Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder

Abstract Background Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD. Methods We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3–12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD. Results Data from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF (Cohen’s d 0.21; 95% CI − 0.46, 0.88 and 0.10; 95% CI − 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks (Cohen’s d − 0.96; 95% CI − 1.73, − 0.15), but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell. Limitations The sample size was limited to 45 children with ASD and we did not impute missing data. We were unable to document significant changes in clinical assessments during clinical visits in those taking SF compared to PL. The clinical results were confounded by placebo effects during the open-label phase. Conclusions SF led to small yet non-statistically significant changes in the total and all subscale scores of the primary outcome measure, while for secondary outcome measures, caregivers’ assessments of children taking SF showed statistically significant improvements compared to those taking PL on the ABC but not the SRS-2. Clinical effects of SF were less notable in children compared to our previous trial of a SF-rich preparation in young men with ASD. Several of the effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02561481) on September 28, 2015. Funding was provided by the U.S. Department of Defense.

Download Full-text

Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease

Scientific Reports ◽

10.1038/s41598-021-89444-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manaf AlQahtani ◽

Abdulkarim Abdulrahman ◽

Abdulrahman Almadani ◽

Salman Yousif Alali ◽

Alaa Mahmood Al Zamrooni ◽

...

Keyword(s):

Standard Therapy ◽

Primary Outcome ◽

Controlled Trial ◽

Severe Disease ◽

Pilot Trial ◽

Standard Of Care ◽

Primary Outcome Measure ◽

Secondary Outcome ◽

Open Label ◽

Plasma Therapy

AbstractConvalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels (p < 0.05) though respiratory indices did not differ. The primary outcome measure was required in 6 controls and 4 patients on CP (risk ratio 0.67, 95% CI 0.22–2.0, p = 0.72); mean time on ventilation (NIV or MV) did not differ. There were no differences in secondary measures at the end of the study. Two patients died in the control and one patient in the CP arm. There were no significant differences in the primary or secondary outcome measures between CP and standard therapy, although a larger definitive study is needed for confirmation. However, the study did show that CP therapy appears to be safe in hospitalized COVID-19 patients with hypoxia.Clinical trials registration NCT04356534: 22/04/2020.

Download Full-text

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

Multiple Sclerosis Journal ◽

10.1177/135245859500100210 ◽

1995 ◽

Vol 1 (2) ◽

pp. 118-135 ◽

Cited By ~ 64

Author(s):

LD Jacobs ◽

DL Cookfair ◽

RA Rudick ◽

RM Herndon ◽

J R Richert ◽

...

Keyword(s):

Primary Outcome ◽

Interferon Beta ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Phase Iii ◽

Secondary Outcome ◽

Recombinant Interferon ◽

Study Population ◽

The Mean ◽

Baseline Characteristics

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-β-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 × 106 IU (30 μg) of IFN-β-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0–3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-β-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

Download Full-text

Association between workarounds and medication administration errors in bar-code-assisted medication administration in hospitals

Journal of the American Medical Informatics Association ◽

10.1093/jamia/ocx077 ◽

2017 ◽

Vol 25 (4) ◽

pp. 385-392 ◽

Cited By ~ 15

Author(s):

Willem van der Veen ◽

Patricia MLA van den Bemt ◽

Hans Wouters ◽

David W Bates ◽

Jos WR Twisk ◽

...

Keyword(s):

Prospective Observational Study ◽

Primary Outcome ◽

Outcome Measure ◽

Medication Administration ◽

Primary Outcome Measure ◽

Secondary Outcome ◽

Bar Code ◽

Implementation Evaluation ◽

Medication Administration Errors ◽

Large Numbers

Abstract Objective To study the association of workarounds with medication administration errors using barcode-assisted medication administration (BCMA), and to determine the frequency and types of workarounds and medication administration errors. Materials and Methods A prospective observational study in Dutch hospitals using BCMA to administer medication. Direct observation was used to collect data. Primary outcome measure was the proportion of medication administrations with one or more medication administration errors. Secondary outcome was the frequency and types of workarounds and medication administration errors. Univariate and multivariate multilevel logistic regression analysis were used to assess the association between workarounds and medication administration errors. Descriptive statistics were used for the secondary outcomes. Results We included 5793 medication administrations for 1230 inpatients. Workarounds were associated with medication administration errors (adjusted odds ratio 3.06 [95% CI: 2.49-3.78]). Most commonly, procedural workarounds were observed, such as not scanning at all (36%), not scanning patients because they did not wear a wristband (28%), incorrect medication scanning, multiple medication scanning, and ignoring alert signals (11%). Common types of medication administration errors were omissions (78%), administration of non-ordered drugs (8.0%), and wrong doses given (6.0%). Discussion Workarounds are associated with medication administration errors in hospitals using BCMA. These data suggest that BCMA needs more post-implementation evaluation if it is to achieve the intended benefits for medication safety. Conclusion In hospitals using barcode-assisted medication administration, workarounds occurred in 66% of medication administrations and were associated with large numbers of medication administration errors.

Download Full-text

A Sternum-Disk Distance Method to Identify the Skin Level for Approaching a Surgical Segment without Fluoroscopy Guidance during Anterior Cervical Discectomy And Fusion

Asian Spine Journal ◽

10.4184/asj.2017.11.1.50 ◽

2017 ◽

Vol 11 (1) ◽

pp. 50-56

Author(s):

Gun Woo Lee ◽

Myun-Whan Ahn ◽

Ji-Hoon Shin ◽

Jae Woo Park ◽

Jae-Hyung Uh ◽

...

Keyword(s):

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Kappa Coefficient ◽

Anterior Cervical Discectomy ◽

Secondary Outcome ◽

Distance Method ◽

Cervical Discectomy ◽

Observer Reliability ◽

The Mean

<sec><title>Study Design</title>A retrospective review of prospectively collected data.</sec><sec><title>Purpose</title>To introduce the sternum-disk distance (SDD) method for approaching the exact surgical level without C-arm guidance during anterior cervical discectomy and fusion (ACDF) surgery and to evaluate its accuracy and reliability.</sec><sec><title>Overview of Literature</title>Although spine surgeons have tried to optimize methods for identifying the skin level for accessing the operative disk level without C-arm guidance during ACDF, success has rarely been reported.</sec><sec><title>Methods</title>In total, 103 patients who underwent single-level ACDF surgery with the SDD method were enrolled. The primary outcome measure was the accuracy of the SDD method. The secondary outcome measures were the mean SDD value at each cervical level from the cranial margin of the sternum in the neutral and extension positions of the cervical spine and the inter- and intra-observer reliability of the SDD outcome determined using repeated measurements by three orthopedic spine surgeons.</sec><sec><title>Results</title>The SDD accuracy (primary outcome measure) was indicated in 99% of the patients (102/103). The mean SDD values in the neutral-position magnetic resonance imaging (MRI) were 108.8 mm at C3–C4, 85.3 mm at C4–C5, 64.4 mm at C5–C6, 44.3 mm at C6–C7, and 24.1 mm at C7–T1; and those in the extension-position MRI were 112.9 mm at C3–C4, 88.7 mm at C4–C5, 67.3 mm at C5–C6, 46.5 mm at C6–C7, and 24.3 mm at C7–T1. The Cohen kappa coefficient value for intra-observer reliability was 0.88 (excellent reliability), and the Fleiss kappa coefficient value for inter-observer reliability as reported by three surgeons was 0.89 (excellent reliability).</sec><sec><title>Conclusions</title>Based on the results of the present study, we recommend performing ACDF surgery using the SDD method to determine the skin level for approaching the surgical cervical segment without fluoroscopic guidance.</sec>

Download Full-text

Combining Lovastatin and Minocycline for the Treatment of Fragile X Syndrome: Results From the LovaMiX Clinical Trial

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.762967 ◽

2022 ◽

Vol 12 ◽

Author(s):

Camille Champigny ◽

Florence Morin-Parent ◽

Laurence Bellehumeur-Lefebvre ◽

Artuela Çaku ◽

Jean-François Lepage ◽

...

Keyword(s):

Clinical Trial ◽

Fragile X Syndrome ◽

Outcome Measures ◽

Primary Outcome ◽

Outcome Measure ◽

Fragile X ◽

Combined Therapy ◽

Primary Outcome Measure ◽

Secondary Outcome ◽

Global Score

Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently.Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS.Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy).Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-CFX), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II).Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance.Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy.

Download Full-text

Open Label Phase I hCT-MSC in Toddlers With Autism Spectrum Disorder

Case Medical Research ◽

10.31525/ct1-nct04294290 ◽

2020 ◽

Author(s):

Keyword(s):

Autism Spectrum Disorder ◽

Phase I ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Open Label ◽

Open Label Phase

Download Full-text

The Feasibility and Acceptability of Delivering Pivotal Response Treatment for Autism Spectrum Disorder via Telehealth: A Pilot Study (Preprint)

10.2196/preprints.32520 ◽

2021 ◽

Author(s):

Krista Nicole Drapalik ◽

David Grodberg ◽

Pamela Ventola

Keyword(s):

Autism Spectrum Disorder ◽

Parent Training ◽

Autism Spectrum ◽

Small Sample ◽

Spectrum Disorder ◽

Training Condition ◽

Stepped Care ◽

Pivotal Response Treatment ◽

Clinical Effects ◽

Children With Asd

BACKGROUND Pivotal Response Treatment (PRT), an evidence-based and parent-delivered intervention, is designed to improve social communication in individuals with autism spectrum disorder (ASD). OBJECTIVE To assess the feasibility, acceptability, and clinical effects of an online model of PRT delivered via MindNest Health that aims to provide self-directed and engaging online modules, real-time coaching and feedback, and accessible stepped-care to large populations of parents seeking resources for their children with ASD. METHODS Male and female children, ages 2-7 years old with single-word to phrase-level speech, were eligible to participate in the study. Families were randomized to the online parent training condition or control condition. The online component of the intervention consisted of eight 20-minute online courses of content describing parent training principles in PRT. Four 1-hour videoconferences were held after course 1, course 3, course 5, and course 8. Parents were given 1-2 weeks to complete each course. Parents completed the Client Expectancies Questionnaire (CCQ) at Week 2 and endpoint, as well as the Behavioral Intervention Rating Scale (BIRS) at endpoint to assess parental expectancies and treatment acceptability and effectiveness. RESULTS 9 of 14 subjects completed the study curriculum in the online parent training condition, and 6 of 12 subjects completed the control condition. A total of 58% subjects completed study curriculum by study closure. Within the online parent training condition, there was a significant increase in mean CCQ Total Scores from 25.38 ± 3.25 at baseline to 27.5 ± 3.74 at endpoint (P = .04), mean CCQ Confidence Scores from 6.0 ± 1.07 at baseline to 6.75 ± 0.89 at endpoint (P = .02), and mean CCQ Other Improvement Scores 5.25 ± 0.89 at baseline to 6.25 ± 1.28 at endpoint (P = .009). Within the control condition, a modest increase in CCQ scores existed (Confidence △M = +.25; Recommend △M = +.25; Total Score △M = +.50), but no significant results were found (Confidence P = .38; Recommend P = .36; Total Score P = .43). Out of the eleven parents that completed the BIRS at endpoint, 83% parents endorsed they slightly agree or agree with over 93% of the Acceptability factor items on the BIRS. CONCLUSIONS The feasibility of this online treatment is endorsed by the high rate of online module completion and attendance to videoconferences within the online parent training group. Acceptability of treatment is supported by strong ratings on the CCQ and significant improvements in scores as well as strong ratings on the BIRS. This study’s small sample size limits the conclusions that can be drawn, however, the PRT MindNest Health platform holds promise to support parents of children with ASD who are unable to access traditional, in-person parent-mediated intervention for their child.

Download Full-text

188 The Use of a Group Based Upper Limb Programme in Improving Outcome in Acute Stroke Rehabilitation

Age and Ageing ◽

10.1093/ageing/afz103.111 ◽

2019 ◽

Vol 48 (Supplement_3) ◽

pp. iii17-iii65

Author(s):

Kerri Donnelly ◽

Enya Mulcahy ◽

Catherine Merrick ◽

Orla Fitzgerald

Keyword(s):

Acute Stroke ◽

Grip Strength ◽

Outcome Measures ◽

Upper Limb ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Secondary Outcome ◽

Dominant Hand ◽

Nine Hole Peg Test

Abstract Background After a stroke 85% of patients experience altered arm function. Current research demonstrates that increasing upper limb rehabilitation results in improved outcomes (Ward et al., 2019). The Graded Repetitive Arm Supplementary Programme (GRASP) group is an established adjunctive therapy in the stroke service. The group provides additional therapy for suitable patients with upper extremity deficits. The group is run jointly by a physiotherapist and an occupational therapist. Patients attend twice weekly for a one hour period in addition to their regular therapy. The GRASP group consists of 3 levels of varying abilities and patients are categorised by their Fugl-Meyer score. Methods A prospective audit was completed in 2019 and data was collected using a word document and excel spread sheet. Standardised outcome measures were completed on admission and discharge to establish upper limb ability. The primary outcome measure was the Fugl-Meyer and the secondary outcome measures were the nine hole peg test and grip strength using the Dynamometer. Results 12 patients attended the GRASP group over this period. 75% were males. The average age was 76 years with the age range from 48-95 years. 58% of patients experienced upper limb weakness in their non-dominant hand. Post intervention data was not obtained for 5 patients due to unforeseeable discharge from the acute setting. Preliminary data to date shows that our primary outcome measure improved in 86% of patients with increases ranging from 2-11 points on the Fugl-Meyer score (Minimally Clinical Important Difference =5points). Our secondary outcome measures demonstrated patients had no change (28%) or an improvement (72%) in grip strength and 100% of patients improved on the time taken to complete the nine hole peg test. Conclusion The GRASP group was found to be effective in improving upper limb outcome measures in an acute stroke inpatient hospital setting.

Download Full-text

Prognostic value of reduction in left atrial size during a follow-up of heart failure: an observational study

BMJ Open ◽

10.1136/bmjopen-2020-044409 ◽

2021 ◽

Vol 11 (2) ◽

pp. e044409

Author(s):

Masayuki Shiba ◽

Takao Kato ◽

Takeshi Morimoto ◽

Hidenori Yaku ◽

Yasutaka Inuzuka ◽

...

Keyword(s):

Heart Failure ◽

Lower Risk ◽

Left Atrial ◽

Primary Outcome ◽

Outcome Measure ◽

No Reduction ◽

Primary Outcome Measure ◽

Secondary Outcome ◽

Group Change

ObjectiveThe association between sequential changes in left atrial diameter (LAD) and prognosis in heart failure (HF) remains to be elucidated. The present study aimed to investigate the link between reduction in LAD and clinical outcomes in patients with HF.DesignA multicentre prospective cohort study.SettingThis study was nested from the Kyoto Congestive Heart Failure registry including consecutive patients admitted for acute decompensated heart failure (ADHF) in 19 hospitals throughout Japan.ParticipantsThe current study population included 673 patients with HF who underwent both baseline and 6-month follow-up echocardiography with available paired LAD data. We divided them into two groups: the reduction in the LAD group (change <0 mm) (n=398) and the no-reduction in the LAD group (change ≥0 mm) (n=275).Primary and secondary outcomesThe primary outcome measure was a composite of all-cause death or hospitalisation for HF during 180 days after 6-month follow-up echocardiography. The secondary outcome measures were defined as the individual components of the primary composite outcome measure and a composite of cardiovascular death or hospitalisation for HF.ResultsThe cumulative 180-day incidence of the primary outcome measure was significantly lower in the reduction in the LAD group than in the no-reduction in the LAD group (13.3% vs 22.2%, p=0.002). Even after adjusting 15 confounders, the lower risk of reduction in LAD relative to no-reduction in LAD for the primary outcome measure remained significant (HR 0.59, 95% CI 0.36 to 0.97 p=0.04).ConclusionPatients with reduction in LAD during follow-up after ADHF hospitalisation had a lower risk for a composite endpoint of all-cause death or HF hospitalisation, suggesting that the change of LAD might be a simple and useful echocardiographic marker during follow-up.

Download Full-text

Psilocybin-assisted therapy for the treatment of resistant major depressive disorder (PsiDeR): protocol for a randomised, placebo-controlled feasibility trial

BMJ Open ◽

10.1136/bmjopen-2021-056091 ◽

2021 ◽

Vol 11 (12) ◽

pp. e056091

Author(s):

James Rucker ◽

Hassan Jafari ◽

Tim Mantingh ◽

Catherine Bird ◽

Nadav Liam Modlin ◽

...

Keyword(s):

Major Depressive Disorder ◽

Informed Consent ◽

Depressive Disorder ◽

Primary Outcome ◽

Rating Scale ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Feasibility Trial ◽

Open Label ◽

Major Depressive

IntroductionPsilocybin-assisted therapy may be a new treatment for major depressive disorder (MDD), with encouraging data from pilot trials. In this trial (short name: PsiDeR) we aimed to test the feasibility of a parallel-group, randomised, placebo-controlled design. The primary outcomes in this trial are measures of feasibility: recruitment rates, dropout rates and the variance of the primary outcome measure of depression.Methods and analysisWe are recruiting up to 60 participants at a single centre in London, UK who are unresponsive to, or intolerant of, at least two evidence-based treatments for MDD. Participants are randomised to receive a single dosing session of 25 mg psilocybin or a placebo. All participants receive a package of psychological therapy. The primary outcome measure for depression is the Montgomery Asberg Depression Rating Scale collected by blinded, independent raters. The primary endpoint is at 3 weeks, and the total follow-up is 6 weeks. With further informed consent, this study collects neuroimaging and omics data for mechanism and biomarker analyses and offers participants an open label extension consisting of a further, open label dose of 25 mg of psilocybin.Ethics and disseminationAll participants will be required to provide written informed consent. The trial has been authorised by the National Research Ethics Committee (20-LO/0206), Health Research Authority (252750) and Medicine’s and Healthcare Products Regulatory Agency (CTA 14523/0284/001-0001) in the UK. Dissemination of results will occur via a peer-reviewed publication and other relevant media.Trial registration numbersEUDRACT2018-003573-97; NCT04959253.

Download Full-text