Placebo-controlled Randomized Clinical Trial Research Articles

Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants

Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants. To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula. The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020. Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days. The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days. The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies. Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula. ClinicalTrials.gov Identifier: NCT02510560.

Effectiveness of Acupuncture for Pain Control After Cesarean Delivery

A pharmacological approach to pain control after cesarean delivery is often insufficient on its own. Acupuncture is a promising method for mitigating postoperative pain and reducing postoperative opioid requirements. To evaluate the efficacy and effectiveness of acupuncture as an adjunctive therapy for pain control after cesarean delivery, compared with a placebo intervention and standard care alone. This single-center, placebo-controlled, patient- and assessor-blinded randomized clinical trial was conducted from January 13, 2015, to June 27, 2018, at a tertiary university hospital in Greifswald, Germany. Participants were women who were scheduled for elective cesarean delivery under spinal anesthesia and were randomized to either the acupuncture group (n = 60) or placebo group (n = 60). Another 60 consecutive patients who met the eligibility criteria and received the standard postoperative analgesia were selected to form a nonrandomized standard care group. The intention-to-treat analysis was performed from August 19, 2019, to September 13, 2019. In addition to standard pain treatment, each patient in the acupuncture group received auricular and body acupuncture with indwelling intradermal needles, whereas patients in the placebo group were treated with nonpenetrating placebo needles. The primary outcome was pain intensity on movement, which was measured using an 11-item verbal rating scale. Secondary outcomes were analgesia-related adverse effects, analgesics consumption, time to mobilization and Foley catheter removal, quality of patient blinding to randomization, and patient satisfaction with treatment of pain. A total of 180 female patients (mean [SD] age, 31 [5] years) were included in the intention-to-treat analysis. The mean pain intensity on movement in the acupuncture group on the first postoperative day was lower than in the placebo group (4.7 [1.8] vs 6.0 [2.0] points; Cohen d, 0.73; 95% CI, 0.31-1.01; P = .001) and the standard care group (6.3 [1.3] points; Cohen d, 1.01; 95% CI, 0.63-1.40; P < .001). On the first postoperative day, 59 patients (98%) in the acupuncture group were fully mobilized vs 49 patients (83%) in the placebo group (relative risk [RR], 1.18; 95% CI, 1.06-1.33; P = .01) and 35 patients (58%) in the standard care group (RR, 1.69; 95% CI, 1.36-2.09; P < .001). The Foley catheter was removed in a total of 57 patients (93%) from the acupuncture group vs 43 patients (72%) from the placebo group (RR, 1.33; 95% CI, 1.12-1.57; P = .003) and 42 patients (70%) from the standard care group (RR, 1.37; 95% CI, 1.14-1.62; P = .002). Other parameters were comparable across the 3 study groups. Results of this trial showed that acupuncture was safe and effective in reducing pain and accelerating mobilization of patients after cesarean delivery. With consideration for personnel and time expenditures, acupuncture can be recommended as routine, supplemental therapy for pain control in patients after elective cesarean delivery. ClinicalTrials.gov Identifier: NCT02364167.

Reduction of serum level of interleukin-2 and pruritus severity after acupuncture at Quchi (LI11) in hemodialysis patients: a placebo-controlled randomized clinical trial

Reduction of serum level of interleukin-2 and pruritus severity after acupuncture at Quchi (LI11) in hemodialysis patients: a placebo-controlled randomized clinical trial

Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial).

TPS407 Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by &lt;8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (&gt;12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507.

Curcumin and Polycystic Ovary Syndrome: a Systematic Review.

Polycystic ovary syndrome (PCOS) is a gynecological endocrine disorder and the leading cause of anovulatory female infertility. This study aimed to systematically review the effects of curcumin or turmeric on PCOS-related parameters. PubMed, Scopus, Embase, and Web of Knowledge databases and Google Scholar were searched up to August 2021 using relevant keywords. All original articles evaluating the effects of turmeric/curcumin on PCOS were eligible. Out of 107 documents, eight animal studies and five randomized placebo-controlled clinical trials (RCTs) assessing the impact of curcumin on PCOS met our inclusion criteria. The reviewed animal studies indicated the beneficial effects of curcumin on the management of hormonal and metabolic disturbances in the PCOS condition. These effects also were confirmed in some, but not all, included RCTs. Therefore, despite promising animal results, the present literature is limited to conclude the beneficial effects of curcumin on the clinical management of PSCO symptoms. The impact of bioavailability-improved formulations of curcumin on PCOS should be assessed in further well-designed RCTs with longer duration and higher doses of curcumin. Besides, mechanistic investigations on the effects of curcumin on PCOS are also recommended.

The efficacy of speed of processing training for improving processing speed in individuals with multiple sclerosis: a randomized clinical trial.

The current study examines the efficacy of speed of processing training (SOPT) to improve processing speed (PS) in individuals with multiple sclerosis (MS). Outcomes included changes in the useful field of view (UFOV) and neuropsychological evaluation (NPE). This double-blind, placebo-controlled randomized clinical trial included 84 participants with clinically definite MS and impaired PS, 43 in the treatment group and 41 in the placebo control group. Participants completed a baseline NPE and a repeat NPE post-treatment. The treatment group was randomized to booster sessions or no contact. Long-term follow-up assessments were completed 6months after treatment. A significant effect of SOPT was observed on both the UFOV (large effect) and pattern comparison with a similar pattern of results noted on letter comparison, albeit at a trend level. The treatment effect was maintained 6months later. The impact of booster sessions was not significant. Correlations between degree of improvement on the UFOV and the number of levels completed within each training task were significant for both speed and divided attention indicating that completion of more levels of training correlated with greater benefit. SOPT is effective for treating PS deficits in MS with benefit documented on both the UFOV and a neuropsychological measure of PS. Less benefit was observed as the outcome measures became more distinct in cognitive demands from the treatment. Long-term maintenance was observed. The number of training levels completed within the 10-sessions exerted a significant impact on treatment benefit, with more levels completed resulting in greater benefit.

Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults

Aging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans. To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health. This double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center in Seattle, Washington, from March 1, 2018, to July 30, 2020. Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 months, and 4 months. Six-minute walk distance and maximal ATP production were assessed using magnetic resonance spectroscopy at baseline and at the end of study at 4 months. The analysis used an intention-to-treat approach. Participants were randomized to receive daily oral supplementation with either 1000 mg urolithin A or placebo for 4 months. The primary end point was change from baseline in the 6-minute walk distance and change from baseline to 4 months in maximal ATP production in the hand skeletal muscle. The secondary end points were change in muscle endurance of 2 skeletal muscles (tibialis anterior [TA] in the leg and first dorsal interosseus [FDI] in the hand). Cellular health biomarkers were investigated via plasma metabolomics. Adverse events were recorded and compared between the 2 groups during the intervention period. A total of 66 participants were randomized to either the urolithin A (n = 33) or the placebo (n = 33) intervention group. These participants had a mean (SD) age of 71.7 (4.94) years, were predominantly women (50 [75.8%]), and were all White individuals. Urolithin A, compared with placebo, significantly improved muscle endurance (ie, increase in the number of muscle contractions until fatigue from baseline) in the FDI and TA at 2 months (urolithin A: FDI, 95.3 [115.5] and TA, 41.4 [65.5]; placebo: FDI, 11.6 [147.4] and TA, 5.7 [127.1]). Plasma levels of several acylcarnitines, ceramides, and C-reactive protein were decreased by urolithin A, compared with placebo, at 4 months (baseline vs 4 mo: urolithin A, 2.14 [2.15] vs 2.07 [1.46]; placebo, 2.17 [2.52] vs 2.65 [1.86]). The mean (SD) increase from baseline in the 6-minute walk distance was 60.8 (67.2) m in the urolithin A group and 42.5 (73.3) m in the placebo group. The mean (SD) change from baseline to 4 months in maximal ATP production in the FDI was 0.07 (0.23) mM/s in the urolithin A group and 0.06 (0.20) mM/s in the placebo group; for the TA, it was -0.03 (0.10) mM/s in the urolithin A group and 0.03 (0.10) mM/s in the placebo group. These results showed no significant improvement with urolithin A supplementation compared with placebo. No statistical differences in adverse events were observed between the 2 groups. This randomized clinical trial found that urolithin A supplementation was safe and well tolerated in the assessed population. Although the improvements in the 6-minute walk distance and maximal ATP production in the hand muscle were not significant in the urolithin A group vs the placebo group, long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers, suggesting that urolithin A may counteract age-associated muscle decline; however, future work is needed to confirm this finding. ClinicalTrials.gov Identifier: NCT03283462.

East Asian Herbal Medicine to Reduce Primary Pain and Adverse Events in Cancer Patients : A Systematic Review and Meta-Analysis With Association Rule Mining to Identify Core Herb Combination.

Objective: Cancer pain is an important factor in cancer management that affects a patient’s quality of life and survival-related outcomes. The aim of this review was to systematically evaluate the efficacy and safety of oral administration of East Asian herbal medicine (EAHM) for primary cancer pain and to explore core herb patterns based on the collected data. Methods: A comprehensive literature search was conducted in 11 electronic databases, namely, PubMed, Cochrane Library, Cumulative Index to Nursing & Allied Health Literature, EMBASE, Korean Studies Information Service System, Research Information Service System, Oriental Medicine Advanced Searching Integrated System, Korea Citation Index, Chinese National Knowledge Infrastructure Database (CNKI), Wanfang Data, and CiNii for randomized controlled trials from their inception until August 19, 2021. Statistical analysis was performed in R version 4.1.1 and R studio program using the default settings of the meta-package. When heterogeneity in studies was detected, the cause was identified through meta-regression and subgroup analysis. Methodological quality was independently assessed using the revised tool for risk of bias in randomized trials (Rob 2.0). Results: A total of 38 trials with 3,434 cancer pain patients met the selection criteria. Meta-analysis favored EAHM-combined conventional medicine on response rate (risk ratio: 1.06; 95% CI: 1.04 to 1.09, p < 0.0001), continuous pain intensity (standardized mean difference: −1.74; 95% CI: −2.17 to −1.30, p < 0.0001), duration of pain relief (standardized mean difference: 0.96, 95% CI: 0.69 to 1.22, p < 0.0001), performance status (weighted mean difference: 10.71; 95% CI: 4.89 to 16.53, p = 0.0003), and opioid usage (weighted mean difference: −20.66 mg/day; 95% CI: −30.22 to −11.10, p < 0.0001). No significant difference was observed between EAHM and conventional medicine on response rate and other outcomes. Patients treated with EAHM had significantly reduced adverse event (AE) incidence rates. In addition, based on the ingredients of herb data in this meta-analysis, four combinations of herb pairs, which were frequently used together for cancer pain, were derived. Conclusion: EAHM monotherapy can decrease adverse events associated with pain management in cancer patients. Additionally, EAHM-combined conventional medicine therapy may be beneficial for patients with cancer pain in increasing the response rate, relieving pain intensity, improving pain-related performance status, and regulating opioid usage. However, the efficacy and safety of EAHM monotherapy are difficult to conclude due to the lack of methodological quality and quantity of studies. More well-designed, multicenter, double-blind, and placebo-controlled randomized clinical trials are needed in the future. In terms of the core herb combination patterns derived from the present review, four combinations of herb pairs might be promising for cancer pain because they have been often distinctly used for cancer patients in East Asia. Thus, they are considered to be worth a follow-up study to elucidate their actions and effects. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021265804

Does application of honey improve surgical outcome in pilonidal cyst excision with secondary intention healing? A prospective randomized placebo-controlled clinical trial

BackgroundPilonidal sinus disease (PSD) is a common chronic inflammatory debilitating illness caused by ingrowth of hair into the skin. Excision and healing by secondary intention is one of the acceptable managements. The post-operative wound care needs frequent and time-consuming follow-ups. Honey is considered to be a traditional remedy for wound healing. The current study aimed at finding if application of honey could improve surgical outcome in pilonidal cyst excision with secondary intention healing.MethodsThis study was designed as a randomized placebo-controlled parallel assignment interventional (clinical trial) study conducted at the surgical ward of Shahid Beheshti Hospital affiliated to the Yasuj University of Medical sciences, Yasuj, Iran, and was consisted of the 48 patients who underwent surgical resection for PSD with secondary intention healing (24 patients in intervention and placebo-controlled groups). The main element of honey medicinal gel was the unheated natural honey of Dena Biosphere Reserve within the Zagros Mountains. Patients' wounds were visited by a surgeon and a nurse on the days 7, 15, 30, 45, 60, and 90 post-operation. The surgical outcomes including the time to complete wound healing, pain intensity, odor, discharge at the site of surgery, use of analgesics, the time of to return to the daily activities, and occurring of any side effects including infection, erythema, and bleeding were all recorded.ResultsIn intervention group, there was significantly lower wound healing time, the lower time to return to the daily activities, lower mean wound volume at the days of 30, 45, 60, and 90 of the follow-up, higher mean post-operative pain level at the days of 15, 30, 45, 60, and 90 of the follow-up, and more usage of analgesics at the days of 15, 30, 45, and 60 of the follow-up. There was no significant difference between intervention and placebo-controlled groups according to the foul smell and fluid discharge at the site of the operation. There were no side effects and complications in both groups of the study.ConclusionsApplication of honey after resection surgery with secondary wound healing is associated with a better surgical outcome and could eventually decrease healing time and reduce duration of return to normal activities, but could increase post-operation pain and analgesic consumption, and no effect on foul smell and discharge.Trial registrationThe project was found to be in accordance to the ethical principles and the national norms and standards for conducting research in Iran with the approval ID and date of IR.YUMS.REC.1399.088 and 2020.05.30 respectively, and is the result of a residency dissertation to get the specialty in general surgery, which has been registered with the research project number 960508 in the Vice Chancellor for Research and Technology Development of Yasuj University of Medical Sciences, Yasuj, Iran, URL: https://ethics.research.ac.ir/EthicsProposalViewEn.php?id=144742

Double-blind placebo-controlled randomized clinical trial to assess the efficacy of montelukast in mild to moderate respiratory symptoms of patients with long COVID: E-SPERANZA COVID Project study protocol

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable.ObjectivesTo evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality.Methods and analysisPhase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast.Ethics and disseminationThis study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals.Trial registrationClinicalTrials.govNCT04695704. Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.

Cardiovascular and Osteoporosis Protection at Menopause with Lycopene: A Placebo-Controlled Double-Blind Randomized Clinical Trial.

Objective:The effect of lycopene (LycoRed) supplementation was evaluated in healthy postmenopausal women by biochemical markers for cardiovascular protection and osteoporosis protection.Study Settings and Design:This was a multi-centric placebo-controlled double-blind randomized clinical trial that screened 198 postmenopausal women at 21 centers across 12 cities in India. Levels of lycopene, lipid profile, high-risk C-reactive protein, and bone turnover markers: amino-terminal propeptide of Type I collagen (P1NP) and C-terminal telopeptide of Type I collagen (β-CTx) were measured at baseline and 6 months postsupplementation with LycoRed or placebo.Interventions:The study was completed with 57 of the 100 women on LycoRed 8 mg (antioxidant potency is equivalent to 24 mg of lycopene) and 43 placebos for 6 months by randomization.Main Outcome Measures:Rise in serum lycopene and effect of serum lycopene on surrogate markers of cardiovascular health and bone health.Results:LycoRed supplementation increases lycopene levels and P1NP and nonsignificant fall in β-CTx levels in healthy postmenopausal women.Conclusions:Lycopene supplementation in Indian menopausal women may confer protection from osteoporosis as shown by the directional change in the surrogate biochemical markers. This study can form a basis for larger studies with different doses to understand the effect of lycopene to prevent and act as adjuvant treatment on clinical endpoints for cardiovascular disease (CVD) and bone health.

Hyaluronidase following buccal infiltrations of articaine with epinephrine for anesthesia of mandibular first molars: A split-mouth, double-blind, placebo-controlled randomized clinical trial.

Adjunctive hyaluronidase has been widely used for ophthalmic anesthesia; however, in Dentistry, very few studies are available so far. Thus, the present study aimed to evaluate anesthetic outcomes of adjunctive hyaluronidase administration following buccal infiltration of articaine with epinephrine for anesthesia of mandibular first molars. Twenty-eight patients received a buccal supraperiosteal infiltration of 4% articaine with 1:100,000 epinephrine for anesthesia of the mandibular first molars, in a split-mouth approach. Afterward, randomly and using the same technique, they received either 1.0 mL of hyaluronidase (150 UTR/mL) or a placebo solution. Considering patients' pain perceptions provoked by electric and mechanical stimulations, as well as using a pain scale, success rate, action onset time, duration of both pulpal and soft tissue anesthesia, and pain immediately after both punctures and on the 2nd day were assessed. The pulpal anesthetic success rate was 85.7% for hyaluronidase and placebo groups. Soft tissue anesthesia showed a shorter action onset time and a longer duration when hyaluronidase was used; however, there was no difference between the groups regarding action onset time and duration of pulpal anesthesia. Pain at the puncture sites did not differ between the groups, regardless of the time point evaluated. Adjunctive hyaluronidase following buccal infiltration of articaine with epinephrine for mandibular first molars seems not to provide any advantage in anesthetic outcomes in which the nerve fibers are intraosseous (i.e., pulpal anesthesia). On the other hand, soft tissue anesthesia may be improved substantially by using this pharmacological strategy. Key words:Hyaluronidase, local anesthesia, dentistry.

Efficacy and safety of acetylcysteine for the prevention of liver injury in COVID-19 intensive care unit patients under treatment with remdesivir.

Aim:The present double-blinded placebo-controlled randomized clinical trial evaluated prophylactic use of acetylcysteine for the prevention of liver injury in patients with severe COVID-19 pneumonia under treatment with remdesivir.Background:Liver injury is reportedly common in patients with severe COVID-19 pneumonia and can occur not only as a result of disease progression, but as an iatrogenic reaction to remdesivir.Methods:A total of 83 adult patients with severe COVID-19 pneumonia were randomly assigned in parallel groups to receive either acetylcysteine or placebo. All the patients received standard care according to institutional protocols, including remdesivir for a total of five days. One gram acetylcysteine was administered intravenously every 12 hours for 42 patients, and 41 patients received the same volume of 0.9% sodium chloride as placebo (Trial Registration: www.irct.ir identifier, IRCT20210726051995N1). Results:After 5 days, median aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in the acetylcysteine than in the placebo group. Of those who received the placebo, 30 (73.2%), 4 (9.7%), and 3 (7.3%) patients had serum AST levels elevated between 1-2.5, 2.5-5, and over 5 times the upper limit of normal (ULN), respectively; while in the acetylcysteine group, 33 (78.6%) and 0 patients had AST levels between 1-2.5 and over 2.5 times ULN, respectively (p-value=0.037). In the acetylcysteine group, 23 (54.8%), 1 (2.4%), and 1 (2.4%) patient had serum ALT levels elevated between 1-2.5, 2.5-5, and over 5 times ULN, respectively; in the placebo group, however, 24 (58.5%), 7 (17.1%), and 1 (2.4%) patient had serum ALT levels between 1-2.5, 2.5-5, and over 5 times ULN, respectively (p-value=0.073). Conclusion:Intravenous administration of acetylcysteine significantly prevents liver transaminases elevation and liver injury in seriously ill COVID-19 patients treated with remdesivir.

Effect of 0.5% povidone-iodine on the nasopharyngeal and oropharyngeal viral loads in patients with COVID-19: A double-blind placebo-controlled randomized clinical trial.

The povidone-iodine (PvP-I) nasal antiseptic has been shown to completely inactivate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro at variable concentrations. This study was performed to investigate the effect of 0.5% PvP-I nasal drops and oral gargles on the nasopharyngeal and oropharyngeal viral loads in SARS-CoV-2-positive patients. This was a double-blind, placebo-controlled, randomized clinical trial among patients aged ≥18 years with reverse-transcriptase polymerase chain reaction confirmed in the mild to moderate category of SARS-CoV-2 infection. A total of 32 patients were randomly assigned to receive either freshly prepared 0.5% PvP-I solution or distilled water in the form of supervised self-administered 4-5 nasal drops, followed by 20 ml for gargling for at least 30 seconds. The main outcome measure was the mean change in viral titer and Ct values in the nasopharyngeal and oropharyngeal samples at baseline, 5 minutes, and 3 hours post intervention. The mean change in viral titers across the time duration for the test group when compared with the control group was not statistically significant (P = 0.109). However, the mean change in Ct value was found to be borderline statistically significant (P = 0.042). Noticeable differences were noted among the mean viral titers and Ct values in the intervention group when plotted against the time of testing as compared to the control group. PvP-I solution at 0.5% dilution was well tolerated, and no evident side effects were reported. This study shows that 0.5% PvP-I has an effect on reducing nasopharyngeal and oropharyngeal viral loads in COVID-19 patients. This can be of substantial aid for the primary care physicians, especially for the practitioners in remote and resource poor areas.

Probiotic milk drink as adjuvant therapy for the treatment of periodontitis: a randomized clinical trial with 180 days follow-up

The effect of probiotic milk drinks associated with non-surgical periodontal therapy (NSPT) in treating periodontitis was evaluated. A double-blind placebo-controlled randomized clinical trial with patients with periodontitis was conducted. Two groups were used: TG (n=15, test group, probiotic milk drink, Lacticaseibacillus casei 01, 8-9 log CFU/mL) and CG (n=15, control group, conventional milk drink). The milk drinks (100 mL) were consumed once a day at breakfast for 15 days. Both groups also received NSPT, supra and subgingival scaling and root planning per quadrant, and oral hygiene instruction. All patients were clinically evaluated after 30, 90, and 180 days of the last NSPT session. Reductions in clinical attachment loss and probing pocket depth were observed at 30 days in both groups, maintained throughout the follow-up. Decreases in visible plaque index (VPI) and bleeding on probing were observed after probiotic milk drink consumption for 30 days, suggesting an effect provided by probiotics in the control of biofilm and inflammation. However, the impact on VPI was not persistent for more than 30 days, demonstrating the need for regular consumption of the probiotic milk drink. In conclusion, probiotic milk drinks may be used as adjuvant therapy to treat periodontitis.

Comparing the Effect of Aromatherapy With Geranium and Lemon Essential Oil on Situational Anxiety and Physiological Indices of Patients After Coronary Angioplasty

Objective: Postoperative anxiety, such as coronary artery bypass graft surgery, is one of the most common stressors in this group of patients, which can endanger their physical and mental health. This study aimed to compare the effect of aromatherapy with geranium and lemon essential oil on situational anxiety and physiological indices of patients after coronary angioplasty. Methods: In this placebo-controlled randomized clinical trial study, 150 patients undergoing coronary angioplasty were selected by convenience sampling method and obtained their informed written consent. They were randomly divided into three groups: geranium essential oil, lemon essential oil, and the control group. The patients’ anxiety was measured using a situational anxiety questionnaire before and after the intervention. Also, the physiological indices of patients were measured before and after the intervention. Data analysis was performed at descriptive and inferential levels (analysis of covariance and the Kruskal-Wallis test) in SPSS version 22. Results: The effect of aromatherapy with geranium essential oil on reducing anxiety (35.94±8.64) in patients was significantly greater than aromatherapy with lemon essential oil (44.16±8.72) and almond oil (41.14±5.08) (P&lt;0.001). There was no significant difference between the effect of aromatherapy with almond oil (41.14±5.08) and lemon essential oil (44.16±8.72) in reducing patients’ anxiety (P = 0.241). Also, the effect of aromatherapy with geranium essential oil on reducing pulse rate and systolic blood pressure was significantly greater than aromatherapy with lemon essential oil (P &lt;0.001). Conclusion: According to the results of the present study on the effect of aromatherapy on anxiety in patients after angioplasty, it is recommended to use aromatherapy as a complementary and low-risk treatment to reduce anxiety in this group of patients.

Glycated hemoglobin as a surrogate for evaluating the effectiveness of drugs in diabetes mellitus trials: a systematic review and trial-level meta-analysis.

The objective of this study was to investigate whether glycated hemoglobin (HbA1c) is a valid surrogate for evaluating the effectiveness of antihyperglycemic drugs in diabetes mellitus (DM) trials. We conducted a systematic review of placebo-controlled randomized clinical trials (RCTs) evaluating the effect of a treatment on HbA1c (mean difference between groups) and clinical outcomes (relative risk of mortality, myocardial infarction, stroke, heart failure, and/or kidney injury) in patients with DM. Then, we investigated the association between treatment effects on HbA1c and clinical outcomes using regression analysis at the trial level. Lastly, we interpreted the correlation coefficients (R) using the cut-off points suggested by the Institute for Quality and Efficiency in Healthcare (IQWiG). HbA1c was considered a valid surrogate if it demonstrated a strong association: lower limit of the 95 percent confidence interval (95 percent CI) of R greater than or equal to .85. Nineteen RCTs were identified. All studies included adults with type 2 DM. None of the associations evaluated was strong enough to validate HbA1c as a surrogate for any clinical outcome: mortality (R = .34; 95 percent CI -.14 to .69), myocardial infarction (R = .20; -.30 to .61), heart failure (R = .08; -.40 to .53), kidney injury (R = -.04; -.52 to .47), and stroke (R = .81; .54 to .93). The evidence from multiple placebo-controlled RCTs does not support the use of HbA1c as a surrogate to measure the effectiveness of antihyperglycemic drugs in DM studies.

Assessment of Erenumab Safety and Efficacy in Patients With Migraine With and Without Aura

Migraine with aura may respond differently to therapies than migraine without aura. Individuals with migraine with aura have an elevated vascular risk, necessitating a safety assessment of migraine preventive treatments in this patient subgroup. To assess the efficacy and safety profiles of erenumab in patients with migraine with aura. This post hoc secondary analysis evaluated 4 double-blind, placebo-controlled randomized clinical trials that were conducted in treatment centers in North America, Europe, Russia, and Turkey between August 6, 2013, and November 12, 2019. Participants were adults aged 18 to 65 years with episodic migraine or chronic migraine and were randomized to receive either erenumab or placebo. One or more dose of erenumab (70 mg or 140 mg once per month) or placebo was administered by subcutaneous injection in the double-blind treatment phase and open-label or dose-blinded active treatment, and erenumab, 70 mg or 140 mg, was administered once per month by subcutaneous injection during extension phases. Efficacy assessments included change from baseline monthly migraine days (MMDs) and monthly acute migraine-specific medication (AMSM) days. Safety end points included patient incidences of adverse events. Subgroups of patients were categorized according to their history of aura. Of the 2682 patients who were randomized in the 4 trials, 1400 (52.2%) received 1 or more dose of erenumab, 70 mg or 140 mg, and 1043 (38.9%) received placebo. Patients had a mean (SD) age of 41.7 (11.2) years and were predominantly women (n = 2055 [84.1%]). Reductions from baseline MMDs and AMSM days were greater in the erenumab than placebo groups in patients with and without a history of aura during the double-blind treatment phase, and these reductions were maintained throughout the extension phases. In patients with episodic migraine and a history of aura, least-squares mean differences in change from baseline MMDs at week 12 were -1.1 (95% CI, -1.7 to -0.6) in those who received erenumab, 70 mg, and -0.9 (95% CI, -1.6 to -0.2) in those who received erenumab, 140 mg, compared with placebo. In patients with chronic migraine with a history of aura, the least-squares mean differences from placebo treatment were -2.1 (95% CI, -3.8 to -0.5) in those who received erenumab, 70 mg, and -3.1 (95% CI, -4.8 to -1.4) in those who received erenumab, 140 mg. Overall safety profiles were similar across treatment groups regardless of aura history and were comparable to that of placebo over 12 weeks, with no increased emergence of adverse events over time. Results of this secondary analysis of 4 randomized clinical trials showed reduced migraine frequency and AMSM days with erenumab treatment in patients with migraine with and without a history of aura. The findings support the efficacy and safety of using erenumab in this patient population. ClinicalTrials.gov Identifiers: NCT01952574, NCT02456740, NCT02483585, NTCT02066415, and NCT02174861.

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome

In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses. This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39.

Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study.

(1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients’ characteristics, medical conditions, and use of other medications. (3) Results: This analysis showed a significant association between hydroxyzine use and reduced mortality (AOR, 0.51; 95%CI, 0.29–0.88, p = 0.016). This association was similar in multiple sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, the use of the FIASMA hydroxyzine was associated with reduced mortality in patients hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the potential usefulness of this medication for outpatients and as post-exposure prophylaxis for individuals at high risk for severe COVID-19.