Placebo-controlled Randomized Trial Research Articles

A randomized, double-blind, placebo-controlled, Phase 1/2a trial protocol to assess the safety and efficacy of TAK-101 administered by microneedles in patients with celiac disease

Introduction: Celiac disease (CD) affects 0.2 to 2.0% of the worldwide population, causing significant enteropathy and systemic symptoms. There is no effective treatment for CD, and patients must follow a strict gluten-free diet lifelong. Recent studies investigated the efficacy of the non-immunosuppressive agent TAK-101 delivered intravenously in reducing immunological response to gluten in CD patients. However, no study has evaluated transdermal delivery, which initiates different immunological pathways. Objective: In a population of CD patients, we aim to assess the safety and pharmacokinetics of TAK-1 delivered by a Hollow Microstructured Transdermal microneedle (MN) (Phase 1) and the efficacy of MN-TAK-101 compared to placebo (Phase 2). Methods: This will be a Phase 1/2a trial lasting 180 days for each phase. Phase 1 will be an open-label, 2-part multicenter study: 1A, a group of patients will be divided into escalating dose cohorts. While, in 1B, another group of patients will be divided into repeated ascending dose cohorts until the maximum tolerated dose is reached. Phase 2 will be a double-blind multicentered randomized (stratified, block) placebo-controlled trial comparing TAK-101 and placebo, using different subjects than those in Phase 1. The primary outcome is the change in Interferon-γ production from baseline after MN-TAK-101 or MN-placebo administration. Secondary outcomes will assess the changes in the ratio of villous height to crypt depth, in the number of intestinal intraepithelial lymphocytes, in CD4, CD8, and γδ cells frequency, in the Celiac symptom index-modified questionnaire and safety measurements. The sample size is between 27-49 patients for phases 1A and 1B; 76 patients in phase 2. For statistical analysis, only descriptive analysis will be done for phase 1, while for Phase 2, the choice of parametric vs. nonparametric tests will be considered according to the normality of the data. This is a first Phase 1/2a placebo control randomized trial to assess the safety and efficacy of TAK-101 applied transdermally for patients with celiac disease. Keywords: Celiac Disease; TAK-101; Microneedle; Gluten intolerance; Gluten desensitization.

1107. A Survey on Remdesivir Use and Antimicrobial Stewardship Restrictions Throughout the COVID-19 Pandemic

Abstract Background Remdesivir (RDV) was the first agent with proven clinical benefit against COVID-19, shortening the time to recovery in a randomized placebo-controlled trial (RCT). Based on this trial, the Food and Drug Administration approved RDV via emergency use authorization. Despite its wide use, RDV remains controversial. Early use of RDV in patients requiring low flow nasal canula has robust evidence. However, benefit in mechanical ventilation (MV), high-flow nasal canula (HFNC) and non-invasive positive pressure ventilation (NIPPV) is conflicting. Multiple studies, most notably the SOLIDARITY and DisCoVeRy trial, have conflicting results on who benefits from RDV. Deploying novel therapeutics in this changing landscape is challenging. We seek to understand RDV practices and the role of antimicrobial stewardship (ASP) in hospitals across the US. Methods A survey was developed and disseminated through Infectious Diseases Society of America (IDSA) IDea network, IDSA Antimicrobial Stewardship Centers for Excellence and the Society for Healthcare Epidemiology messaging boards. Data collected included city, presence of RDV therapeutic restrictions, and RDV use by degree of oxygen needs for each COVID-19 wave. Results A total of 78 responses were collected, representing wide geographic reach in the US (Figure 1). RDV was restricted in 53% of facilities. Hospitals without restrictions commonly used RDV for patients on MV, NIPPV and HFNC, with more use on HFNC than on NC during the first winter, Delta and Omicron waves (Figure 2). Use on MV declined with each surge. Hospitals with RDV restrictions had more use of RDV on NC than all other ordinal scales (Figure 3). Use in MV, NIPPV and HFNC compared to NC declined in the restricted group with each COVID-19 surge. Figure 1.Geographic distribution of hospitals represented in the survey Figure 2. Remdesivir use by oxygen requirements in hospitals without remdesivir therapeutic restrictions. Figure 3 Remdesivir use by oxygen requirements in hospitals without remdesivir therapeutic restrictions. Conclusion A wide gap between evidence-based guidelines and actual practice exists. This gap was wider in hospitals without COVID-19 therapeutic restrictions in place for RDV. In the unrestricted group, RDV was commonly used for MV, HFNC and NIPPV, where robust RCT evidence of benefit is lacking. Though this practice occurred in both groups, the restricted RDV group prioritized RDV use in NC and did so at higher percentages each subsequent COVID-19 surge. ASP restrictions can have an important role in guiding COVID-19 therapy. Disclosures All Authors: No reported disclosures.

Feasibility and Safety of High-Definition Infraslow Pink Noise Stimulation for Treating Chronic Tinnitus—A Randomized Placebo-Controlled Trial

IntroductionTinnitus has been linked to activity and connectivity changes in the auditory cortex (AC), parahippocampus (PHC), and posterior cingulate cortex (PCC). Although previous studies have targeted these areas individually, no study has yet modulated them simultaneously. Furthermore, novel stimulation designs may be superior to traditional alternating or direct current stimulation. This pilot study investigated the feasibility and safety of a novel brain stimulation technique (high-definition transcranial infraslow pink noise stimulation [HD-tIPNS]) for treating chronic tinnitus targeting the AC, PHC, and PCC. Materials and MethodsA pilot, double-blind, randomized two-arm placebo-controlled parallel trial was conducted, with clinical outcomes collected at baseline, three days, and ten days after treatment. Participants with chronic tinnitus (n = 20) received 12 sessions (three per week for four weeks) of either HD-tIPNS or acti-sham stimulation. Primary outcomes included feasibility, safety, and resting-state electroencephalography (rsEEG) measures, and secondary outcomes included tinnitus and quality of life questionnaires. Feasibility, safety, and secondary measures were assessed using descriptive statistics. rsEEG was analyzed using standard low-resolution electromagnetic brain tomography. ResultsNo long-term adverse events were reported. Mild side effects included headache and dizziness, indicating the safety of this stimulation. Participants were rapidly recruited and adhered to the study protocol with minimal difficulty. Drop-out rate was 13%, and the treatment approach was acceptable to participants, supporting the feasibility of the protocol. Tinnitus measures were similar between HD-tIPNS and acti-sham stimulation. rsEEG analyses revealed decreased beta-1 activity in PCC ten days after treatment for acti-sham. The HD-tIPNS group showed decreased beta-1 activity in inferior parietal lobule three days after treatment. Increased functional connectivity in the beta-1 frequency between left and right PHC was found in the HD-tIPNS group compared with the acti-sham group, three days after treatment. ConclusionsIn conclusion, the novel approach is safe and feasible and revealed EEG changes unsupported by clinical benefit. Further research is essential to evaluate the potential of this multifocal network stimulation approach. Clinical Trial RegistrationThis study was registered with the Australia New Zealand Clinical Trial Registry (Registry number: ACTRN12621000151831; Universal Trial Number: U1111-1261-6945).

Semaglutide 2.4 Mg for the Management of Overweight and Obesity: Systematic Literature Review and Meta-Analysis.

Semaglutide has demonstrated safe and effective weight loss for overweight and obesity, including participants with concomitant type 2 diabetes mellitus (T2DM), in randomized placebo-controlled trials (RCTs). We conducted a systematic literature review (SLR) and network meta-analyses (NMA) to compare weekly semaglutide 2.4 mg with pharmacological comparators for weight management in overweight or obesity. The SLR was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. NMAs were performed to compare weight change for semaglutide 2.4 mg with comparators using data identified in the SLR. The populations of interest were total population, normal glucose tolerance, non-T2DM, pre-diabetes, and T2DM. Included outcomes were weight change from baseline (CFB, %) at 52 weeks and proportion of participants losing ≥5% baseline fasting body weight at 12 weeks (at full therapeutic dose). The SLR identified 108 RCTs examining non-surgical interventions, of which 41 were considered for inclusion in the NMAs. In all populations, semaglutide 2.4 mg was associated with a greater percentage weight CFB with 52 weeks of treatment versus all available comparators. In all populations, semaglutide was associated with a higher likelihood of participants losing ≥5% of baseline fasting body weight at 12 weeks versus all available comparators. In NMA, semaglutide 2.4 mg demonstrated effective weight loss (≥5%) in the total population and all subpopulations of glucose tolerance versus active comparators. Semaglutide is an effective treatment that may address unmet need in the management of overweight and obesity.

Statins as an antiepileptogenic or disease-modifying treatment? A survey of what UK patients and significant others think about repurposing and trialing them for epilepsy

ObjectiveTo identify the views of people with epilepsy (PWE), and their significant others, on the repurposing and trialing of statins as a potential antiepileptogenic or disease-modifying treatment for those who have had the first seizure. MethodsOnline questionnaire. Participants needed to be aged ≥ 16 years, UK residents, and able to independently complete a questionnaire in English. User groups distributed study adverts. Embedded infographics explained repurposing, why anti-seizure treatment is not typically started after a first seizure and the nature of randomized placebo-controlled trials (RCTs).The questionnaire asked participants to reflect and rate their expected willingness to have started an unspecified treatment after their first seizure/s (or that of the person with epilepsy they knew). They also rated willingness if the treatment were a statin, views of statins, the importance of an RCT of statins to their community, the outcomes it should assess, and their willingness to have taken part in it. The estimated number needed for the survey was 324. ResultsResponses from 213 persons were analyzed; 111 (52.1%) were PWE and 102 (47.9%) significant others. The median years diagnosed was 10 and PWE suffered from relatively severe epilepsy.One hundred and seventeen (54.9%) said they would have started an unspecified treatment after their first seizure/s (or supported the person with epilepsy they knew to have). A similar proportion (55.4%) said they would have started the treatment if it were a statin. Participants’ main concern about statins, expressed by 79%, was their possible side effects. Repurposing was a concern for only 25%. Most (85.8%) rated an RCT of statins as of extreme or high importance; 54.4% said they would have participated. ConclusionThe PWE and significant others (SOs) responding to our survey expressed views towards repurposing statins that were generally positive and indicate a trial in those who have had a first seizure might be feasible. Concerns regarding side effects are common. Our findings could help optimize a future trial’s design and the case for funding. Limitations include that we did not survey persons who had experienced a first seizure and did not go on to develop epilepsy. Also, persons with uncontrolled epilepsy were overrepresented.

Nutrition, Sleep, and Exercise as Healthy Behaviors in Schizotypy: A Scoping Review.

We systematically reviewed the existing literature on these topics through databases including: PsycINFO, Scopus, APA PsycNet, ScienceDirect, Wiley Online Library, and SpringerLink. Of the 59 studies found, a total of 29 studies met the inclusion criteria on the review topic. Included studies reflect varying study designs (cross-sectional, multiple time-point, intervention, randomized-placebo controlled trials), assessment of schizotypy and associated healthy behaviors, focus on various samples and lifespan (e.g., undergraduates, adolescents, at-risk individuals), and stem from different countries. While a moderate number of studies address the role of nutrition, sleep, and physical exercise in relation to schizotypy, studies intersecting these topics are limited. Of the limited studies that do exist, the majority are correlational with the beginnings of causal support from intervention studies. As such, more research is needed on the topics of nutrition, sleep, and exercise in relation to schizotypy. Specifically, future research should focus on providing a more holistic understanding of schizotypal traits and its subtypes, and which specific or combination of behaviors may reduce levels of schizotypy.

Effect of pre-operative 40 mg oral methylprednisolone on post- odontectomy facial swelling, intraoral redness, pain and level of TNF-α

Odontectomy is the surgical removal of teeth by making a mucoperiosteal flap and reducing the jawbone. This procedure is likely to cause injury and damage to soft and hard tissues, stimulate inflammatory responses, and generate release of proinflammatory cytokines, one of which is TNF- ɑ, resulting in the facial swelling, intraoral redness, and pain. This study was aimed at observing effects of 40 mg methylprednisolone, administered 1 hour before odontectomy on facial swelling, intraoral redness, and pain and level of TNF-ɑ after odontectomy. The randomized placebo-control trial study involved 24 subjects who underwent odontectomy at the Oral Surgery and Maxillofacial clinic of Prof. Soedomo Dental Hospital, Universitas Gadjah Mada. To comply with the inclusion criteria, the subjects were divided into placebo group (12 patients) and methylprednisolone group (12 patients). The observation of facial swelling, intraoral redness, pain (VAS) and level of TNF-ɑ (ELISA) was done before odontectormy, H+1 (24 hours after odontectomy) and H+3 (72 hours after odontectomy). The data gathered were analyzed using Repeated Measures ANOVA and post-hoc Bonferroni (p < 0.05). The results showed that those administered with methylprednisolone an hour before odontectomy experienced less postoperative facial swelling (p = 0.000), a lower score of intraoral redness (p = 0.000), a lower score of pain (p = 0.000) and a lower level of TNF-ɑ (p = 0.000) compared to the placebo. The changes in TNF-α showed the strongest correlation with the changes in postoperative pain and intraoral redness compared with facial swelling. Oral administration of 40 mg methylprednisolone an hour before odontectomy is more effective in reducing facial swelling, intraoral redness, pain and level of TNF-ɑ following odontectomy of mandibular third molar compared with the placebo.

The Dose and Duration-dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer's Dementia: A Network Meta- Analysis of Randomized Placebo-Controlled Trials.

While Alzheimer's dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin for cognition have been divergent across trials. The current network meta-analysis (NMA) was conducted under the frequentist model to evaluate the potential beneficial effects of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison to other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric). The primary outcome was the changes in the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer's dementia. The secondary outcomes were changes in the quality of life, behavioral disturbance, and acceptability (i.e., drop-out due to any reason and rate of any adverse event reported). The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed the medium-term lowdose melatonin to be associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo. The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

Effects of neuromuscular gait modification strategies on indicators of knee joint load in people with medial knee osteoarthritis: A systematic review and meta-analysis.

This systematic review aimed to determine the effects of neuromuscular gait modification strategies on indicators of medial knee joint load in people with medial knee osteoarthritis. Databases (Embase, MEDLINE, Cochrane Central, CINAHL and PubMed) were searched for studies of gait interventions aimed at reducing medial knee joint load indicators for adults with medial knee osteoarthritis. Studies evaluating gait aids or orthoses were excluded. Hedges' g effect sizes (ES) before and after gait retraining were estimated for inclusion in quality-adjusted meta-analysis models. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seventeen studies (k = 17; n = 362) included two randomised placebo-controlled trials (RCT), four randomised cross-over trials, two case studies and nine cohort studies. The studies consisted of gait strategies of ipsilateral trunk lean (k = 4, n = 73), toe-out (k = 6, n = 104), toe-in (k = 5, n = 89), medial knee thrust (k = 3, n = 61), medial weight transfer at the foot (k = 1, n = 10), wider steps (k = 1, n = 15) and external knee adduction moment (KAM) biofeedback (k = 3, n = 84). Meta-analyses found that ipsilateral trunk lean reduced early stance peak KAM (KAM1, ES and 95%CI: -0.67, -1.01 to -0.33) with a dose-response effect and reduced KAM impulse (-0.37, -0.70 to -0.04) immediately after single-session training. Toe-out had no effect on KAM1 but reduced late stance peak KAM (KAM2; -0.42, -0.73 to -0.11) immediately post-training for single-session, 10 or 16-week interventions. Toe-in reduced KAM1 (-0.51, -0.81 to -0.20) and increased KAM2 (0.44, 0.04 to 0.85) immediately post-training for single-session to 6-week interventions. Visual, verbal and haptic feedback was used to train gait strategies. Certainty of evidence was very-low to low according to the GRADE approach. Very-low to low certainty of evidence suggests that there is a potential that ipsilateral trunk lean, toe-out, and toe-in to be clinically helpful to reduce indicators of medial knee joint load. There is yet little evidence for interventions over several weeks.

Prophylactic efficacy of intravenous ondansetron in prevention of spinal anaesthesia induced hypotension

Background: Spinal anesthesia is used in wide range of surgical procedures, but it is associated with potential complications such as hypotension and shivering. Thus the present study was aimed to compare the effect of 6mg ondansetron and placebo 10 minutes before spinal anesthesia for prevention of hypotension and shivering in patients undergoing non-obstetric surgeries. Methods: A double blinded randomized placebo control trial was conducted in 50 patients. Patients were randomized into ondansetron group (n =25) and placebo group (n=25).The primary outcome was the measurement of SBP(Systolic Blood Pressure), DBP(Diastolic Blood Pressure), MAP(Mean Arterial Pressure) and HR(Heart Rate) at baseline, 5, 10, 15 and 30 minutes after subarachnoid block. Results: There was a significant mean difference in SBP and DBP at 5, 10, 15 and 30 minutes after subarachnoid block (SAB) between the groups (p<0.05). Further, significant decreased MAP was observed at 5,10,15 and 30 minutes after SAB in placebo as compared to ondansetron group (p<0.05). Further 30 minutes after SAB, 28% of patients in placebo group and 4% of patients in ondansetron group had shivering (p=0.04). Conclusion: The present study shows that ondansetron is a suitable agent for the mitigation of spinal anesthesia-induced hypotension and shivering during non-obstetric surgeries.

Five challenges for manual therapies trials with placebo controls: A proposal

Randomised placebo-controlled trials (RCT) are implemented to determine whether a particular therapy is superior to placebo and can thus be considered effective. However, adopting the standard RCT design in contexts other than pharmacological trials, such as manual therapy, may result in systematic biases. These biases may occur due to: the impossibility of traditional “double-blinding” in manual therapy trials; insufficient pre-training of operators delivering the treatment and/or sham therapy; biased recruitment of study participants; the problematic use of subjective and/or objective outcomes; and finally, the presence of phenomena mimicking placebo effects. From the perspective of placebo studies, the purpose of this paper is to discuss and make appropriate recommendations to address these five issues in manual therapy research.

Antioxidant Effects of a Polyphenol-Rich Dietary Supplement Incorporating Pinus massoniana Bark Extract in Healthy Older Adults: A Two-Arm, Parallel Group, Randomized Placebo-Controlled Trial.

Oxidative stress is a key physiological phenomenon underpinning the ageing process and plays a major developmental role in age-associated chronic diseases. This study investigated the antioxidant effects of a polyphenol-rich dietary supplement containing Pinus massoniana bark extract (PMBE) in healthy older adults. In a double-blinded, placebo-controlled clinical trial, participants were randomised (in a 1:1 ratio) to receive a 50 mL/day dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) for 12 weeks. The primary outcome was fasting plasma malondialdehyde (MDA) concentrations and secondary outcomes were plasma inflammatory markers. MDA concentrations significantly reduced following PMBE for 6 weeks (−1.19 nmol/mL, 95%CI −1.62, −0.75, p < 0.001) and 12 weeks (−1.35 nmol/mL, 95%CI −1.74, −0.96, p < 0.001) compared to baseline. MDA did not significantly change after the placebo. MDA levels at 6 and 12 weeks were significantly lower following PMBE compared to placebo (p < 0.001). At 12 weeks in the PMBE group, fibrinogen concentrations significantly reduced (−0.25 g/L, 95%CI −0.39, −0.11; p < 0.0001) and interleukin-6 significantly increased compared to placebo (0.30 pg/mL, 95%CI 0.02, 0.59; p < 0.05). PMBE in a polyphenol-rich dietary supplement reduced oxidative stress in healthy older adults. Further studies are warranted to investigate the antioxidant capacity of PMBE in conditions with heightened oxidative stress, such as osteoarthritis, hypertension, type 2 diabetes, or other lifestyle related diseases.

The effect of androstenedione supplementation on testosterone, estradiol, body composition, and lipid profile: a systematic review and meta-analysis of randomized controlled trials.

To date, no meta-analysis has been carried out to collect evidence from randomized placebo-controlled trials (RCTs) for the purpose of comprehensively summarizing the effect of androstenedione supplementation. Therefore, the aim of this research was to perform a systematic review and meta-analysis of all RCTs that explored the effect of androstenedione supplementation on individual hormonal, lipid, and anthropometric indices. We searched five databases (Web of Science, SCOPUS, Embase, PubMed/MEDLINE, and Google Scholar) using a combination of medical subject headings (MeSH) and non-MeSH terms. Using the random-effects model, we summarized the outcomes as weighted mean difference (WMD) with 95% confidence interval (CI). Eight eligible articles were included in the meta-analysis. The pooled effect sizes suggested a significant effect of androstenedione supplementation on serum estradiol concentrations (WMD: 20.82ng/ml, 95% CI: 7.25 to 34.38, p = 0.003), triglycerides (TG, WMD: -0.19mg/dl, 95% CI: - 0.96, 0.57, p = 0.000), and high-density lipoprotein (HDL)-cholesterol (WMD: - 0.13mg/dl, 95% CI: - 0.23 to - 0.03, p = 0.009); however, it had no effect on testosterone (WMD: 0.098ng/ml, 95% CI: - 0.499 to 0.696, p = 0.748), body weight (WMD: 0.579kg, 95% CI: - 4.02 to 5.17, p = 0.805), body mass index (BMI, WMD: - 0.73kg/m2, 95% CI: - 2.98, 1.50, p = 0.519), low-density lipoprotein (LDL)-cholesterol (WMD: - 0.074mg/dl, 95% CI: - 0.37 to 0.22, p = 0.622), and total cholesterol (TC, WMD: - 0.15mg/dl, 95% CI: - 0.49, 0.17, p = 0.198). These findings indicate that androstenedione supplementation can lower TG and HDL-cholesterol and increase estradiol concentrations.

Comparing treatment options for large vessel vasculitis

ABSTRACT Introduction Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the major forms of large vessel vasculitis (LVV). Glucocorticoids represent the cornerstone of LVV treatment, however, relapses and recurrences frequently occur when they are tapered or stopped, determining a prolonged exposure to glucocorticoids and a subsequent increased risk of glucocorticoid-related side effects. Therefore, conventional and biologic immunosuppressive drugs have been proposed to obtain a glucocorticoid-sparing effect. Areas covered We searched PubMed® using the keywords ‘giant cell arteritis/drug therapy’ and ‘Takayasu Arteritis/drug therapy’ OR ‘Takayasu Arteritis/surgery’ This review focuses on the management of LVV, based on the current evidence while highlighting the differences in terms of therapeutic management of TAK and GCA. Expert opinion Conventional disease modifying anti-rheumatic drugs, such as methotrexate or azathioprine, are recommended in association to glucocorticoids for selected GCA and all TAK patients. Two randomized placebo-controlled trials recently demonstrated the efficacy of tocilizumab in reducing relapses and cumulative prednisone dosage in GCA patients with newly diagnosed or relapsing disease. Observational evidence and two small randomized controlled trials support the use of TNF-alpha inhibitors and tocilizumab as glucocorticoid-sparing agents in relapsing TAK, albeit high-quality evidence regarding the management of TAK is still lacking.

Rationale, design, and methods: A randomized placebo-controlled trial of an immunomodulatory probiotic intervention for Veterans with PTSD

BackgroundUnited States military Veterans from recent conflicts are experiencing symptoms related to posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy). Alternative treatment approaches are needed. An underlying feature of PTSD is exaggerated inflammation, both peripherally and in the central nervous system. This inflammation is thought to play an important role in the vulnerability to, aggravation of, and persistence of PTSD symptoms. Therefore, an innovative intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. Here we describe the rationale, design, and methods of a randomized placebo-controlled trial (RCT) of Lactobacillus rhamnosus GG (LGG; ATCC 53103) for posttraumatic stress disorder (PTSD). MethodsThis is a Phase IIa trial of LGG for United States military Veterans with PTSD, using a longitudinal, double-blind, randomized placebo-controlled design. The primary outcome measure is plasma concentration of high-sensitivity C-reactive protein. ConclusionDespite the fact that symptoms associated with PTSD can be disabling, individuals living with this trauma-related disorder have limited options in terms of evidence-based interventions. Recent research efforts aimed at highlighting the biological mechanisms of PTSD suggest that increased inflammation and altered autonomic nervous system activity may be treatment targets, and that immunoregulatory probiotics, such as LGG, have the potential to decrease trauma-induced inflammatory responses, as well as associated symptoms. This manuscript describes the best powered human subjects Phase IIa trial, to date, of a probiotic intervention for those living with PTSD.

Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light.

Background:Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.Objective:A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).Methods:The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.Results:Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).Conclusion:This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.

Acetazolamide: Old drug, new evidence?

Acetazolamide is an old drug used as an antiepileptic agent, amongst other indications. The drug is seldom used, primarily due to perceived poor efficacy and adverse events. Acetazolamide acts as a noncompetitive inhibitor of carbonic anhydrase, of which there are several subtypes in humans. Acetazolamide causes an acidification of the intracellular and extracellular environments activating acid‐sensing ion channels, and these may account for the anti‐seizure effects of acetazolamide. Other potential mechanisms are modulation of neuroinflammation and attenuation of high‐frequency oscillations. The overall effect increases the seizure threshold in critical structures such as the hippocampus. The evidence for its clinical efficacy was from 12 observational studies of 941 patients. The 50% responder rate was 49%, 20% of patients were rendered seizure‐free, and 30% were noted to have had at least one adverse event. We conclude that the evidence from several observational studies may overestimate efficacy because they lack a comparator; hence, this drug would need further randomized placebo‐controlled trials to assess effectiveness and harm.

Secondary hypertension and its treatment in cats

Secondary hypertension caused by an underlying disease is common in older cats, especially in those with chronic kidney disease and/or hyperthyroidism. Systolic blood pressure should be measured whenever an associated disease is diagnosed and persistent systolic blood pressure &gt;160mmHg should prompt treatment to prevent or reverse target organ damage. Amlodipine and telmisartan are licensed in the UK to treat feline hypertension and both drugs have been evaluated in prospective randomised placebo-controlled clinical trials in hypertensive cats with systolic blood pressure of 160–200mmHg that did not have evidence of target organ damage. Initial reductions of 20–30mmHg can be expected with either medication, and cats should be re-evaluated after 14 days and dose adjustments made as required. No studies have compared the performance of one drug against the other and either medication should be selected as the first-line treatment for feline hypertension. At present, there are more data in the literature to support the use of amlodipine in cats with severe hypertension (systolic blood pressure &gt;200mmHg), or with evidence of ocular or neurological target organ damage.

Efficacy of Fluoxetine, Riluzole and Amiloride in treating neuropathic pain associated with secondary progressive multiple sclerosis. Pre-specified analysis of the MS-SMART double-blind randomised placebo-controlled trial

BackgroundEvidence-based treatment of pain in people with MS presents a major unmet need. ObjectiveWe aimed to establish if use of Fluoxetine, Riluzole or Amiloride improved neuropathic pain outcomes in comparison to placebo, in adults with secondary progressive MS participating in a trial of these putative neuroprotectants. MethodsIn pre-specified secondary analyses of the MS SMART phase-2b double-blind randomised controlled trial (NCT01910259), we analyzed reports of neuropathic pain, overall pain, and pain interference. Multivariate analyses included adjustment for baseline pain severity. Additionally, we explored associations of pain severity with clinical and MRI brain imaging variables. Results445 Participants were recruited from 13 UK neuroscience centres. We found no statistically significant benefit of active intervention on any rating of neuropathic pain, or pain overall. Compared to placebo, adjusted mean difference in pain intensity was 0.38 (positive values favouring placebo, 95%CI -0.30 to 1.07, p = 0.27) for Amiloride; 0.52 (-0.17 to 1.22, p = 0.14) for Fluoxetine; and 0.40 (-0.30 to 1.10, p = 0.26) for Riluzole. Pain severity was positively correlated with depressive symptoms (Spearman correlation 0.19, 95%CI 0.10–0.28) and fatigue (Rho 0.30, 95%CI 0.20–0.39). ConclusionUse of Fluoxetine, Riluzole or Amiloride was not associated with improvement in neuropathic pain symptoms, in comparison to placebo.