTs), evaluating topical capsaicin in OA patients. Standard Cochrane methods were used to extract data and to appraise eligible studies. Eight double-blind RCTs involving 498 patients were included. Five trials (62.5%) were at an overall low risk of bias, and three (37.5%) were at a high risk of bias. Meta-analysis showed that, in various OA patients, compared with placebo, topical capsaicin (0.0125%-5%) may reduce pain severity measured with visual analog scale (standardized mean difference = -0.84, 95% confidence intervals [CIs] = -1.48 to -0.19, p = 0.01; eight studies). However, topical capsaicin may increase burning sensation at the application site (risk ratio = 5.56, 95% CI = 1.75-17.69, p = 0.004, numbers needed to harm = 3; five studies) when compared with placebo. Limitations include short study durations, small sample sizes, high heterogeneity, and overall low-to-very-low certainty of the evidence. Topical capsaicin may reduce OA pain at follow-ups of up to 3 months. Larger trials, potentially evaluating capsaicin in combination with phytopharmaceuticals having anti-inflammatory effects, with longer follow-ups might be needed to reduce the existing uncertainties. Topical capsaicin might be recommended for short-term management of pain in OA patients intolerant to nonsteroidal anti-inflammatory drugs.

Effect of erythropoietin on SOFA score, glasgow coma scale and mortality in traumatic brain injury patients: a randomized-double blind controlled trial

Effect of erythropoietin on SOFA score, glasgow coma scale and mortality in traumatic brain injury patients: a randomized-double blind controlled trial

Sacubitril/valsartan and cardiovascular biomarkers among patients with recent COVID-19 infection: The PARACOR-19 randomized clinical trial.

The PARACOR-19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID-19) infection. PARACOR-19 was a single-centre, double-blind RCT of patients with cardiovascular risk factors and a history of COVID-19 infection 4-16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co-primary endpoints were change from baseline to 12 weeks in high-sensitivity cardiac troponin T (hs-cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th-75th) time from COVID-19 diagnosis to enrolment was 67 (48-80) days. Median age was 67 (62-71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co-primary endpoints of change from baseline in hs-TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 51% greater reduction in C-terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. In this pilot RCT of patients who recovered from acute COVID-19, sacubitril/valsartan did not lower hs-cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT-proBNP and CITP. Sacubitril/valsartan was well tolerated. ClinicalTrials.gov NCT04883528.

Effects of short foot exercises with ultrasound bio-feedback on motor learning and foot alignment: A double blinded randomized control trial.

Short foot exercises (SFE) take a long time to master and require a feedback tool to improve motor learning. This study aimed to investigate the effect of bio-feedback of talonavicular joint movements in learning SFE with ultrasound (US) imaging. This study included thirty-one healthy volunteers and was designed as a double-blind randomized control trial. Subjects were randomly assigned to one of two groups: the control group, which performed SFE under verbal instruction, and the US bio-feedback (USBF) group, which performed SFE with real-time bio-feedback of the talonavicular joint alignment. All subjects underwent two sessions of 5 minutes each, and SFE was performed as a self-exercise, between sessions, for one week. The difference in foot length and navicular height were assessed at baseline, after Session1, before Session2, and one week after Session2. These differences were compared between the two groups using the Mann-Whitney U test. In terms of navicular height change, the USBF group (7.5 ± 4.3 mm) was significantly higher than the control group (4.2 ± 3.3 mm) one week after session 2 (p= 0.04, effect size = 0.86). SFE with USBF is an effective intervention for performing SFE.

Immediate fortification of human milk with a bovine milk-derived human milk fortifier in very low birth weight infants: a randomized clinical trial.

Double-blind randomized control trial of early addition of a bovine milk-derived human milk fortifier (HMF) in very low birth weight (VLBW) infants (NCT05228535). VLBW infants were randomized to receive bovine milk-derived HMF with first feedings or delayed fortification at 80 ml/kg/day. Anthropometrics were assessed weekly through 36 weeks postmenstrual age (PMA). Unadjusted and adjusted (race, gender, gestational age, and birth weight) differences between study arms were examined using two-sample t-test and ANCOVA, respectively. Fifty-two VLBW infants (57% female, 60% Black) were enrolled. Baseline demographics did not differ between groups. Weight velocity at DOL 28 did not differ between study arms. Secondary outcomes including NPO occurrence, incidence of metabolic acidosis, NEC, retinopathy, or late-onset sepsis did not differ between groups. Immediate fortification of enteral feedings with a bovine milk-derived HMF appears safe and well-tolerated although no clear growth benefit could be established.

Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.

To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD). We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events. Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies. A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.

Comparison of the effect of intraoperative dexmedetomidine versus ketamine on postoperative analgesia in fracture femur patients operated under subarachnoid block – A prospective randomized double-blind controlled trial

Abstract Background and Aims: Intravenous sedation during spinal anesthesia has the advantages of increased duration of spinal anesthesia and better postoperative pain control. The aim of this study was to compare the effect of intravenous bolus and infusion of dexmedetomidine versus ketamine given intraoperative on the postoperative analgesia in fracture femur patients operated under subarachnoid block. Material and Methods: In this prospective randomized double-blind controlled study, 75 patients aged 18–65 years posted for elective surgery were selected and randomly divided into three groups to receive ketamine (group K), dexmedetomidine (group D), and saline (control group C). Postoperative pain was evaluated using the numerical rating scale (NRS). The duration of analgesia and the amount of analgesic consumption were also recorded. Student’s t-test and Chi-square test were used to compare the two groups, and one-way ANOVA with posthoc analysis was performed for comparison of the three groups. Results: Patients in the ketamine group had better postoperative analgesia as assessed by decreased pain (on the NRS scale) and decreased need for postoperative rescue analgesics (P < 0.001). The duration of sensory block and motor block was prolonged in group K as compared to the other two groups (P < 0.001). Conclusion: Intraoperative use of intravenous ketamine was superior to dexmedetomidine for postoperative analgesia in fracture femur patients operated under subarachnoid block.

Efficacy of Intrawound Vancomycin in Prevention of Periprosthetic Joint Infection After Primary Total Knee Arthroplasty: A Prospective Double-Blinded Randomized Control Trial

BackgroundPeriprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is a devastating complication. Intrawound vancomycin powder has been shown to reduce infection rates in spine surgery, but its role in arthroplasty remains controversial. This prospective randomized control trial aimed to evaluate the efficacy of intrawound vancomycin in preventing PJI after primary TKA. MethodsA total of 1,022 patients were randomized to the study group (n = 507, who received 2 grams intrawound vancomycin powder before arthrotomy closure) or to the control group (n = 515, no local vancomycin) with a minimum follow-up of 12-months. The primary outcome was the incidence of PJI or surgical site infection (SSI). Secondary outcomes included associated minor complications such as stitch abscess, persistent wound drainage, and delayed stitch removal. Other parameters evaluated include reoperation rates and incidences of nephrotoxicity. ResultsThe overall infection rate in 1,022 patients was 0.66%. There was no significant difference in PJI rate in the study group (N = 1; 0.2%) versus the control group (N = 3; 0.58%), P = .264. Reoperation rates in the study group (N = 4; 0.78%) and control (N = 5; 0.97%), and SSI rates in the study (N = 1; 0.2%) and control groups (N = 2; 0.38%) were comparable. The Vancomycin cohort, however, demonstrated a significantly higher number of minor wound complications (n = 67; 13.2%) compared to the control group (n = 39; 7.56%, P < .05). Subgroup analysis showed diabetics in the study group to also have a higher incidence of minor wound complications (24 [14.1%] versus 10 [6.2%]; P < 05]. Multivariate analyses found that vancomycin use (odds ratio = 1.64) and smoking (odds ratio = 1.85) were associated with an increased risk of developing minor wound complications. No cases of nephrotoxicity were reported. ConclusionsIntrawound vancomycin powder does not appear to reduce PJI/SSI rate in primary total knee arthroplasties, including high-risk groups. Although safe from a renal perspective, intrawound vancomycin was associated with an increase in postoperative aseptic wound complications. Intrawound vancomycin may not be effective in reducing the rate of PJI in primary TKA.

Comparison between Surgeon Administered Intraoperative Transverse Abdominis Plane Block with Wound Site Local Anesthetic Infiltration in Patients Undergoing Open Appendicectomy: A Prospective Double-Blinded Randomised Control Trial

Transversus abdominis plane (TAP) block is a defined technique for managing postoperative pain. In particular, the use of surgeon-administered TAP blocks needs more comprehensive research. Therefore, our objective was to record the pain relief needed in patients who underwent surgical administered TAP blocks followed with an open appendectomy in comparison to those who received local anaesthetic infiltration at the wound site. Additionally, we aimed to assess the time until the first postoperative analgesic application and compare tramadol requirements in the postoperative period for these two groups. We conducted a controlled, prospective, randomised, double-blind study involving patients who underwent open appendicectomy at Hospital Sultanah Aminah Johor Bahru from April 2017 to October 2017. Of 61 patients, 31 were in the intervention group, and 30 were in the control group. Both groups of patients received a dose of 10cc of 0.25% levobupivacaine. Patients in the intervention group experienced a longer interval before requiring their first rescue analgesia (2.6 hours versus 1.17 hours; p=0.02, SD=1.66-2.97). The total tramadol dose needed over the first 24 hours in the intervention group was slightly lower at 115.8mg compared to the control group, which used 136.7mg (p=0.32, sd=72.42-89.96). Notably, patients in the intervention group also had a significantly shorter hospital stay (1.39 versus 1.68 days, p=0.02). It was worth noting that none of our patients experienced any adverse events during the study. Considering our study's effectiveness and safety profile, we recommended the routine use of surgeon-administered TAP blocks in open appendicectomy. This approach not only enhanced patient postoperative analgesia but also reduced the duration of hospitalisation.

The Role of Proton Pump Inhibitors in the Realm of Idiopathic Pulmonary Fibrosis and its Associated Comorbidities: A Systematic Review.

As the global incidence of idiopathic pulmonary fibrosis (IPF) is on the rise, there is a need for better diagnostic criteria, better treatment options, early and appropriate diagnosis, adequate care, and a multidisciplinary approach to the management ofpatients. This systematic review explores the role of proton pump inhibitors (PPIs) in IPF and answers the question, "Does proton pump inhibitor improve only the prognosis of gastroesophageal associated idiopathic pulmonary fibrosis or for other types of idiopathic pulmonary fibrosis too?" We used PubMed (PMC) and Google Scholar for data collection for this systematic review and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting this review. After in-depth literature screening and quality appraisal, 12 articles were selected for this systematic review. On the one hand, the efficacy of PPI therapy is supported by research such as the CAPACITYand ASCEND trials, a pilot randomized control trial (RCT) investigating the role of omeprazole in IPF and a bidirectional two-sample Mendelian randomization (MR) study, respectively. On the other hand, a systematic reviewand meta-analysison antacid and antireflux surgery in IPFnegate these results and show no statistical significance. Questions regarding the efficacy of PPI therapy must be dealt with in an adequately powered multicenter and double-blinded randomized control trial. The anti-inflammatory properties of antacids can serve as the cornerstone for future trials. In the following systematic review, antacid, antireflux therapy, omeprazole, and proton pump therapy are synonymous with stomach acid suppression therapy.

Effectiveness of Phloroglucinol in Shortening the Active Phase of the First Stage of Labour in Term Pregnancies

Background: Labour is a normal physiological process, involving increasing myometrical contractions, cervical dilation and effacement resulting in delivery of the fetus and placenta and the initiation of the process of lactation. First Stage of labour lasts for 12-16hrs in primigravida and 6-8 hrs in multigravida. Two important characteristics of labour are uterine contractions and cervical effacementObjectives: To determine the effectiveness of phloroglucinol in shortening the 1st stage of labour in term pregnancies.Material and Methods: It was a double blinded randomized control trial (RCT) conducted in Obs and Gynae department of Hayatabad Medical Complex, MTI, Peshawar Pakistan, over a period of 6 months from 20th October 2022 to 20th April 2023. Patients were selected randomly for placebo and pluroghlucinol group and recorded on structured proforma. Total 375 women were selected in first stage of labour. In which 187 were given Phloroglucinol and 188 women received placebo. Results: The mean age of patients in phloroglucinol group was 28.3 ± 4.01 and in control group was 26.6 ± 6.8 years. The mean period of gestation in Phloroglucinol group was 37.3 ± 4.0 while in control group was 38.6 ± 2.08 weeks. The mean BMI of patients in Phl group was 22.12 ± 1.4 while in control group was 21.6 2 ± 1.5. The mean duration of active phase of 1st stage of labour in Phl group was 290.4 ± 29.7 minutes while in control group was 402.4 ± 29.7 minutes. Conclusion: Phloroglucinolhas significant effect in shortening the 1st stage of labour.Keywords: Active phase, Labour, Phloroglucinol, Pregnancy.

The effects of intranasal oxytocin on the efficacy of psychotherapy for major depressive disorder: a pilot randomized controlled trial.

Although both pharmacotherapy and psychological treatments are considered to be efficacious in the treatment of major depressive disorder (MDD), one third of patients do not respond to treatment and many experience residual symptoms post-treatment. In this double-blind placebo-controlled randomized control trial (RCT), we assessed whether intranasal oxytocin (OT) augments the therapeutic efficacy of psychotherapy for MDD and improves the therapeutic alliance. Twenty-three volunteers (12 female) with MDD underwent 16 sessions of interpersonal therapy. Prior to each session, volunteers self-administered 24 International Units of intranasal OT (n = 12; Syntocinon) or placebo (n = 11). Depressive symptoms were assessed with the Inventory of Depressive Symptomatology at pre- and post-treatment, and at a six month follow-up. Multilevel modeling found a significant effect of OT on the negative slope of depressive symptoms over time (p < 0.05), with medium-large effect sizes at post-treatment (Cohen's d = 0.75) and follow-up (Cohen's d = 0.82). Drug intervention also predicted the intercept when examining the weekly ratings of the therapeutic alliance (p < 0.05), such that volunteers receiving OT, relative to placebo, reported improved therapeutic alliance at session 1. The agreement of goals between therapists and participants, a facet of the therapeutic alliance, mediated the relationship between drug intervention and clinical outcome. In this pilot study, the administration of intranasal OT, relative to placebo, improved the therapeutic alliance at the beginning of therapy and therapeutic efficacy of psychotherapy in persons with MDD. Future RCTs should attempt to replicate these findings in larger samples with different therapeutic modalities (ClinicalTrials.gov: NCT02405715).

Assessing the Efficacy of Buffered Versus Nonbuffered Lidocaine in Dental Extractions: A Double-Blinded Randomized Controlled Trial

Injections using buffered lidocaine may decrease discomfort, have a quicker onset, and be a more efficacious local anesthetic. Previous studies have been inconclusive in the oral context. To address if bicarbonate buffered 2% lidocaine can decrease pain from the use of local anesthesia, has a quicker onset time, and is more efficacious. The design was a single-center double-blinded randomized control trial, set in an outpatient oral and maxillofacial clinic housed in the University of Cincinnati Medical Center. Inclusion criteria for the study were patients requiring a single tooth extraction due either to caries or periodontal disease. The predictor variable was the local anesthetic used either nonbuffered 2% lidocaine with 1:100,000 epinephrine (control) or bicarbonate buffered 2% lidocaine with 1:100,000 epinephrine (study) was randomly assigned. Primary outcome variables were injection pain score, and postoperative pain, time to anesthetic onset, and the number of rounds of injections required to achieve adequate anesthesia. The covariates were jaw involved, age, sex, and race, American Society of Anesthesiologists score, body mass index, current tobacco use, history of psychiatric illness, chronic pain, and preoperative pain score. Test statistics were calculated using Wilcoxon rank-sum test, Kruskal-Wallis test, Spearman rank correlation test, χ2 test for bivariate analyses, and Fisher's exact test. P values≤.05 were considered statistically significant. The final sample was 114 subjects. The mean age of the sample was 42.97years, standard deviation ±13.43years. The sample was 39.47% male. The racial demographics were Caucasian (62.28%) and African American (33.33%). Buffered lidocaine did not have a statistically significant relationship with any of the outcomes. The jaw involved had a statistically significant association to the injection pain score (P value=.006), and the number of rounds of anesthetic required (P value=.047). Age showed a statistically significant association to injection pain score (P value=.032), and the number of rounds of anesthetic required (P value=.027). Finally, preoperative pain had a statistically significant relationship with injection pain score (P value= < .001). In this study, bicarbonate buffered lidocaine did not exhibit any discernible advantages over nonbuffered lidocaine for any study outcomes.

Intravenous Hemin, a potential heme oxygenase-1 activator, does not protect from post-ERCP acute pancreatitis in humans: Results of a randomized multicentric multinational placebo-controlled trial

ObjectiveHemin, a heme oxygenase 1 activator has shown efficacy in the prevention and treatment of acute pancreatitis in mouse models. We conducted a randomized controlled trial (RCT) to assess the protective effect of Hemin administration to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients at risk. MethodsIn this multicenter, multinational, placebo-controlled, double-blind RCT, we assigned patients at risk for PEP to receive a single intravenous dose of Hemin (4 mg/kg) or placebo immediately after ERCP. Patients were considered to be at risk on the basis of validated patient- and/or procedure-related risk factors. Neither rectal NSAIDs nor pancreatic stent insertion were allowed in randomized patients. The primary outcome was the incidence of PEP. Secondary outcomes included lipase elevation, mortality, safety, and length of stay. ResultsA total of 282 of the 294 randomized patients had complete follow-up. Groups were similar in terms of clinical, laboratory, and technical risk factors for PEP. PEP occurred in 16 of 142 patients (11.3%) in the Hemin group and in 20 of 140 patients (14.3%) in the placebo group (p = 0.48). Incidence of severe PEP reached 0.7% and 4.3% in the Hemin and placebo groups, respectively (p = 0.07). Significant lipase elevation after ERCP did not differ between groups. Length of hospital stay, mortality and severe adverse events rates were similar between groups. ConclusionWe failed to detect large improvements in PEP rate among participants at risk for PEP who received IV hemin immediately after the procedure compared to placebo. Trial registration numberClinicalTrials.gov number, NCT01855841).

Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased? Exploratory meta- and subgroup analysis

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters,mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indicationsof TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, andimpact on cognition. An overview ofthe drug'sorigins,pharmacology, and standard treatment regimen are provided. Theoutcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlinedto demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative toketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD,propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, includingketamine, esketamine, treatment-resistant depression, and biomarkers,using automation toolsalong with selective search engine results.After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

Safety, tolerability, and effect of a single aural dose of Dornase alfa at the time of ventilation tube surgery for otitis media: A Phase 1b double randomized control trial

BackgroundOne third of children require repeat ventilation tube insertion (VTI) for otitis media. Disease recurrence is associated with persistent middle ear bacterial biofilms. With demonstration that Dornase alfa (a DNase) disrupts middle ear effusion biofilms ex vivo, we identified potential for this as an anti-biofilm therapy to prevent repeat VTI. First, safety and tolerability needed to be measured. MethodsThis was a phase 1B double-blinded randomized control trial conducted in Western Australia. Children between 6 months and 5 years undergoing VTI for bilateral middle ear effusion were recruited between 2012 and 2014 and followed for two years. Children's ears were randomized to receive either Dornase alfa (1 mg/mL) or 0.9 % sodium chloride (placebo) at time of surgery. Children were followed up at 2 weeks post-VTI and at 3-monthly intervals for 2 years. Outcomes assessed were: 1) safety and tolerability, 2) otorrhoea frequency, 3) blocked or extruded ventilation tube (VT) frequency, 4) time to blockage or extrusion, 5) time to infection recurrence and/or need for repeat VTI. ResultsSixty children (mean age 2.3 years) were enrolled with 87 % reaching study endpoint. Treatment did not change otorrhoea frequency. Hearing improved in all children following VTI, with no indication of ototoxicity. Dornase alfa had some effect on increasing time until VT extrusion (p = 0.099); and blockage and/or extrusion (p = 0.122). Frequency of recurrence and time until recurrence were similar. Fourteen children required repeat VTI within the follow-up period. ConclusionA single application of Dornase alfa into the middle ear at time of VTI was safe, non-ototoxic, and well-tolerated. Trial registrationACTRN12623000504617.

Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Evaluation of the effectiveness of tell-show-do and ask-tell-ask in the management of dental fear and anxiety: a double-blinded randomized control trial.

The objective of behavioral guidance is to establish effective communication that aligns with a child's requirements to manage disruptive behavior. This study aimed to evaluate the effectiveness of the Tell-Show-Do and Ask-Tell-Ask techniques in managing dental anxiety in children during their initial appointment. The study included 50 children (28 boys and 22 girls) without any prior experience between the ages of 7 and 11 at their first dental visit. The children were randomly categorized into two groups: Group 1, Tell Shows Do, and Group 2, Ask-Tell-Ask. Subsequently, all children underwent noninvasive treatment procedures such as restorations, sealants, and oral prophylaxis. Furthermore, behavioral management techniques were employed based on the allocated group. Finally, anxiety levels for all children were assessed using the Raghavendra, Madhuri, and Sujata Pictorial Scale (RMS-PS) and heart rate at three different intervals (before, during, and after). The obtained data were entered into Microsoft Excel, and statistical analysis was performed using SPSS software. A paired t-test and Mann-Whitney U-test were used to compare the mean and median values of the two groups and determine their effectiveness. Children in the TSD group exhibited statistically significant heart rates and RMS-PS scores in intra-group comparisons. However, children in the ask-tell-ask group showed a significant reduction only in the RMS-PS scores (P < 0.001) but not in the measures used to assess heart rate (P < 0.001). Tell-Show-Do was more effective than ask-tell-ask in alleviating dental anxiety in children. The simultaneous application of these two strategies can synergistically alleviate dental anxiety during a child's initial dentist appointment.

Efficacy of Pistacia lentiscus Plant (Rumi Mastagi) in Comparison to Levosulpiride in Patients with Diabetic Gastroparesis: A Double-Blind Non-Inferior Randomised Control Trial Study.

Gastrointestinal neuropathies are frequently found in diabetic patients. The pathogenesis of diabetic gastroparesis (DG) is multifactorial. The usual treatment for DG includes dietary modifications, prokinetic and antiemetic agents. There is increasing demand for more effective medicines to treat DG. The current study was conducted on the Pistacia lentiscus stem extract to add to the armamentarium of DG treatment and to find the efficacy of P. lentiscus plant extract (mastic gum) in comparison to levosulpiride in DG for improvement in gastroparesis symptoms and gastric emptying scintigraphy (GES) in a single centric double-blind non-inferiority randomised control trial. Thirty-eight individuals were recruited and equally randomised into two study groups based on Gastroparesis Cardinal Symptom Index (GCSI) score and TC99 Radionuclide GES, mastic gum group and levosulpiride group. Both pre and post-intervention (8 weeks) GCSI scores were calculated, GES was performed to quantify the improvement in gastric emptying. Power analysis was performed using G*POWER software version 3.1.9.7 and data analysis using SPSS 23.0, variables measured in mean ± standard deviation (SD). Various statistical tests were used such as independent t-test, Chi-square test or Fisher's exact test, Wilcox Mann-Whitney test, analysis of variance (ANOVA) test, and posthoc pairwise tests. The mastic gum is found effective in the improvement of 4 h gastric emptying percentage from the mean (SD) 76.60 (± 9.96) to mean (SD) 97.20 (2.17)% (P < 0.001). Mastic gum has the property of HbA1c reduction, which is more significant than that of levosulpiride (P = 0.044). Mastic gum also had significant Low density lipoprotein (LDL) (mg/dL) levels reduction, (P < 0.001), compared to levosupiride. An absolute increase was observed in haemoglobin (HB) level in mastic gum at a 2-month mean (SD) of 1.03 (0.77) (g/dL) (P-value <0.001). To our knowledge, this is the first study to compare the effect of levosulpiride with mastic gum concerning improvement in diabetic gastroparesis (DG) using GES. In the study, mastic gum was found to have great properties to improve DG with many important pleiotropic effects.