Placebo-controlled Randomized Trial Research Articles

Effect of Lactobacillus plantarum DAD-13 and Fructo-oligosaccharides on Short-Chain Fatty Acid Profile and Nutritional Status in Indonesian Stunting Children

BACKGROUND: Chronic gut inflammation is a generalized disturbance of small intestine structure and function is likely to play a large role in the incidence of stunting. It will be disturbances the absorption of nutrients, therefore, it can indirectly reduce on nutritional status. AIM: The aim of this study is to examine the effect of Lactobacillus plantarum DAD-13 and fructooligosaccharide on short-chain fatty acid (SCFA) profile and nutritional status in Indonesian stunting children. METHODS: The study design was used double-blind randomized placebo-controlled trial, 39 stunting children under five received daily oral supplementations of L. plantarum DAD-13 1 × 1010 cfu and fructooligosaccharide 700 mg (symbiotic group) or placebo group for 90 days. SCFA profile was analyzed using gas chromatography and nutritional status was assessed by WAZ, HAZ, and WHZ. RESULTS: The result shows in symbiotic and control group, the mean age was 26 ± 8.34 and 29 ± 5.78, and the mean weight was 8.5 ± 0.94 kg and 9.0 ± 0.82 kg, while the mean height was 78.96 ± 5.4 cm and 80.9 ± 4.55 cm, respectively. Concentrations of acetate, propionate, and butyrate in the symbiotic group after consumption were 17.10 ± 2.97, 7.70 ± 2.05, and 7.47 ± 1.76 while in placebo group 12.44 ± 3.61, 5.20 ± 1.66, and 6.12 ± 1.16, respectively. There was a significant difference in the mean SCFA concentration between the symbiotic and placebo groups (p < 0.05), where the SCFA concentration in the symbiotic group was significantly higher than the placebo group. Nutritional status (WAZ, HAZ, and WHZ) was observed significantly in symbiotic group (p < 0.05), only on WHZ has cutoff point >-2SD after the intervention, while WAZ and HAZ <-2SD. CONCLUSIONS: L. plantarum DAD-13 and fructooligosaccharide 90 days supplementation have increase acetate, butyrate, and propionate that are important fuels for intestinal epithelial cells that can play an important role in the maintenance of health.

Vitamin D and Depressive Symptoms in Adults with Multiple Sclerosis: A Scoping Review

Background. Vitamin D deficiency has been correlated with Multiple Sclerosis (MS) risk and disease activity. There is some controversy as to whether vitamin D could have an impact on depressive symptoms in people with MS (pwMS). The aim of this scoping review was to evaluate the association between vitamin D status and depressive symptoms in pwMS. Methods. We searched databases to include studies published up to March 2021 to provide an overview of the available evidence on the correlation between vitamin D status and depressive symptoms in pwMS. The eligibility criteria were as follows: studies evaluating the use of vitamin D measurement on depressive symptoms in patients suffering from MS, including randomized and non-randomized studies; studies written in English; and studies exploring an adult population over the age of 18. Results. Eleven studies met our inclusion criteria: two of them were abstracts only; the majority were cross-sectional studies; two were prospective longitudinal studies; one was a retrospective cohort study; and one was a randomized placebo-controlled trial (RCT). Of the eleven studies selected, seven showed a potential correlation between low vitamin D levels and depressive symptoms. Conclusion. Future RCT studies should include patients with greater severity of depressive symptoms and should consider confounding factors such as sun exposure and seasonal variation of vitamin D.

Effects of colchicine on major adverse cardiac events in next 6-month period after acute coronary syndrome occurrence; a randomized placebo-control trial

BackgroundCardiovascular disease in particular acute coronary syndrome (ACS) is remained one of the most cause of morbidity and mortality, annually. Considering inflammatory pathway of atherosclerosis, colchicine as an anti-inflammatory drug is introduced to be effective in pathogenesis, prognosis and mortality rate of these patients. So in order to find out the effects of this drug we conducted this trial to know whether it reduces major adverse cardiac events (MACE) in ACS patients or not.MethodsIn a prospective randomized double-blinded placebo-controlled trial, we enrolled ACS patients (40–70 years) with recent ST-segment elevation myocardial infarction (STEMI) or NSTE-ACS diagnosed by coronary angiography and managed with either medical therapy or percutaneous coronary intervention. Patients were assigned to two groups either receiving colchicine 0.5 mg daily or placebo for 6 months. Both groups simultaneously received standard medical therapy as accessible guidelines. MACE occurrence consists of decompensated heart failure, ACS, stroke and survival rate compared between two groups.ResultsA total of 249 patients were recruited between October 2019-March 2020 with mean age of 56.89 ± 7.54, 69.5% males; 120 assigned to the colchicine group and 129 assigned to the placebo group. Over the 6 months’ period, 36 MACE occurred that were 8 events in the colchicine group compared with 28 events in the placebo group experiencing the event (P = 0.001). All of four deaths in the colchicine group and two in the placebo group were due to cardiovascular events. Evaluating adverse effects, gastrointestinal symptom was the most with the rate of 15 (12.5%) in the colchicine group and 3 (2.5%) in the controls. (P = 0.002).ConclusionThe addition of colchicine to standard medical therapy in ACS patients significantly reduces MACE occurrence and improves survival rate over the time.

Invasive versus conservative strategy in the very elderly with non-ST-elevation acute coronary syndrome: A meta-analysis of randomized controlled trials.

To investigate the optimal treatment strategy in patients older than 80 years with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). All published randomized, placebo-controlled trials (RCTs) reporting on comparisons between invasive and conservative strategies for patients aged 80 years or older with NSTE-ACS were identified. The literature search was performed using PubMed, EMBASE, Cochrane Library, and the ISI Web of Science, from their establishment to July 2021 with no language restriction. The pooled risk ratios (RRs) with 95% confidence intervals (CI) for dichotomous outcomes were calculated. Three RCTs involving a total of 893 cases met the inclusion criteria. Compared with the conservative group, the invasive strategy could significantly improve the incidence rate of composite endpoint (I2 = 21.9%; RR 0.727, 95% CI 0.619 to 0.855, P < 0.001), recurrent myocardial infarction (MI) (I2 = 0.0%; RR 0.585, 95% CI 0.441 to 0.776, P < 0.001) and revascularization (I2 = 0.0%; RR 0.239, 95% CI 0.126 to 0.455, P < 0.001). However, no benefits were observed on outcomes of all-cause death (I2 = 0.0%; RR 0.888, 95% CI 0.681 to 1.160, P=0.384), cardiac death (I2 = 0.0%; RR 0.769, 95% CI 0.412 to 1.433, P=0.408) and stroke (I2 = 0.0%; RR 0.778, 95% CI 0.392 to 1.543, P=0.473). The major bleeding events were comparable between the two groups (I2 = 0.0%; RR 1.582, 95% CI 0.622 to 4.025, P=0.336). Compared with a conservative strategy, the invasive treatment could reduce the incidence of composite endpoint, recurrent MI, and revascularization in the very elderly with NSTE-ACS. However, no benefits were observed on mortality. Geriatr Gerontol Int 2022; 22: 36-41.

Does a psychiatric history play a role in the development of psychiatric adverse events to perampanel… and to placebo?

ObjectiveThe purpose of this study was to establish whether a past psychiatric history could play a role in the development of psychiatric treatment-emergent adverse events (PTEAEs) in patients randomized to perampanel (PER) or placebo. MethodsThe development of PTEAEs was compared between patients with/without a psychiatric history in a post hoc analysis from four randomized placebo-controlled trials (RPCTs) of PER (304/305/306/335) in patients with treatment-resistant focal epilepsy. ResultsAmong the 2,187 patients enrolled in the RPCTs, 352 (16.1%) had a psychiatric history (PER n = 244; placebo n = 108), while 1835 patients (83.9%) did not (PER n = 1325; placebo n = 510). Compared to patients without a psychiatric history, those with a positive history reported more PTEAEs for both patients randomized to PER (11.8% vs. 29.9%, p < 0.01) or to placebo (9.2% vs. 19.4%, p < 0.01). The prevalence of PTEAEs was not higher among patients randomized to 2 mg and 4 mg/day doses than placebo in both those with and without psychiatric history. Rather, the higher prevalence rates were among subjects randomized to 8 mg (29.8%) and 12 mg (36.4%) PER doses in patients with a past psychiatric history. SignificanceA psychiatric history appears to increase the risk of PTEAEs in patients randomized to placebo and to PER at doses of 8 and 12 mg/day. It should be identified in all patients considered for treatment with PER, particularly when prescribed at doses above 4 mg/day.

Melatonin and melatonin-agonists for metabolic syndrome components in patients treated with antipsychotics: A systematic review and meta-analysis.

Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long-term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin-agonists in attenuating antipsychotic-induced metabolic abnormalities. We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random-effect meta-analysis of double-blind, randomized placebo-controlled trials (RCTs) involving melatonin and melatonin-agonists in the treatment of antipsychotic-induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia-spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD -0.28, 95% CI=-0.39÷-0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD -3.266, 95% CI=-6.020÷-0.511; fasting glucose MD -3.766, 95% CI=-5.938÷-1.593; triglycerides MD -9.800, 95% CI=-19.431÷-0.169; HDL MD 2.995, 95% CI=0.567÷5.423), except waist circumference. Melatonin/ramelteon augmentation may be beneficial for non-anthropometric metabolic syndrome components in patients treated with antipsychotics.

Metabolic improvement during short-term treatment with a GLP-1 receptor agonist does not improve cardiac diastolic function in patients type 2 diabetes: a randomized double-blind placebo-controlled trial

Abstract Background/Introduction The cardioprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes is still not well explained. In these patients, diastolic dysfunction is significant and linked to outcome, and the cardioprotective effect of GLP-1 receptor agonists may be by improving diastolic function. Purpose To investigate if short-term treatment of liraglutide a GLP-1 receptor agonist improves left ventricular diastolic function. Methods In an investigator-initiated double-blind randomized placebo-controlled trial the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in type 2 diabetes patients and echocardiographic signs of diastolic dysfunction (echo-Doppler determined E/e'≥9 or/and lateral e'≤10 cm/sec). Primary outcomes were improved left ventricle filling (the early peak filling rate, ePFR) and left atrium ease of emptying (the passive emptying fraction, LAPEF), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress (glycopyrrolate 4 mg/kg; a cholinergic receptor antagonist increasing heart rate, and thereby inducing chronotropic stress without also affecting contractility). Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness, and echocardiographic diastolic parameters. Results Forty patients were randomized to liraglutide s.c. 1.8 mg/day (n=20) or placebo (n=20). Liraglutide reduced HbA1c (−0.47% 95% CI (−0.88 to −0.06)) and weight (−2.9kg 95% CI (−4.6 to −1.2)), both p&amp;lt;0.03). Liraglutide did not change ePFR at rest −24±60 vs. −6±46 ml/sec, during stress 2±58 vs. −2±38 ml/sec, or the changes from rest and stress 12.9±72.5 vs. 4.7±104.0, all p&amp;gt;0.05. LAPEF decreased with liraglutide during stress (median (Q1, Q3)) −3.1 (−9.0, 1.1) vs. 1.0 (−2.9, 6.1) %, p=0.049, but no changes were evident at rest −4.3 (−7.9, 1.9) vs. −0.6 (−3.1, 2.2) %, p=0.19, or for the changes from rest to stress −1.7±8.4 vs. 0.8±8.2, p=0.4. All secondary outcomes were unchanged by liraglutide. Conclusions Short-term treatment with liraglutide did not improve diastolic function in patients with type 2 diabetes and echocardiographic signs of diastolic dysfunction. This suggests that the cardioprotective effect seen in long-term studies of liraglutide is not related to the improvement of left ventricular diastolic function. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): ASB has received funding from the Danish Heart Association [16-R107-A6790-22002, and 18-R125-A8444-22110]. Novo Nordisk supported the study by an unrestricted grant covering the costs of CMR scans and blood analyses. Novo Nordisk provided free study medication and matching placebo pens. None of the funding sources played any role in the process of conduction, interpretation of results or publishing the study Primary OutcomesSecondary Outcomes

A Double-Blind, Placebo-Controlled Study of Ultrasound-Guided Pulsed Radiofrequency Treatment of the Saphenous Nerve for Refractory Osteoarthritis-Associated Knee Pain

While the efficacy of pulsed radiofrequency (PRF) for shoulder pain has been demonstrated, its efficacy on the saphenous nerves for knee osteoarthritis (OA)-associated pain has only been reported in observational studies. The aim of this study was to compare saphenous nerve PRF to placebo for knee OA-associated pain. Patients, practitioners, and outcome assessor-blinded randomized placebo-controlled trial. Pain management clinics at 2 hospitals in Japan. Patients were randomly allocated to the PRF (n = 37) or placebo group (n = 33). Patients aged 40-85 years with refractory anteromedial knee pain. PRF in the saphenous nerve under ultrasound guidance. The placebo group underwent the same procedure, but with motor stimulation. The primary endpoint was the average pain intensity measured using the visual analog scale (VAS) at the 12-week post-treatment visit; secondary outcomes included the average VAS at 1 and 4 weeks, and pain intensities at rest, in flexion, at standing, and at walking. Other secondary outcomes were knee pain, symptoms, activities of daily living, knee-related quality of life, mobility, range of motion, and adverse events. In the PRF group, the mean VAS score was 52.41 ± 26.17 at 12 weeks, while in the sham group, the mean VAS score was 63.06 ± 27.12 (P < 0.05). There were no significant differences between the groups in any of the secondary outcomes. Patients with comorbidities were excluded from this study. The follow-up time was limited to 12 weeks. Ultrasound-guided saphenous nerve PRF proved to be effective for at least 12 weeks in patients with knee OA and showed no adverse events.

Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials.

Background: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs).Methods: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates.Results: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96–393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21–30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15–18.30), ivermectin (OR 6.33, 95% CI 1.22–32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12–24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43–17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09–0.19), imatinib (OR 0.49, 95% CI 0.25–0.96), and baricitinib (OR 0.58, 95% CI 0.42–0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08–0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13–0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients.Conclusion: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.

Acupuncture for combat post-traumatic stress disorder: trial development and methodological approach for a randomized controlled clinical trial

BackgroundPost-traumatic stress disorder (PTSD) is a significant public health problem, affecting approximately 7% of the general population and 13–18% of the combat Veteran population. The first study using acupuncture for PTSD in a civilian population showed large pre- to post-treatment effects for an empirically developed verum protocol, which was equivalent to group cognitive behavior therapy and superior to a wait-list control. The primary objective of this study is to determine both clinical and biological effects of verum acupuncture for combat-related PTSD in treatment-seeking US Veterans.MethodsThis is a two-arm, parallel-group, prospective randomized placebo-controlled clinical trial. The experimental condition is verum acupuncture and the placebo control is sham (minimal) acupuncture in 1-h sessions, twice a week for 12 weeks. Ninety subjects will provide adequate power and will be allocated to group by an adaptive randomization procedure. The primary outcome is change in PTSD symptom severity from pre- to post-treatment. The secondary biological outcome is change from pre- to post-treatment in psychophysiological response, startle by electromyographic (EMG) eyeblink. Assessments will be conducted at pre-, mid-, post-, and 1-month post-treatment, blind to group allocation. Intent-to-treat analyses will be conducted.DiscussionThe study results will be definitive because both clinical and biological outcomes will be assessed and correlated. Issues such as the number needed for recruitment and improvement, use of sham acupuncture, choice of biological measure, and future research need will be discussed.Trial registrationClinicalTrials.gov NCT02869646. Registered on 17 August 2016.

Design and methods for the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) study: A randomized controlled trial

Human papillomavirus (HPV) infection, a common sexually transmitted infection, is causally associated with cervical cancer. Vaccination against HPV provides protection; however, HPV vaccines are exclusively prophylactic. Carrageenan, an extract from red algae, demonstrated potent anti-HPV activity in in vitro and animal studies. We describe the protocol for the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) study, an ongoing randomized controlled trial among sexually active young females, aimed at evaluating the efficacy of a carrageenan-based gel in reducing type-specific incidence (i.e. new detections of HPV) and prevalence (i.e. absence of a previously detected HPV) of genital HPV infections as well as participant adherence to the intervention. The CATCH study is a phase IIB double-blind randomized placebo-controlled trial. Eligible women 18 years and older are randomized 1:1 to the carrageenan-containing gel or placebo gel arm. For the first month, participants use the study gel intra-vaginally every other day, and over the 12-month study period, prior to and after each act of vaginal intercourse. At each study visit (months 0, 0.5, 1, 3, 6, 9, 12), participants provide a self-collected vaginal sample and record information on sexual activities, adherence, and adverse events using a computerized questionnaire. The primary outcomes are incident and prevalent type-specific cervicovaginal HPV infection. The primary analyses are based on intention-to-treat whereas per-protocol analyses are conducted based on measures of adherence.Trial registration: ISRCTN96104919.

Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.

Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.

P–375 Intralipid supplementation in women with unexplained recurrent implantation failure and elevated uterine natural killer cell levels - A randomized placebo controlled trial

Abstract Study question Does intralipid supplementation in women with unexplained recurrent implantation failure (RIF) with elevated uterine natural killer cell (uNK) levels improve pregnancy outcomes during IVF? Summary answer Intralipid supplementation appears to improve clinical pregnancy rate in women with unexplained RIF with elevated uNK cell levels. What is known already The increased numbers of uNK cells in peri-implantation endometrium have been reported in women with recurrent miscarriage (RM) and RIF after IVF. However, reports are contradictory when it comes to correlation of increased numbers of uNK cells with pregnancy outcome. Current opinion suggests there is a potential for intralipid therapy in improving reproductive outcome, although data on live birth rate is very limited. No studies have assessed the effect of intralipid on IVF outcomes in RIF women based on elevated uNK cells. Identified studies have all used pNK cell testing as preferred diagnostic tool for analysis of NK cell levels. Study design, size, duration A randomized placebo controlled trial was conducted at Division of Reproductive Medicine at tertiary care institute. Thirty women with RIF and fifty fertile controls with age &amp;lt;35 years having regular menstrual cycles and no hormonal treatment in last 3 months were enrolled in the study from January 2019 to December 2020 for uNK cell testing. Randomization was done using random numbers and sealed envelopes. Only the subjects were masked and allocation concealment was done. Participants/materials, setting, methods Subjects included RIF 20–35 years, normal ovarian reserve, unexplained and tubal factors, normal karyotype and normal uterine cavity. Cut off for uNK cells was derived from fertile controls by immunohistochemical staining of CD56+ cells from midluteal endometrial biopsy sample. Subjects with elevated uNK cell levels were randomized during IVF to group A (Intralipid) or group B ( saline ). The infusion was repeated within one week of positive pregnancy test and then every 2 weeks. Main results and the role of chance The mean age and BMI were comparable between fertile control and study group(29.45±3.3 vs 31.17±3.3 years, 22.97±1.89 vs 23.21±2.2 kg/m2 ;p&amp;gt;0.05). The median uNK cell levels was 7%(used as cut off) in fertile controls and 13.5% in RIF. 18 women (60%, 18/30) with RIF who had elevated uNK cell level (&amp;gt;7%) were randomized. Four women were lost to follow up. The median age, BMI, number of previous failed cycles and duration of infertility were comparable between Group A(n = 7) and Group B(n = 7){30(IQR:27–31) vs 33(IQR:30–34)years, 22.7(IQR:21.08–24.4) vs 22.6(IQR:21.37–24.2)kg/m2, 2(IQR:2–3) vs 2(IQR:2–3), 8(IQR:7–8) vs 8(IQR:7–10)years}. The median FSH, AMH and AFC were 5.86(IQR:5.13–7.67)mIU/l, 2.4(IQR:2.16–6.12)ng/ml, 10(IQR:8–12) in Group A which were comparable with Group B {6.2(IQR:4.78–6.5)mIU/l, 4.8(IQR:2.67–6.25)ng/ml, 12(IQR:12–16) }. All patients underwent antagonist protocol. The clinical pregnancy rate was 57.14%(4/7) in group A which was significantly higher as compared to 28.6%(2/7) in group B(p &amp;lt; 0.05). None of the patients reported any side effects due to intralipid. Limitations, reasons for caution The limitation of present study is its small sample size. However, the study is currently recruiting more RIF patients, and these are the interim results of the same. More RCTs with larger sample size are required to assess the efficacy of intralipid in this specific subset of population. Wider implications of the findings: The present study suggests the beneficial effect of intralipid in women with unexplained RIF with elevated uNK cell levels in increasing the chemical and clinical pregnancy rate. However, ongoing pregnancy rate and live birth rate should be investigated further in this subset of population. Trial registration number CTRI/2019/01/017213

The impact of extracorporeal shock wave therapy for the treatment of young patients with vasculogenic mild erectile dysfunction: A prospective randomized single-blind, sham controlled study.

Low-intensity extracorporeal shock wave therapy (ESWT) for the treatment of vasculogenic erectile dysfunction (ED) has emerged as a promising method directly targeting the underlying pathophysiology of the disease. To compare outcomes in ED patients after ESWT and placebo treatment. Prospective randomized placebo-controlled single-blinded trial on 66 patients with mild ED. The study comprised a 4-week washout phase, a 4-week treatment phase, and a 48-week follow-up. Inclusion criteria included age between 18 and 75years and diagnosis of mild ED (IIEF-EF score=17-25) being made at least six months prior to study inclusion and being confirmed by Penile Doppler ultrasonography (US) at baseline examination. Efficacy endpoints were changes from baseline in patient-reported outcomes of erectile function (International Index of Erectile Function domain scores [IIEF-EF]), as well as erection hardness and duration (Sexual Encounter Profile diary [SEP] and Global Assessment Questions [GAQ]). Safety was assessed throughout the study. A total of 66 enrolled patients were allocated to ESWT (n=44) or placebo (n=22). Mean age of ESWT and placebo group was 42.32±9.88 and 39.86±11.64 (p=0.374), respectively. Mean baseline IIEF-EF scores of ESWT group and placebo were 20.32±2.32 and 19.68±1.55 respectively (p=0.34). At 3-months follow-up, mean IIEF-EF scores were significantly higher in ESWT patients than in placebo patients (23.10±2.82 vs. 20.95±2.19, p=0.003), and IIEF-EF scores of ESWT patients remained high during the 6months (22.67±3.35 vs. 19.82±1.56) follow-up. The percentage of patients reporting both successful penetration (SEP2) and intercourse (SEP3) in more than 50% of attempts was significantly higher in ESWT-treated patients than in placebo patients (p=0.001). A minimal clinically important difference between the IIEF=EF baseline and 3-months follow-up was found in 74% of ESWT and 36% of placebo. No serious adverse events were reported. ESWT significantly improved the erectile function of relatively young patients with vasculogenic mild ED when compared to placebo and the beneficial effect of this treatment up to 6months. These findings suggest that ESWT could be a useful treatment option in vasculogenic ED.

Best timing of tranexamic acid administration for bleeding after trauma or childbirth remains to be established

Haemorrhage is worldwide the leading cause of maternal death1 and an important cause of death after trauma.2 Antifibrinolytic drugs inhibit the lysis of a fibrin clot and are, therefore, used...

Nephroprotective effect of novel oral sugar-reducing medicines: glyflosins

The review is devoted to the consideration of the nephroprotective effect and its mechanisms in new hypoglycemic drugs gliflozins, identified in largescale randomized placebo-controlled trials and experimental studies. It was found that inhibition of sodium-glucose co-transporter 2 (SGLT2) in the proximal tubules of the kidneys when using these drugs not only leads to a decrease in blood glucose levels, a decrease in blood pressure, body weight, and uric acid content in blood plasma but also delays the progression of chronic kidney disease, inhibiting the development of diabetic nephropathy. This beneficial effect is multifactorial. It is caused by the diuretic and natriuretic effects, a decrease in albuminuria, a decrease in glucotoxicity in the cells of the renal tubules, a hemodynamic effect on kidney function, and a direct anti-inflammatory effect. It is discussed why the use of SGLT2 inhibitors restores tubuloglomerular feedback, which is disrupted in the initial period of diabetic nephropathy and leads to hyperfiltration in the remaining nephrons. Information is provided on the restoration of impaired mitochon drial function due to the positive effect of drugs on the ionic composition of renal tubule cells. This greatly contributes to the enhancement of autophagy, the lysosome-mediated pathway of degradation and removal of damaged organelles, and normalizes intracellular homeostasis. The probable mechanism of autophagy enhancement through increased activity of energy deprivation sensors of AMPK and SIRT1 cells is considered. Possible mechanisms of development of anti-inflammatory and antioxidant action of SGLT2 inhibitors through inhibition of inflammasome activity are discussed. The question of the possible use of gliflozins in chronic kidney disease, the pathogenesis of which is not associated with diabetes mellitus, is considered.

N-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.

BackgroundMethamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.MethodsA parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.ResultsParticipants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 76). Both groups had a median (IQR) of 24 (15–28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4–4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6–7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.InterpretationThese findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.

Improvements in clinical signs of Parkinson\u2019s disease using photobiomodulation: a prospective proof-of-concept study

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disease with no cure and few treatment options. Its incidence is increasing due to aging populations, longer disease duration and potentially as a COVID-19 sequela. Photobiomodulation (PBM) has been successfully used in animal models to reduce the signs of PD and to protect dopaminergic neurons.ObjectiveTo assess the effectiveness of PBM to mitigate clinical signs of PD in a prospective proof-of-concept study, using a combination of transcranial and remote treatment, in order to inform on best practice for a larger randomized placebo-controlled trial (RCT).MethodsTwelve participants with idiopathic PD were recruited. Six were randomly chosen to begin 12 weeks of transcranial, intranasal, neck and abdominal PBM. The remaining 6 were waitlisted for 14 weeks before commencing the same treatment. After the 12-week treatment period, all participants were supplied with PBM devices to continue home treatment. Participants were assessed for mobility, fine motor skills, balance and cognition before treatment began, after 4 weeks of treatment, after 12 weeks of treatment and the end of the home treatment period. A Wilcoxon Signed Ranks test was used to assess treatment effectiveness at a significance level of 5%.ResultsMeasures of mobility, cognition, dynamic balance and fine motor skill were significantly improved (p < 0.05) with PBM treatment for 12 weeks and up to one year. Many individual improvements were above the minimal clinically important difference, the threshold judged to be meaningful for participants. Individual improvements varied but many continued for up to one year with sustained home treatment. There was a demonstrable Hawthorne Effect that was below the treatment effect. No side effects of the treatment were observed.ConclusionsPBM was shown to be a safe and potentially effective treatment for a range of clinical signs and symptoms of PD. Improvements were maintained for as long as treatment continued, for up to one year in a neurodegenerative disease where decline is typically expected. Home treatment of PD by the person themselves or with the help of a carer might be an effective therapy option. The results of this study indicate that a large RCT is warranted.Trial registrationAustralian New Zealand Clinical Trials Registry, registration number: ACTRN12618000038291p, registered on 12/01/2018.

Effects of Oral N -Acetylcysteine on Oxidative Stress in Patients with Sickle Cell Disease

Oxidative stress (OS) has been demonstrated to play a central role in the pathophysiology of sickle cell disease (SCD). The antioxidant N -acetylcysteine (NAC) is an important precursor of cysteine, which is the rate limiting substrate for glutathione (GSH) synthesis, and can thereby exert intracellular antioxidant effects. Yet, because of its thiol group, NAC can also act extracellularly as a reducing agent to break protein disulfide bonds, or to scavenge reactive oxidants. Pilot studies with NAC in SCD have demonstrated various beneficial effects, reducing markers of red blood cell membrane damage, hemolysis and OS. The major plasma modulator of OS is the amino acid cysteine (Cys), with the ratio of its reduced form to the oxidized form reflecting the plasma redox state. Under oxidative stress, relatively low levels of free thiol Cys and high levels of protein bound Cys are observed (Fu et al. Blood 2015; 126:1044). The aim of this study was to assess the effects of oral NAC on the thiol redox balance in SCD patients. Moreover, we explored correlations of the thiol redox balance at baseline with other clinical and pathophysiological markers of SCD.Plasma was analyzed from 2 completed prospective studies that evaluated the effect of oral NAC in SCD: 1) an open label, uncontrolled, pilot study consisting of 6 weeks of NAC 1,200 -2,400mg daily, and 6 weeks follow-up in patients with HbSS or HbSβ⁰-disease (N=10, Nur et al. Ann Hematol. 2012; 91:1097-105); and 2) a randomized, placebo-controlled trial (RCT) of oral NAC 1,200mg daily for 6 months in HbSS, HbSC, HbSβ⁰ or HbSβ⁺ patients (N=96, Sins et al. Br J Haematol. 2017 ) . Using liquid chromatography-tandem mass-spectrometry, we assessed the following markers of the thiol redox balance: total NAC, total and free (reduced) Cys, and protein bound (oxidized) Cys.In both studies, oral NAC significantly increased levels of total NAC and free Cys, and decreased levels of protein bound Cys, as compared to baseline (figure 1). In the pilot study, total Cys was decreased as compared to baseline, however, no significant difference was observed in the RCT. In addition, when comparing the mean change from baseline of these parameters between the NAC arm and the placebo arm of the RCT, similar results were found. Yet, differences in mean change of protein bound and total Cys did not reach statistical significance in this analysis (results not shown).Multivariate linear regression analysis of baseline thiol redox values in the RCT was performed, adjusting for genotype and use of HU. In this analysis, higher levels of free Cys (less OS) were independently associated with a higher MCV (standardized β [sβ] 0.36, P<.001), TAT (sβ 0.19, P=0.040) and levels of Nε-(carboxymethyl)lysine (CML, advanced glycation end product; sβ 0.27, P=.005), lower sP-selectin levels (sβ -0.33, P=.001) and a lower number of hospital admissions in the 3 years prior to randomization (sβ -0.21, P=.027). Higher levels of protein bound Cys (more OS) were independently associated with VWF:ag levels (sβ 0.24, P=.016) and the HbSS/HbSβ0 genotype (sβ -0.25, P=.020). Lastly, higher levels of total Cys (more OS) were independently associated with older age (sβ 0.21, P=.027) and the HbSS/HbSβ0 genotype (sβ -0.21, P=.042), and higher levels of VWF:ag (sβ 0.28, P=.004), CML (sβ 0.17, P=.046) and prothrombin activation fragment F1-2 (sβ 0.18, P=.038).In line with previous intravenous studies, oral treatment with NAC significantly improved the thiol plasma redox balance in patients with SCD. These effects appeared to be most apparent in the uncontrolled pilot study, possibly due to poor adherence and a relatively low dosage in the RCT. Nevertheless, these findings emphasize the role of NAC as an extracellular reducing agent of protein disulfide bonds, beyond acting as a substrate for glutathione synthesis or as a direct scavenger of reactive oxygen species. Moreover, a higher extracellular oxidant burden at baseline was independently associated with endothelial and coagulation activation, and with the number of hospital admissions. Thereby, we provide indirect evidence that improvement of the thiol redox balance may be an important therapeutic target in SCD, improving other pathophysiological processes of the disease, and potentially even reducing the number of hospital admissions. Hence, the use of NAC and other thiol antioxidants in SCD deserves further investigation. [Display omitted] DisclosuresRijneveld:Jazz pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Delannoy:Innate Pharma: Honoraria.

The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial.

Background: Cognitive impairment is prevalent and often highly burdensome in people with schizophrenia. The aim of this study was to investigate if mangosteen (Garcinia mangostana Linn.) pericarp extract may be an effective intervention to improve cognitive performance in this population.Methods: This was a secondary analysis of a larger randomized placebo-controlled trial that investigated a 24-weeks intervention of mangosteen pericarp extract supplementation in people diagnosed with schizophrenia. A subset of n = 114 participants with completed cognitive outcomes at follow up were included in this analysis. Using the Cogstate Brief Battery, the following cognitive outcomes were assessed: psychomotor function, attention, visual learning and memory (visual and working). Subgroup analyses investigated whether baseline clinical parameters (baseline cognitive functioning, illness severity and duration, depressive symptoms) moderated the relationship between mangosteen pericarp extract intervention and change in cognitive outcomes.Results: There were no significant between-group changes in any cognitive outcomes assessed. Subgroup analysis based on baseline cognition and clinical characteristics did not reveal any significant between-group difference in change.Conclusions: Mangosteen pericarp extract did not affect cognitive outcomes in people with schizophrenia. Further investigation regarding optimal dosing strategies for mangosteen interventions and the testing of additional cognitive domains may be warranted.Trial Registration: ANZCTR.org.au identifier: ACTRN12616000859482, registered 30 June 3 2016.