Blinded Efficacy Research Articles

Transcranial Temporal Interference Stimulation of the Right Globus Pallidus in Parkinson's Disease.

Invasive deep brain stimulation (DBS) has been shown to be effective in treating patients with Parkinson's disease (PD), yet its clinical use is limited to patients at the advanced stage of the disease. Transcranial temporal interference stimulation (tTIS) may be a novel nonneurosurgical and safer alternative, yet its therapeutic potential remains unexplored. This pilot study aims to examine the feasibility and safety of tTIS targeting the right globus pallidus internus (GPi) for motor symptoms in patients with PD. Twelve participants with mild PD completed this randomized, double-blind, and sham-controlled experiment. Each of them received either 20-minute or sham tTIS of the right GPi. Before and immediately after the stimulation, participants completed the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) in the "medication-on" state to assess the motor symptoms. The blinding efficacy and side effects were also assessed. tTIS was well tolerated by participants, with only mild, transient adverse effects reported. tTIS significantly reduced MDS-UPDRS-III scores by 6.64 points (14.7%), particularly in bradykinesia (23.5%) and tremor (15.3%). The left side showed more significant alleviation in motor symptoms, particularly bradykinesia, compared to the right side. Participants with severer bradykinesia and tremor before stimulation experienced greater improvement after tTIS. This pilot study suggests that the tTIS, as a novel noninvasive DBS approach, is feasible and safe for alleviating motor symptoms in mild PD, especially bradykinesia and tremor. Future larger-scale and more definitive studies are needed to confirm the benefits. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The relationship between blinding integrity and medication efficacy in randomised-controlled trials in patients with anxiety disorders: A systematic review and meta-analysis.

Blinding is thought to minimise expectancy effects and biases in double-blind randomised-controlled trials (RCTs). However, whether blinding integrity should be assessed and reported remains debated. Furthermore, it is unknown whether blinding failure influences the outcome of RCTs in anxiety disorders. We carried out a systematic review to understand whether blinding integrity is assessed and reported in anxiolytic RCTs. A secondary aim was to explore whether blinding integrity is associated with treatment efficacy. Our protocol was pre-registered (PROSPERO CRD42022328750). We searched electronic databases for placebo-controlled, randomised trials of medication in adults with generalised and social anxiety disorders, and in panic disorder, from 1980. We extracted data regarding blinding integrity and treatment efficacy. Risk of bias was assessed with the Cochrane risk of bias tool. Where possible, we subsequently calculated Bang's Blinding Index, and assessed the association between blinding integrity and treatment effect size. Of the 247 RCTs that met inclusion criteria, we were able to obtain assessments of blinding integrity from nine (3.64%). Overall, blinding failed in five of these trials (55.56%), but blinding was intact in 80% of placebo arms. We found a significant association between reduced blinding integrity among assessors and increased treatment effect size (betas < -1.30, p's < 0.001), but this analysis involved only four studies of which two were outlying studies. In patients, we saw a non-significant trend where reduced blinding integrity in the placebo groups was associated with increased treatment efficacy, which was not present in active medication arms. [Correction added on 19 August 2024, after first online publication: Results of the RCTs and its assessment of blinding integrity have been updated.] CONCLUSION: Consistent with work in other psychiatric disorders, blinding integrity is rarely reported in anxiolytic RCTs. Where it is reported, blinding appears to often fail. We found signals that suggest unblinding of clinician assessors (driven by two studies with complete unblinding), and of patients in placebo arms, might be associated with larger treatment effect sizes. We recommend that data regarding blinding integrity, along with the reasons patients and assessors offer for their beliefs regarding group allocation, are systematically collected in RCTs of anxiolytic treatment.

Efficacy of Bravecto® Plus spot-on solution for cats (280 mg/ml fluralaner and 14 mg/ml moxidectin) in the prevention of feline Aelurostrongylus abstrusus infection evaluated in a multi-diagnostic approach

BackgroundAelurostrongylus abstrusus is one of the most important respiratory nematodes of felines. Infections may lead to respiratory clinical signs with varying severity or even death, emphasizing the need for preventive treatment of cats with outdoor access to circumvent patent infections.MethodsTherefore, the preventive efficacy of a spot-on formulation of 280 mg/ml fluralaner and 14 mg/ml moxidectin (Bravecto® Plus spot-on solution for cats, MSD) against A. abstrusus was evaluated in a negative controlled, randomized and partially blinded efficacy study with 28 purpose-bred cats in a non-terminal design. In three different treatment regimes, the minimum recommended dose of 40 mg fluralaner and 2.0 mg moxidectin/kg bodyweight (BW) was administered once at 12, 8 or 4 weeks (study group G1, G2 and G3, respectively) prior to experimental infection with 300 third-stage A. abstrusus larvae, while G4 served as placebo-treated control.ResultsFrom 30 to 46 days post infection (dpi; SD 114 to 130), faeces were sampled to monitor first-stage larvae (L1) excretion for efficacy determination. Secondary efficacy criteria, including respiratory parameters, serological antibody levels and computed tomography (CT) findings, were assessed once before enrolment (SD −7 to −1) and before infection (SD 75 to 83). After infection, CT evaluation was performed once at 47–50 dpi (SD 131 to 134), and respiratory parameters and antibody levels were regularly assessed twice or once a week, respectively (1 up to 78 dpi, SD 85 up to 162). All animals in the control group excreted L1 by 33–37 dpi and remained positive throughout the study period from 41 to 46 dpi (SD 125 to 130). In the treatment groups, only one animal each of G1 and G2 excreted L1 at two consecutive days, and four cats of G1, two of G2 and three of G3 were positive on single occasions. While the geometric mean (GM) of the maximum number of excreted L1 per 5 g of faeces was 7380.89 in the control group (G4), GMs were significantly lower in the treatment groups with 1.63 in G1, 1.37 in G2 and 0.79 in G3. Thus, based on GMs, the reduction in excreted L1 exceeded 99.9% in all three treatment groups. Based on CT severity scores, all lungs of the animals of the control group showed severe pulmonary changes post infection, whereas lungs of the cats of the treatment groups were either unaltered (4 animals), mildly (11 animals), or moderately altered (5 animals). Moreover, seroconversion was observed in all cats of the control group, but not in those of the treatment groups.ConclusionsThe combination of diagnostic methods used in this non-terminal study yielded coherent and reliable results. A single administration of Bravecto® Plus spot-on solution for cats was well tolerated and effective in the prevention of aelurostrongylosis for at least 12 weeks.Graphical

Transcutaneous auricular vagus nerve stimulation modifies cortical excitability in middle-aged and older adults.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABAAergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation.

Network-based transcranial direct current stimulation enhances attention function in healthy young adults: a preliminary study.

Attention, a complex cognitive process, is linked to the functional activities of the brain's dorsal attention network (DAN) and default network (DN). This study aimed to investigate the feasibility, safety, and blinding efficacy of a transcranial direct current stimulation (tDCS) paradigm designed to increase the excitability of the DAN while inhibiting the DN (DAN+/DN-tDCS) on attention function in healthy young adults. In this randomized controlled experiment, participants were assigned to either the DAN+/DN-tDCS group or the sham group. A single intervention session was conducted at a total intensity of 4 mA for 20 min. Participants completed the Attention Network Test (ANT) immediately before and after stimulation. Blinding efficacy and adverse effects were assessed post-stimulation. Forty participants completed the study, with 20 in each group. Paired-sample t-test showed a significant post-stimulation improvement in executive effect performance (t = 2.245; p = 0.037) in the DAN+/DN-tDCS group. The sham group did not exhibit any significant differences in ANT performance. Participants identified the stimulation type with 52.50% accuracy, indicating no difference in blinding efficacy between groups (p = 0.241). Mild-to-moderate adverse effects, such as stinging, itching, and skin reddening, were reported in the DAN+/DN-tDCS group (p < 0.05). DAN+/DN-tDCS enhanced attention function in healthy young individuals, particularly in improving executive effect performance. This study presents novel strategies for enhancing attentional performance and encourages further investigation into the mechanisms and outcomes of these interventions across diverse populations.

Abstract 10128: Recombinant Human Placental Growth Factor-2 Treatment in Porcine Ischemic Cardiomyopathy

Background: Placental growth factor (PlGF)-2 induces neovascularization and improves myocardial function in atherosclerotic rodent myocardial ischemia models without stimulating plaque angiogenesis. This promising therapeutic profile of PlGF-2 warrants a double blind, randomized, and placebo-controlled feasibility and efficacy study in a large animal model, representative of human disease. Methods: We induced myocardial infarction (MI) in domestic pigs using a 75 min balloon occlusion of the mid-LAD followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF&lt;40%) to continuous IV infusion of 5, 15, 45 μg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated treatment effect 8 w after MI using comprehensive MRI analysis of LV function and structure and performed postmortem histological analyses of LV vascularization and fibrotic remodeling. Results: In the pilot study (3 pigs/dose), PIGF plasma concentrations showed stable and sustained dose-dependent increases for 28 days without organ-specific side effects or systemic toxicity. Myocardial Ischemia/reperfusion induced LV dysfunction at 4 w (infarct size, 16±4 % of LV mass, n=42; LVEF, 34±4 %, range 19%-40%). In the dose escalation study using 5 (n=10), 15 or 45 μg/kg/day PlGF (n=11 per group), global LV function, and regional myocardial blood flow at rest or during stress, and infarct size did not differ between CON (n=10) and PlGF (Figure 1). Capillary densities and extent of LV interstitial fibrosis in infarct core and border zone were comparable between CON and PlGF. Conclusions: In this blinded randomized controlled trial, rhPIGF-2 did not improve global cardiac function in a porcine model of chronic ischemic cardiomyopathy, and failed to recapitulate therapeutic neovascularization reported in rodents. Our data emphasize the critical need for robust double blind, placebo controlled trials in representative large animal models before clinical translation.

Temporal interference stimulation targeting right frontoparietal areas enhances working memory in healthy individuals.

Temporal interference (TI) stimulation is a novel technique that enables the non-invasive modulation of deep brain regions. However, the implementation of this technology in humans has not been well-characterized or examined, including its safety and feasibility. We aimed to examine the feasibility, safety, and blinding of using TI on human participants in this pilot study. In a randomized, single-blinded, and sham-controlled pilot study, healthy young participants were randomly divided into four groups [TI and transcranial alternating current stimulation (tACS) targeting the right frontoparietal region, TI-sham, and tACS-sham]. Each participant was asked to complete N-back (N = 1 to 3) tasks before, during, and after one session of stimulation to assess their working memory (WM). The side effects and blinding efficacy were carefully assessed. The accuracy, reaction time (RT), and inverse efficiency score (IES, reaction time/accuracy) of the N-back tasks were measured. No severe side effects were reported. Only mild-to-moderate side effects were observed in those who received TI, which was similar to those observed in participants receiving tACS. The blinding efficacy was excellent, and there was no correlation between the severity of the reported side effects and the predicted type of stimulation that the participants received. WM appeared to be only marginally improved by TI compared to tACS-sham, and this improvement was only observed under high-load cognitive tasks. WM seemed to have improved a little in the TI-sham group. However, it was not observed significant differences between TI and TI-sham or TI and tACS in all N-back tests. Our pilot study suggests that TI is a promising technique that can be safely implemented in human participants. Studies are warranted to confirm the findings of this study and to further examine the effects of TI-sham stimulation as well as the effects of TI on deeper brain regions.

Blinding efficacy and adverse events following repeated transcranial alternating current, direct current, and random noise stimulation

As transcranial electrical stimulation (tES) protocols advance, assumptions underlying the technique need to be retested to ensure they still hold. Whilst the safety of stimulation has been demonstrated mainly for a small number of sessions, and small sample size, adverse events (AEs) following multiple sessions remain largely untested. Similarly, whilst blinding procedures are typically assumed to be effective, the effect of multiple stimulation sessions on the efficacy of blinding procedures also remains under question. This is especially relevant in multisite projects where small unintentional variations in protocol could lead to inter-site difference. We report AE and blinding data from 1,019 participants who received up to 11 semi-consecutive sessions of active or sham transcranial alternating current stimulation (tACS), direct current stimulation (tDCS), and random noise stimulation (tRNS), at 4 sites in the UK and US. We found that AEs were often best predicted by factors other than tES, such as testing site or session number. Results from the blinding analysis suggested that blinding was less effective for tDCS and tACS than tRNS. The occurrence of AEs did not appear to be linked to tES despite the use of smaller electrodes or repeated delivery. However, blinding efficacy was impacted in tES conditions with higher cutaneous sensation, highlighting a need for alternative stimulation blinding protocols. This may be increasingly necessary in studies wishing to deliver stimulation with higher intensities.

Shilajit an elixir of Ayurveda: A literary review of traditional usage as well as modern findings

Shilajit is being widely used to cure a number of diseases across the world. It has wide medicinal values in various traditional systems of medicine worldwide. Shilajit has an important place in the Ayurvedic classic texts and being used as like a panacea, as Acharya Charaka cited in their popular verse that there is no curable decease on the earth, which could not be treated with the proper administration of Shilajit Rasayana. In modern days a number of research have been conducted across the world on parameters as defined and established on modern paradigms, and it has been concluded that Shilajit may play an important Roles in curing various life style deceases or infectious deceases. The aim and objective of current study to summarize the modern findings available online or offline on resources like Pub-Med, Google Scholar, and Science direct and another database, and cross relate the same with the establishment and verses of classical Ayurvedic Texts. The physical and chemical properties of Shilajit has also been discussed and summarized with special reference to modern findings. After going through a number of literature it may be concluded that Shilajit obviously have miraculous property as described in classical text and folk lore, but there is a limitation when reviewed on modern parameters, and that limitations is definitely lack of appropriate numbers of double blinded clinical trials and efficacy evaluation. Maximum studies available now a days are either in-vivo or in-vitro study, only a few human clinical trials are present.

Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?

Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.

Efficacy of Bravecto\xae Plus spot-on solution for cats (280 mg/ml fluralaner and 14 mg/ml moxidectin) for the prevention of aelurostrongylosis in experimentally infected cats

BackgroundThe feline lungworm Aelurostrongylus abstrusus affects the lower respiratory tract in cats worldwide. As infections may lead to chronic respiratory changes or even death, preventive treatment in cats with outdoor access is warranted.MethodsThe preventive efficacy of a spot-on solution (Bravecto® Plus spot-on solution for cats, MSD) against cat aelurostrongylosis was evaluated using three different preventive treatment regimes in a negative controlled, randomized and partially blinded laboratory efficacy study with 31 purposed-bred cats. The minimum recommended dose of 2.0 mg moxidectin + 40 mg fluralaner/kg bodyweight was applied once 12 (Group [G]1), 8 (G2) or 4 (G3) weeks before experimental infection with 300 third-stage larvae (L3) of A. abstrusus. Another group served as untreated control (G4). Individual faecal samples were analysed as of day 30 post infection (pi) to monitor larvae excretion. Necropsy was performed at days 47–50 pi. The lungs were examined macroscopically for pathological findings and (pre-)adult worms were counted to assess preventive efficacy.ResultsBeginning at day 32–40 pi, all cats of the control group were constantly shedding larvae of A. abstrusus, whereas only one animal of G1 excreted larvae at several consecutive days. In addition, two cats of G1 and G3 and three of G2 were positive on a single occasion. The geometric mean (GM) of the maximum number of excreted larvae was 7574.29 in the control group compared to 1.10 (G1), 1.19 (G2) and 0.53 (G3), resulting in a GM reduction of > 99.9% in all treatment groups. All lungs of the control animals showed severe or very severe alterations at necropsy, while in 94.44% of the treated cats lung pathology was rated as absent or mild. The GM number of (pre-)adult A. abstrusus retrieved from the lungs was 26.57 in the control group, 0.09 in G1 and 0.00 in G2 and G3. Thus, GM worm count reduction was 99.66% in G1 and 100% in G2 and G3.ConclusionsA single application of Bravecto® Plus spot-on solution at a dose of 2.0 mg moxidectin + 40 mg fluralaner/kg bodyweight reliably prevents cat aelurostrongylosis for at least 12 weeks.Graphical

Insecticidal efficacy of afoxolaner against Stomoxys calcitrans (Diptera: Muscidae) in dogs

The insecticidal activity of oral afoxolaner (NexGard®) against stable flies Stomoxys calcitrans (Diptera: Muscidae) that had fed on dogs was evaluated in a blinded, randomised, and negative controlled efficacy study. The efficacy assessments were based on survival rates of fed flies after challenges to treated dogs. For a challenge, each dog was exposed to 50 unfed S. calcitrans for 30 minutes, after which time live fed flies were collected and incubated in an insectarium for viability assessment after 48, 72 and 96 hours. Fourteen dogs were randomly allocated to an untreated control group and an afoxolaner-treated group of seven dogs each. NexGard® was administered on Day 0 per label instructions to the treated group. All dogs were challenged on Days 1, 7, 14, 21 and 28. Efficacy was calculated by comparison of the proportion of incubated live fed flies for each individual after their related 30-min challenges in the control and treated groups after 48, 72 and 96 hours of incubation. A significant afoxolaner activity against S. calcitrans was demonstrated, with efficacy at 96 hours after blood-feeding ranging from 76.4 to 98.5% through Day 28.

A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson's disease

IntroductionCVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. MethodsPatients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). ResultsMost frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were −0.092 L, −0.097 L, and −0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5–91.9% over 12 months. ConclusionCVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

Evaluation of Efficacy Endpoints for a Phase IIb Study of a Respiratory Syncytial Virus Vaccine in Older Adults Using Patient-Reported Outcomes With Laboratory Confirmation

ObjectivesThere are no approved vaccines for respiratory syncytial virus (RSV), and consensus on methods to assess RSV vaccine efficacy has not been established. In this study of an adjuvanted RSV vaccine, we evaluated an RSV disease endpoint using a patient-reported outcome instrument (the inFLUenza Patient-Reported Outcome instrument [FLU-PRO]) and molecular testing for virologic confirmation. MethodsIn a randomized, blinded efficacy study (NCT02508194), 1900 adult participants aged ≥60 years who had any respiratory symptom lasting ≥24 hours recorded symptoms in a FLU-PRO–based workbook for 21 days, self-collected nasal swabs on illness days 2 to 4, and had a site-collected swab obtained on (approximately) day 4. The endpoint, acute RSV-associated respiratory illness (ARA-RI), required specific symptoms with virologic confirmation. ResultsThe FLU-PRO demonstrated reliability, ability to detect change, and validity and had high participant adherence and acceptable patient burden in the setting of an RSV prevention trial. The ARA-RI endpoint definition captured all 33 virologically confirmed RSV illnesses for which symptom data were provided, and in 32 of these, at least 1 lower respiratory symptom was reported. Sensitivity analysis with an endpoint requiring ≥2 lower respiratory symptoms captured greater symptom severity but fewer cases. Results of self- and site-collected swabs were highly correlated. Self-swabbing detected 9 additional cases that would have been missed by site swabbing only. ConclusionsThese results demonstrated the reliability and validity of the ARA-RI definition and of the FLU-PRO for use in RSV studies. Self-swabbing improved RSV detection.

Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial

BackgroundEither benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America.MethodsThe goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20–65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12–18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60–80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80–90% power; one-sided alpha level 1%).DiscussionThe EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents.Trial registrationClinicalTrials.gov, NCT02369978. Registered on 24 February 2015.

How Placebo Needles Differ From Placebo Pills?

Because acupuncture treatment is defined by the process of needles penetrating the body, placebo needles were originally developed with non-penetrating mechanisms. However, whether placebo needles are valid controls in acupuncture research is subject of an ongoing debate. The present review provides an overview of the characteristics of placebo needles and how they differ from placebo pills in two aspects: (1) physiological response and (2) blinding efficacy. We argue that placebo needles elicit physiological responses similar to real acupuncture and therefore provide similar clinical efficacy. We also demonstrate that this efficacy is further supported by ineffective blinding (even in acupuncture-naïve patients) which may lead to opposite guesses that will further enhances efficacy, as compared to no-treatment, e.g., with waiting list controls. Additionally, the manner in which placebo needles can exhibit therapeutic effects relative to placebo pills include enhanced touch sensations, direct stimulation of the somatosensory system and activation of multiple brain systems. We finally discuss alternative control strategies for the placebo effects in acupuncture therapy.

New multi-targeting strategy in hair growth promotion: in vitro and in vivo studies.

Considering the importance of hair in our modern society and the impact of hair loss, the efforts of researchers are addressed to better understand the mechanisms behind the hair cycle regulation and dysregulation. Because hair loss is multifactorial, differenced and new approaches are required. In particular we addressed our attention to two recently identified targets in hair cycling and growth control: olfactory receptor and autophagy. The aim of the study was to evaluate: the possible pro-autophagic effect of N1-methylspermidine (a spermidine analogue) in vitro and, in a double blind clinical trial, the safety and efficacy of topical daily application of a lotion containing N1-methylspermidine and Sandalore®. Autophagic modulation by N1-methylspermidine was monitored in vitro by LC3 and p62 fluorescent signal cell line. Topical daily application of the lotion was tested in 60 male and female subjects with chronic telogen effluvium by means of non-invasive objective evaluation. The results obtained by in vitro tests showed the capacity of N1-methylspermidine to increase autophagic process while the clinical trials performed confirmed the safety and anti hair loss efficacy of the lotion reporting a reduction of hair loss (modified wash test) and hair growth stimulation as evaluated by hair density, hair shaft diameter, % of anagen hair and Hair Mass Index increase after 3 months of treatment. The lotion efficacy remained statistically significant for the above-mentioned parameters, with the exception of hair lost during wash, also 3 months after the end of treatment. Based on the obtained results, the daily use of the N1-methylspermidine and Sandalore®-based lotion is efficient to counteract hair loss and increase hair growth by a multifunctional targeting approach.

Assessment of the insecticidal activity of afoxolaner against Aedes aegypti in dogs treated with NexGard®.

Twelve healthy dogs were studied in this parallel group, blinded, randomised, and negative controlled efficacy study. On Day -1, the 12 dogs included were ranked within sex in descending order of individual pre-treatment (Day -5) fed mosquito counts and randomly allocated by blocks of two dogs to the untreated control group or the afoxolaner-treated group. NexGard® (Merial, now part of Boehringer Ingelheim Animal Health) was administered orally on Day 0 in accordance with the European label instructions. On Days 1, 7, 14, 21 and 28, all dogs were exposed for a duration of 1 hour to 50 ± 5 unfed Aedes aegypti females. After each exposure, mosquitoes were collected after 1 hour and assessed for viability during collection and at 24 ± 2 hours. The arithmetic (and geometric) mean values of live fed mosquito counts at 24 hours after the exposure periods for the negative control group ranged from 33.7 (32.3) to 49.8 (49.7), indicating that this was a vigorous mosquito strain. There was no significant difference between control and treated groups in the number of live and fed mosquitoes at each 1 hour post-exposure collection time. Based on arithmetic and geometric mean values at 24 hours after each exposure, significantly fewer live fed mosquitoes were recorded in the treated group, compared to the negative control group, throughout the study (p < 0.001). The afoxolaner insecticidal efficacy against A. aegypti varied from 98% (Day 2) to 75.3% (Day 29) based on arithmetic means, and 98.7% (Day 2) to 89.8% (Day 29) based on geometric means.

Efficacy of Double-Blind Peer Review in an Imaging Subspecialty Journal.

Many scientific journals use double-blind peer review to minimize potential reviewer bias concerning publication recommendations. However, because neuroradiology is a relatively small subspecialty, this process may be limited by prior knowledge of the authors' work or associated institutions. We sought to investigate the efficacy of reviewer blinding and determine the impact that unblinding may have on manuscript acceptance. For manuscripts submitted to the American Journal of Neuroradiology (AJNR) from January through June 2015, reviewers completed a brief anonymous questionnaire after submitting their evaluations, assessing whether they were familiar with the research or had knowledge of the authors or institutions from which the work originated. The response rate for 1079 questionnaires was 98.8%; 12.9% of reviewers knew or suspected that they knew authors, and 15.3% knew or suspected that they knew the associated institutions. Reviewers correctly identified the authors in 90.3% of cases and correctly stated the institutions in 86.8% of cases. Unblinding resulted from self-citation in 34.1% for both authorship and institutions. The acceptance rate when reviewers knew or suspected that they knew the authors was 57/137 (41.6%) and 262/929 (28.2%) when reviewers did not. The acceptance rate when reviewers knew or suspected that they knew the institutions was 60/163 (36.8%) and 259/903 (28.7%) when they did not. The Fisher exact test showed that author (P < .038) and institution (P < .039) familiarity was associated with greater manuscript acceptance. While the AJNR process of double-blind peer review minimizes reviewer bias, perceived knowledge of the author and institution is associated with a higher rate of manuscript acceptance.

Efficacy of a topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel (Broadline(®)) against naturally acquired infections with cestodes of the genus Joyeuxiella in cats.

Cats are host to dipylidiid cestodes of the genera Diplopylidium, Dipylidium and Joyeuxiella. Broadline(®), a topical broad-spectrum combination parasiticide containing fipronil (8.3% w/v), (S)-methoprene (10% w/v), eprinomectin (0.4% w/v) and the cestocide praziquantel (8.3% w/v), has previously been shown to be efficacious against Dipylidium caninum and Diplopylidium spp. in cats. To evaluate its efficacy against Joyeuxiella species, a blinded clinical efficacy study was conducted according to GCP. All cats had evidence for naturally acquired dipylidiid cestode infection as confirmed by pre-treatment examination. Cats were allocated randomly to two groups of 13 cats each based on bodyweight: Control (untreated) and Broadline(®) at 0.12mL/kg bodyweight administered once topically. Based on the comparison of helminth counts in the treated and untreated cats seven days post treatment, Broadline(®) demonstrated >99% efficacy (p < 0.01) against mature J. fuhrmanni and J. pasqualei, with 11 and 13 of the untreated cats harbouring 1 to 102 or 2 to 95 cestodes, respectively. In addition, parasite counts indicated 95.9% efficacy (p = 0.006) against the rictularoid nematode Pterygodermatites cahirensis.