Placebo-controlled Randomized Clinical Trial Research Articles

Myo-inositol supplementation improves cardiometabolic factors, anthropometric measures, and liver function in obese patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of metabolic syndrome is closely associated with type 2 diabetes mellitus. Myo-inositol (MI)-a 6-C sugar alcohol-with insulin-mimetic, anti-diabetic, lipid-lowering, and anti-inflammatory properties has exerted favorable effects on insulin resistance-related disorders and metabolic disease, while recent animal studies revealed its positive effects on liver function. This study aimed to investigate the effects of MI supplementation on cardiometabolic factors, anthropometric measures, and liver function in obese patients with NAFLD. This double-blinded placebo-controlled randomized clinical trial was carried out on 48 obese patients with NAFLD who were randomly assigned to either MI (4g/day) or placebo (maltodextrin 4g/day) along with dietary recommendations for 8 weeks. Glycemic indices, lipid profile, liver enzymes anthropometric measures, and blood pressure were evaluated pre- and post-intervention. Dietary intakes were assessed using a 3-day 24 h recall and analyzed by Nutritionist IV software. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), and beta-cell function (HOMA-B) was also estimated. Anthropometric measures decreased significantly in both groups, while the reduction in weight (p = 0.049) and systolic blood pressure (p = 0.006) in the MI group was significantly greater than in the placebo group after adjusting for baseline values and energy intake. Although energy and macronutrient intakes decreased significantly in both groups, between-group differences were not significant after adjusting for the potential confounders. MI supplementation led to a significant reduction in serum fasting insulin (p = 0.008) and HOMA-IR (p = 0.046). There were significant improvements in lipid profile, liver enzymes, and aspartate aminotransferase/alanine aminotransferase ratio as well as serum ferritin level in the MI group, compared to the placebo group at the endpoint. By MI supplementation for eight weeks, 1 in 3 patients reduced one- grade in the severity of NAFLD. MI supplementation could significantly improve IR, lipid profile, and liver function in patients with NAFLD. Further clinical trials with larger sample sizes, longer duration, different MI doses, and other inositol derivatives are recommended.

Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior. To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD. This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021. Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo. Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal. Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02). Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire. isrctn.org Identifier: ISRCTN17271094.

Saroglitazar, a Dual PPAR α/γ Agonist, Improves Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver Disease: A Pooled Analysis

Cardiovascular disease is the leading cause of mortality in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effects of saroglitazar, a dual peroxisome proliferator-activated receptor α/γ agonist, on serum lipids in patients with NAFLD. A total of 221 patients (saroglitazar, 130; placebo, 91) with NAFLD from phase 2 and 3 double-blinded placebo-controlled randomized clinical trials were pooled to assess the impact of saroglitazar magnesium 4 mg on traditional lipids, very low density lipoprotein cholesterol (VLDL-C), and small dense LDL-C (sdLDL-C). Change from baseline in lipid parameters was performed by using analysis of covariance including treatment as fixed effect and baseline value, diabetes, hypertension, and statin use as covariates. Treatment with saroglitazar significantly improved total cholesterol (-17 mg/dL, 95% confidence interval [CI], -24 to 9; P < .001), triglyceride (-45 mg/dL, 95% CI, -60 to 31; P < .001), low-density lipoprotein cholesterol (-8 mg/dL, 95% CI, -15 to -1; P= .01), and VLDL-C (-8mg/dL, -14 to -3; P < .001). Saroglitazar improved serum lipids as early as 4-6 weeks of initiation of therapy, and these effects persisted for duration of therapy. Saroglitazar also improved the highly atherogenic sdLDL-C (-10 mg/dL, -17 to -2; P= .01). In subgroup analysis of patients with either diabetes or hypertension, saroglitazar significantly improved serum lipids. Saroglitazar improved the serum atherogenic lipoprotein profile in patients with NAFLD, irrespective of comorbid conditions and statin use. Saroglitazar has the potential to not only positively affect liver disease but also reduce cardiovascular risk in patients with NAFLD. (Trials registrations: CTRI 2015/10/006236, CTRI 173300410A0106, NCT03863574, and NCT03061721).

PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE HEPATITIS: OVERLAPPING CHALLENGES IN DIAGNOSIS AND TREATMENT

Abstract Overlap syndromes (OS) describe the simultaneous presentation of more than one immune-mediated liver disease in a singular patient, and present unique challenges both in diagnosis and treatment. Here we report a case of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) OS, ultimately treated with Vancomycin. A 30-year-old female with known ulcerative pancolitis (UC) and alcoholic cirrhosis in the setting of AIH presented to the ED with severe abdominal pain, bloody diarrhea, and bilious emesis. Initial labs showed ESR 48 mm/hr, CRP 32.97 mg/L, fecal calprotectin 1131.2 µg/mg, AST 45 IU/L, and total protein 9.1 g/dL. Clostridium Difficile and stool studies were negative. Patient was admitted with concern for acute UC flare. CT scan showed mild worsening of intrahepatic and extrahepatic biliary ductal dilatation suspicious for PSC, and a cirrhotic liver with signs of portal hypertension and splenomegaly (Fig. 1a). Endoscopy revealed multiple non-bleeding duodenal ulcers and grade II esophageal varices. Colonoscopy found moderately active UC Mayo score 2, worsened from prior exam. MRCP was significant for cirrhotic liver morphology with nodular surface contour, and intrahepatic and extrahepatic biliary dilatation with beading and irregularity of the intrahepatic biliary tree and cystic duct, consistent with PSC (Fig. 1b). She was diagnosed with PSC-AIH OS and underwent treatment with Prednisone, Azathioprine, and Ustekinumab with minimal improvement. Only after the addition of Vancomycin was there normalization of biochemical markers and clinical status. Autoimmune liver disease is generally categorized into hepatic (AIH) or cholestatic (PSC and PBC) predominance. PSC is known to be associated with IBD, specifically UC. It is hypothesized that PSC evolves in UC patients due to uptake into the enterohepatic circulation of proinflammatory cells from the colon; these agents typically concentrate in the biliary system where they ultimately cause the biliary ductal damage frequently seen with PSC. By targeting enteric bacteria, Vancomycin decreases the absorption of these inflammatory biliary toxins. For PSC patients with UC and co-occurring AIH, the addition of Vancomycin could significantly reduce mortality and disease burden. Several case reports and one pilot study have investigated Vancomycin’s role in the treatment of PSC. However, it remains a vastly underutilized therapy, and its role specifically in PSC-AIH OS has not been previously reported. There remains an evident need for a large double blind randomized placebo-controlled clinical trial to further support the addition of Vancomycin to the standard treatment regimen for PSC, and to establish clear parameters on effective dosage and length of treatment. In the meantime, clinicians should be aware of the possible use of Vancomycin to treat patients with PSC +/- AIH and IBD. Figure 1a: CT abdomen pelvis with IV contrast highlighting stigmata of cirrhosis with portal hypertension and splenomegaly. Image also shows worsening of intrahepatic and extrahepatic biliary ductal dilatation in the setting of PSC given the patient’s underlying history of ulcerative colitis. Figure 1b: MRCP showing beading and irregularity of the intrahepatic biliary tree and cystic duct, in keeping with known history of primary sclerosing cholangitis. This image also highlights the dilation of the intrahepatic and extrahepatic biliary system.

The Static and dynamic functional connectivity characteristics of the left temporoparietal junction region in schizophrenia patients with auditory verbal hallucinations during low-frequency rTMS treatment.

Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia. Low-frequency (e.g., 1 Hz) repetitive transcranial magnetic stimulation (rTMS) targeting language processing regions (e.g., left TPJ) has been evident as a potential treatment for AVH. However, the underlying neural mechanisms of the rTMS treatment effect remain unclear. The present study aimed to investigate the effects of 1 Hz rTMS on functional connectivity (FC) of the temporoparietal junction area (TPJ) seed with the whole brain in schizophrenia patients with AVH. Using a single-blind placebo-controlled randomized clinical trial, 55 patients with AVH were randomly divided into active treatment group (n = 30) or placebo group (n = 25). The active treatment group receive 15-day 1 Hz rTMS stimulation to the left TPJ, whereas the placebo group received sham rTMS stimulation to the same site. Resting-state fMRI scans and clinical measures were acquired for all patients before and after treatment. The seed-based (left TPJ) static and DFC was used to assess the connectivity characteristics during rTMS treatment in patients with AVH. Overall, symptom improvement following 1 Hz rTMS treatment was found in the active treatment group, whereas no change occurred in the placebo group. Moreover, decreased static FC (SFC) of the left TPJ with the right temporal lobes, as well as increased SFC with the prefrontal cortex and subcortical structure were observed in active rTMS group. Increased dynamic FC (DFC) of the left TPJ with frontoparietal areas was also found in the active rTMS group. However, seed-based SFC and DFC were reduced to a great extent in the placebo group. In addition, these changed FC (SFC) strengths in the active rTMS group were associated with reduced severity of clinical outcomes (e.g., positive symptoms). The application of 1 Hz rTMS over the left TPJ may affect connectivity characteristics of the targeted region and contribute to clinical improvement, which shed light on the therapeutic effect of rTMS on schizophrenia with AVH.

Vitamin D supplementation on prediabetic adults with vitamin D deficiency: a double-blind placebo-controlled randomized clinical trial

Hypovitaminosis D (&lt;20 ng/mL) is thought to increase insulin resistance and meta-inflammation contributing to the pathogenesis of diabetes mellitus (DM). Correcting vitamin D deficiency in people with prediabetes might halt its progression to DM. The aim of this study was to examine the effect of vitamin D supplementation on insulin resistance, glycemic status, and inflammation in prediabetic adults with vitamin D deficiency. This doubleblind randomized placebo-controlled trial was done among 27 newly detected prediabetic adults with hypovitaminosis D randomly assigned to 60,000 IU of vitamin D weekly for eight weeks followed by monthly for the next four months or placebo along with lifestyle modification in both groups [vitamin D (n= 14) vs. Placebo (n=13). They were comparable in terms of sex, age and borlymass index. Glycemic status, fasting plasma glucose (FPG) and Hemoglobin A1C (HbA1C), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR) and inflammatory marker high sensitivity C reactive protein (hs-CRP) were measured at baseline and after six months of intervention. Vitamin D levels (ng/mL) increased in both groups from baseline (vitamin D vs. placebo: 12.2±5.9 vs. 3.9±3.5, mean±SD). FPG (mmol/L) significantly decreased in the Vitamin D group (before vs. after: 5.9±0.6 vs. 5.5±0.7, P=0.016, mean±SD), whereas HbA1C (%) and hs- CRP (mg/L) significantly increased in the placebo group (before vs. after- HbA1C: 5.8±0.3 vs. 6.0±0.4, P&lt;0.001; hs-CRP: 5.0±4.4 vs. 5.6±4.9, P=0.039, mean±SD). Percent changes in glycemic status, HOMA-IR, and hs-CRP were statistically similar between the groups. Our study failed to demonstrate the positive effects of vitamin D supplementation on reducing glucose, insulin resistance, or inflammatory marker in prediabetic adult patients with hypovitaminosis D. BSMMU J 2022; 15(3): 167-174

Apremilast in Palmoplantar Psoriasis and Palmoplantar Pustulosis: A Systematic Review and Meta-analysis.

This review's goals were to investigate apremilast's efficacy versus placebo in palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP), and apremilast's efficacy versus methotrexate in PP. A literature search was conducted in PubMed, clinicaltrials.gov, and Embase in July 2022. Publications investigating subjects with PP or PPP, treated with apremilast, which reported palmoplantar-specific outcomes were used. Exclusion criteria included cases of drug-induced PP/PPP, case studies, non-English texts, omission of palmoplantar-specific outcomes, and incomplete publications. Studies were assessed for risk of bias using Cochrane Review Manager application and CASP checklist. Primary endpoints were a 50% improvement of the Palmoplantar Psoriasis/Pustulosis Area and Severity Index (PPPASI 50) and improvement of the Palmoplantar Physician Global Assessment (PPPGA) to 0 or 1 in patients with baseline PPPGA ≥ 3. Seventeen original studies including five placebo-controlled randomized clinical trials (RCTs), one phase II clinical trial, two randomized methotrexate comparative trials, six cohort studies, and three case series were analyzed, totaling 1117 participants. Meta-analysis of four placebo-controlled RCTs investigating PP found apremilast treatment to be superior to placebo in achieving a PPPGA of 0/1 (baseline PPPGA of ≥ 3) after 16weeks of treatment (n = 244; OR = 2.69 [1.39-5.22]). Apremilast was superior to placebo in achieving PPPASI 50 at week 16 in the only placebo-controlled RCT of PPP (78.3 vs. 40.9%) [P = 0.0003]. Apremilast was comparable to methotrexate in achieving PPPASI 50 at week 16 in PP (59.5 vs. 64.3%; n = 84; [P = 0.65]). Non-randomized studies generally showed marked improvement in PPPASI, PPPGA, and DLQI scores following apremilast treatment. Apremilast treatment in PP and PPP resulted in significant improvement in objective, palmoplantar-specific clinical parameters versus placebo, and comparable efficacy with methotrexate in PP. Limitations in interpreting these results include variations in palmoplantar-specific metrics used and risk of bias of included studies.

The effectiveness of galactomyces ferment filtrate, dexpanthenol, and Centella asiatica combination serum in the treatment of post-acne hyperpigmentation

Background: Acne vulgaris is a chronic inflammation of the pilosebaceous gland that may result in non-inflammatory and inflammatory lesions. A hypermelanotic reaction to skin inflammation causes post-acne hyperpigmentation (PAH). It can occur secondary to the inflammation process and, depending on the severity, may persist for a prolonged period.&#x0D; Objective To determine the effectiveness of galactomyces ferment filtrate (GFF), dexpanthenol, and Centella asiatica combination serum in the treatment of PAH&#x0D; Methods: This was a placebo-controlled randomized clinical trial. Sixty-eight subjects were divided into two groups: the experimental group received combination serum while the control group received a placebo for eight weeks. Three drops of serum were applied to the area with PAH twice daily in the morning and night. The melanin, erythema, roughness, and L*, a*, and b* scores were assessed objectively using mexameter, chromameter and skin analyzer every two weeks. Pearson’s correlation test and independent T-test were used to assess the trend of the parameters and compare the results of both groups.&#x0D; Results: The results of statistical calculations using the Pearson correlation test showed the treatment group showed a significant decreasing trend of the melanin and spots score. Both groups showed a significant decreasing trend in erythema, L* score and roughness. However, no significant difference was found between both groups in all parameters.&#x0D; Conclusion: The combination serum may decrease the melanin and spot scores suggesting that it affects the melanocyte activity. It has shown good efficacy in treating PAH.

Evaluation of the effect of melatonin in patients with Burning mouth syndrome: a double-blind, placebo-controlled randomized clinical trial

The present study was carried out to evaluate the effect of Melatonin and Placebo in the patient with the Burning mouth (BMs). This double-blind, placebo-controlled randomized clinical trial study was carried out on 30 patients who were suffering from BMS. During this period patients were divided into 2 study and control groups. The study group used four 3 mg Melatonin daily and the control group received a placebo. Then the severity of the burning sensation was measured by the physician Sleep quality was measured using the VAS scale using the Petersburg questionnaire. Data in the application Enter SPSS 20 and then using T test or equivalent Nonparametric was analyzed, mean sleep score and mean severity of oral irritation before and after treatment in two the group was evaluated using T-test Independent. Level significance was considered 0.05. The results of the present study show that the use of melatonin and a placebo in patients with BMS reduces sensation and improves their sleep quality, although it may not reduce it completely. In this study severity of burning was 4.93±2.56 after treatment in the study group and 6.93±2.12 in the control group, which was statistically significant (P =0.036). No significant difference was observed between the two groups in the sleep quality score (P-value = 0.43). Using Melatonin can be a reliable way to treat pain for which there is no standard treatment to date. Although evidence suggests an association between sleep disorders and BMS, melatonin was not superior to a placebo in reducing BMS-induced burning in the present study. Identification of stressors and the ways to struggle with them, further studies with larger samples and higher oral doses, extended follow-up periods and control of psychological factors, and measurement of body mass index that may affect pharmacokinetics are recommended.

Effect of vitamin A on recovery from the acute phase of multiple sclerosis-related optic neuritis, double-blind, randomized, placebo-controlled trial.

Optic neuritis (ON) is one of the main neuro-ophthalmic presentations of multiple sclerosis (MS), and it causes optic nerve atrophy and axonal loss. However, so far, there is no effective treatment to improve long-term outcomes. In a double-blind placebo-controlled randomized clinical trial, 50 patients with MS-related ON were allocated into two arms (24 in the control group and 26 in the intervention group) receiving either 25000IU retinyl palmitate or an identical placebo for six months. Visual evoked potential (VEP), visual acuity, and the retinal nerve fiber layer (RNFL) thickness were evaluated and compared before and after the treatment. RNFL thickness reduction in the affected eyes at sixth month compared to the baseline were 14.81 and 19.46 μm, in the intervention and control groups, respectively (P=0.017). However, VitA therapy did not affect visual acuity and VEP. Vitamin A supplementation in the patients with acute ON in MS could lessen optic nerve axonal loss.

The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial.

Effective parenteral and enteral amino acid replacement is crucial for critically ill patients with altered amino acid metabolism. This study aimed to assess the effects of l-citrulline supplementation on the clinical and laboratory outcomes in critically patients. This was a double-blind placebo-controlled randomized clinical trial. 82 critically ill patients who were expected to receive mechanical ventilation for more than 72 hours were selected. The patients were assigned to either a placebo or an intervention group. The patients in the placebo group received 10 gr of microcrystalline cellulose and the ones in the intervention group were given l-citrulline daily for 7 days. Serum levels of fasting blood sugar (FBS), lipid profile, hepatic enzymes, serum electrolytes, urea nitrogen, creatinine, and C-reactive protein (CRP) were evaluated before and after the intervention. Duration of invasive ventilation, intensive care unit (ICU) length of stay, ventilator-free days, and 28-day mortality rate were recorded and compared between groups. Eighty-two patients completed the trial. No statistically significant differences were observed between the two groups in terms of age (p = 0.46), sex (p = 0.49), body mass index (BMI) (p = 0.41), Sequential Organ Failure Assessment (SOFA) Score (p = 0.08), Clinical Pulmonary Infection Score (CPIS) score (p = 0.76), Acute Physiology and Chronic Health Evaluation (APACHE II) score (p = 0.58), risk factors (p = 0.13), ICU stay before randomization (p = 0.32), and reason of admission (p = 0.50) before the intervention. Citrulline group had a notable reduction in FBS (p = 0.04), total cholesterol (TC) (p = 0.02), low density lipoprotein (LDL-C) (p <0.001) and high-sensitivity CRP (hs-CRP) (p <0.001). Also, a significant increase in lactate dehydrogenase (LDH) concentration (p <0.001) was observed in the intervention group at the end of the trial. Total duration of invasive ventilation and the mean SOFA score on 7th day were significantly lower in the citrulline group compared to the control group. Moreover, a significant increase in days alive and ventilator-free days within 28 days after admission was found in the citrulline group at the end of the trial. Also, there were no significant differences between the groups in terms of mortality rate during intervention, serious adverse events, endotracheal intubation, the use of tracheotomy or non-invasive ventilation after extubation, length of ICU stay, ICU-free days at 28 days, and CPIS and APACHE II scores. For mortality, in the citrulline group, there was two deaths compared to eight deaths in the control group. This resulted in an absolute risk reduction (ARR) of 14.05% (95% CI: 0.39-27.71%) and a number needed to treat (NNT) of 7.1 (95% CI: 3.6-29.5), regarding mortality. The results of the present study demonstrated the probable positive effects of citrulline supplementation on lipid profile, hs-CRP levels, duration of invasive ventilation, and SOFA score. Also, l-citrulline consumption may increase the probability of survival without mechanical ventilation.

The Effects of Pharmacological Treatment of Nightmares: A Systematic Literature Review and Meta-Analysis of Placebo-Controlled, Randomized Clinical Trials.

Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and meta-analysis of the effects of different pharmacological placebo-controlled randomized clinical trials, covering the period up to 1 December 2022, was performed. Searches were conducted in PubMed, Embase, Web of Science, PsychInfo, Cinahl, and Google Scholar, resulting in the identification of 1762 articles, of which 14 met the inclusion criteria: pharmacological intervention of nightmares, based on a placebo-controlled randomized trial published in a European language, reporting outcomes either/or in terms of nightmare frequency, nightmare distress, or nightmare intensity, and reporting sufficient information enabling calculation of effect sizes. Most studies involved the effect of the α1-adrenergic antagonist prazosin in samples of veterans or soldiers suffering from posttraumatic stress disorder. Other medications used were hydroxyzine, clonazepam, cyproheptadine, nabilone, and doxazosin. The vast majority of studies were conducted in the USA. The studies comprised a total of 830 participants. The Clinician-Administered PTSD Scale was the most frequently used outcome measure. The results showed an overall effect size of Hedges' g = 0.50 (0.42 after adjustment for publication bias). The synthetic cannabinoid nabilone (one study) showed the highest effect size (g = 1.86), followed by the histamine H1-antagonist hydroxyzine (one study), and prazosin (10 studies), with effect sizes of g = 1.17 and g = 0.54, respectively. Findings and limitations are discussed, and recommendations for future studies are provided.

Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates

Extremely low gestational age neonates are at risk of disorders of fluid balance (FB), defined as change in fluid weight over a specific period. Few data exist on the association between FB and respiratory outcomes in this population. To describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of extremely low gestational age neonates. This study is a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 874 extremely premature neonates born at 24 to 27 weeks' gestation who were enrolled in the PENUT study. Secondary analysis was performed in November 2021. Primary exposure was peak FB during the first 14 postnatal days. The FB was calculated as percent change in weight from birth weight (BW) as a surrogate for FB. The primary outcome was mechanical ventilation on postnatal day 14. The secondary outcome was a composite of severe bronchopulmonary dysplasia (BPD) or death. A total of 874 neonates (449 [51.4%] male; mean [SD] BW, 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity; 226 [25.9%] Black, 569 [65.1%] White, 51 [5.8%] of other race, and 28 [3.2%] of unknown race) were included in this analysis. Of these 874 neonates, 458 (52.4%) received mechanical ventilation on postnatal day 14, and 291 (33.3%) had severe BPD or had died. Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). A total of 93 (10.6%) never decreased below their BW. Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not require mechanical ventilation (15% above BW vs 8% above BW, P < .001). On postnatal day 3, neonates requiring mechanical ventilation were more likely to have a higher FB (5% below BW vs 8% below BW, P < .001). The median time to return to BW was shorter in neonates who received mechanical ventilation (7 vs 8 days, P < .001) and those with severe BPD (7 vs 8 days, P < .001). After adjusting for confounding variables, for every 10% increase in peak FB during the first 14 postnatal days, there was 103% increased odds of receiving mechanical ventilation at postnatal day 14 (adjusted odds ratio, 2.03; 95% CI, 1.64-2.51). In this secondary analysis of a randomized clinical trial, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death. Fluid balance in the first 3 postnatal days and time to return to BW may be potential targets to help guide management and improve respiratory outcomes. ClinicalTrials.gov Identifier: NCT01378273.

Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial

ObjectivesTo evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. MethodsWe performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. ResultsEighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61–1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DiscussionMelatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.

One way or another: Treatment effects of 1 Hz rTMS using different current directions in a small sample of tinnitus patients

IntroductionSo far studies on the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for tinnitus are inconclusive. Two large scale placebo-controlled randomized clinical trials (RCT) examined the efficacy of low frequency temporal cortex rTMS and report different findings. As the used TMS devices differ in their used primary current direction by default, this technical parameter was speculated as a potential reason for the observed incongruences in tinnitus-related outcomes. The aim of the present pilot study was to investigate the treatment effect of 1 Hz rTMS using two different current flows. Materials and MethodsNine tinnitus patients were treated in two different groups each comprised of 10 treatment sessions á 3000 biphasic pulses of 1 Hz rTMS applied over the left temporo-parietal cortex using either an anterior-posterior to posterior-anterior (AP-PA) or posterior-anterior to anterior-posterior (PA-AP) induced current flow. Results1 Hz rTMS with a primary posterior-anterior to anterior-posterior (PA-AP) current flow caused a superior reduction in tinnitus-related symptoms, particularly tinnitus unpleasantness, loudness and tinnitus-related distress. ConclusionsThe present pilot study demonstrated that the technical TMS parameter current direction might be essential for the efficacy of rTMS as a treatment for tinnitus. Systematic investigations of technical TMS parameters like current direction in larger samples of tinnitus patients are highly needed.

1946. Efficacy of Approved versus Unapproved Vaccines for SARS-CoV-2 Infection in Randomised Blinded Clinical Trials

Abstract Background Five SARS-CoV-2 vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Corbevac, Medicago, Clover and Cansino, but are not approved in high income countries. This meta-analysis compared the efficacy of approved and unapproved vaccines in randomised clinical trials (RCTs). Methods A systematic review of clinical trial registries, PUBMED and EMBASE identified placebo-controlled RCTs of SARS-CoV-2 vaccines prospectively evaluating risks of symptomatic or severe infection with clearly defined endpoints. For each trial, risk of bias was assessed using Cochrane tool 2.0 and the CONSORT checklist. In the pre-defined meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method). Results There were 21 RCTs assessing efficacy of the COVID-19 vaccines identified. One RCT was excluded for high risk of bias. Ten RCTs in 206,667 participants evaluated 5 approved vaccines; 10 RCTs in 158,599 participants evaluated 8 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% C.I. 68-92%) for approved vaccines versus 72% (95% C.I. 65-77%) for unapproved vaccines, with no significant difference between vaccine types (p=0.13). Prevention of severe SARS-CoV-2 infection was 95% (95% C.I. 78-99%) for approved vaccines versus 84% (95% C.I. 72-91%) for unapproved vaccines (p=0.12). In addition, the risk of serious adverse events was similar between vaccine types (p=0.49). Efficacy of approved and unapproved SARS-CoV-2 vaccines Percentage efficacy of approved and unapproved SARS-CoV-2 vaccines against symptomatic infection (Panel A) and severe disease (Panel B). Vaccines are arranged by approval-status (approved vaccines to the left and unapproved vaccines to the right of discontinuous line) and colour-coded by vaccine type. Error bars represent 95% confidence intervals. RIBSP, Research Institute for Biological Safety Problems; IFV, Instituto Finlay de Vacunas. Conclusion This meta-analysis of 20 RCTs in 365,266 participants, showed no significant difference in efficacy between the approved and unapproved SARS-CoV-2 vaccines for endpoints of either symptomatic or severe infection. Differences in study design, end-point definitions, variants and prevalence of infection may have influenced the results. Head-to-head RCTs will be required to make definitive conclusions. If efficacy is proved definitively, new patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly. Disclosures All Authors: No reported disclosures.

Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy

Postoperative sleep disturbance (PSD) is common in patients after surgery. To examine the effect of intraoperative esketamine infusion on the incidence of PSD in patients who underwent gynecological laparoscopic surgery. This single-center, double-blind, placebo-controlled randomized clinical trial was conducted from August 2021 to April 2022 in the First Affiliated Hospital of Zhengzhou University in China. Participants included patients aged 18 to 65 years with an American Society of Anesthesiologist Physical Status classification of I to III (with I indicating a healthy patient, II a patient with mild systemic disease, and III a patient with severe systemic disease) who underwent gynecological laparoscopic surgery. Patients were randomly assigned to either the esketamine group or control group. Data were analyzed using the per protocol principle. Patients in the esketamine group received a continuous infusion of esketamine, 0.3 mg/kg/h, intraoperatively. Patients in the control group received an equivalent volume of saline. The primary outcome was the incidence of PSD on postoperative days (PODs) 1 and 3. Postoperative sleep disturbance was defined as a numeric rating scale score of 6 or higher or an Athens Insomnia Scale score of 6 points or higher. The secondary outcomes included postoperative anxiety and depression scores using the Hospital Anxiety and Depression Scale, postoperative pain using the visual analog scale, postoperative hydromorphone consumption, and risk factors associated with PSD. A total of 183 female patients were randomized to the control group (n = 91; median [IQR] age, 45 [35-49] years) and the esketamine group (n = 92; median [IQR] age, 43 [32-49] years). The incidence of PSD in the esketamine group was significantly lower than in the control group on POD 1 (22.8% vs 44.0%; odds ratio [OR], 0.38 [95% CI, 0.20-0.72]; P = .002) and POD 3 (7.6% vs 19.8%; OR, 0.33 [95% CI, 0.13-0.84]; P = .02). There were no differences in postoperative depression and anxiety scores between the 2 groups. Postoperative hydromorphone consumption in the first 24 hours (3.0 [range, 2.8-3.3] mg vs 3.2 [range, 2.9-3.4] mg; P = .04) and pain scores on movement (3 [3-4] vs 4 [3-5] points; P < .001) were significantly lower in the esketamine group than in the control group. On multivariable logistic regression, preoperative depression (OR, 1.31; 95% CI, 1.01-1.70) and anxiety (OR, 1.67; 95% CI, 1.04-1.80) scores, duration of anesthesia (OR, 1.04; 95% CI, 1.00-1.08), and postoperative pain score (OR, 1.92; 95% CI, 1.24-2.96) were identified as risk factors associated with PSD. Results of this trial showed the prophylactic effect of intraoperative esketamine infusion on the incidence of PSD in patients who underwent gynecological laparoscopic surgery. Further studies are needed to confirm these results. Chinese Clinical Trial Registry Identifier: ChiCTR2100048587.

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol

IntroductionSepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one...

Prevention of young infant infections using oral azithromycin in labour in Fiji (Bulabula MaPei): study protocol of a randomised control trial

IntroductionInfections are a leading cause of neonatal mortality globally and can be transmitted from mother-to-child vertically or horizontally. Fiji has higher rates of serious neonatal infections and infant skin and...

Influence of Vitamin D Supplementation on Growth, Body Composition, and Pubertal Development Among School-aged Children in an Area With a High Prevalence of Vitamin D Deficiency

Vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] <20 ng/mL) is prevalent among children living in temperate climates and has been reported to associate independently with stunting, obesity, and early activation of the hypothalamic-pituitary-gonadal axis. Phase 3 randomized clinical trials to investigate the influence of long-term vitamin D replacement on growth, body composition, and pubertal development of school-aged children with vitamin D deficiency are lacking. To determine whether weekly oral vitamin D supplementation influences linear growth, body composition, or pubertal development in school-aged children living in a setting where vitamin D deficiency is highly prevalent. This secondary analysis of a double-blind, placebo-controlled randomized clinical trial was conducted from June 2016 to June 2019 at 18 grade schools in Ulaanbaatar, Mongolia. School-aged children (6 to 13 years at baseline) attending participating schools were included. Exclusion criteria included a positive QuantiFERON-TB Gold in-tube assay result, conditions or medications associated with altered vitamin D metabolism, use of vitamin D supplements, signs of rickets, or intention to move from Ulaanbaatar within 4 years. Of 11 475 children invited to participate in the study, 9814 underwent QFT testing, and 8851 with negative results were included in the study. All but 1 participant in the placebo group completed follow-up and were included in the present analysis. Data were analyzed from November 2021 to February 2022. Weekly oral doses of vitamin D3, 14 000 IU, (n = 4418), or placebo (n = 4433) for 3 years. Mean z scores for height for age, body mass index for age, and waist-to-height ratio; mean percentage body fat, fat mass, and fat-free mass; and mean Tanner scores for pubertal development. Of 8851 participants, 4366 (49.3%) were female, and 8165 (92.2%) were of Khalkh ethnicity; the mean (SD) age was 9.4 (1.6) years. A total of 8453 participants (95.5%) were vitamin D deficient at baseline, and mean end-of-study 25(OH)D concentrations among participants randomized to vitamin D vs placebo were 31.0 vs 10.7 ng/mL (mean difference, 20.3; 95% CI; 19.9-20.6). However, vitamin D supplementation did not influence mean height for age, body mass index for age, waist-to-height ratio, percentage body fat, fat mass, fat-free mass, or Tanner scores, either overall or within subgroups defined by baseline 25(OH)D concentration less than 10 ng/mL vs 10 ng/mL or greater, estimated calcium intake less than 500 mg/d vs 500 mg/d or greater, or male vs female sex. In school-aged children in this study with low baseline vitamin D status, oral vitamin D3 supplementation at a dose of 14 000 IU per week for 3 years was effective in elevating 25(OH)D concentrations but did not influence growth, body composition, or pubertal development. ClinicalTrials.gov Identifier: NCT02276755.