Placebo Effect Research Articles

Identifying perceptions and knowledge gaps among pre-clinical and clinical medical students regarding placebo therapy

Background: Misleading definitions and perceptions of placebo and placebo effect result in fewer realizations on the subject, hence reducing its perceived importance and applications. This study aims to assess undergraduate medical students' perceptions and knowledge gaps regarding placebo therapy across different stages of their education. Methods: A comparative cross-sectional study was conducted for six months, from December 2022 to May 2023, among 350 pre-clinical students (1st and 2nd year MBBS) and 526 clinical students (3rd, 4th, and Final-year MBBS) to assess their perceptions regarding placebo and placebo effect through a validated questionnaire. SPSS was used for analyses, and Pearson's Chi-square was applied, keeping the statistically significant value of <0.05. Results: The study included 876 medical students, with 350 pre-clinical and 526 clinical participants. The mean age was 21.32 years (±1.606). A significant gender distribution was observed, with 45.5% males and 54.5% females. Clinical students demonstrated a greater acceptance of placebo use (68.3% vs. 62.3%, p=0.031) and were more likely to find placebo therapy ethical in psychological cases (70.3% vs. 60.3%, p=0.006). Knowledge assessment revealed that 65% had fair knowledge of placebo therapy, 31.8% had good knowledge, while only 3.2% were highly knowledgeable. Conclusion: The study revealed that many pre-clinical and clinical students held misconceptions about placebo therapy, believing it permissible and beneficial in treating organic disorders. This highlights a significant knowledge gap, emphasizing the need for improved education on placebo use and ethics.

Time-Efficacy Relationship of Semaglutide in the Treatment of Type 2 Diabetes Mellitus: A Model-Based Meta-Analysis.

Our objective was to quantify the efficacy of subcutaneous once-weekly semaglutide in treating type 2 diabetes mellitus (T2DM) over time. Based on a literature search of the PubMed, Embase, Cochrane, and Web of Science databases, a modified maximum effect (Emax) model including rebound effects was built using model-based meta-analysis with change from baseline in glycated hemoglobin as the efficacy endpoint. This was combined with the covariate model to form a final model, and then theoretical values of Emax and time to reach 50% of Emax (ET50) were obtained for each dose. Model fit and prediction were assessed using goodness-of-fit plots and visual prediction checking. Emax and ET50 were influenced by the proportion of males and the baseline values, respectively. There was no evidence of a placebo effect with semaglutide. The efficacy of other doses became more significant over time, and a rebound effect was observed after maximum efficacy, at a rate of 0.018. Simulation of the typical efficacy at the different doses yielded a maximum efficacy of -1.58% with 0.5 mg and a maximum efficacy of -1.87% with 1 mg. In addition, the six simulated doses (0, 0.1, 0.2, 0.5, 1, and 2 mg) showed a dose-dependent relationship between dose and efficacy except for 0.4 mg and 0.8 mg. A higher dose would result in greater efficacy and a faster onset of action. The efficacy of semaglutide in glucose control was investigated using the model-based meta-analysis method, which yields new insights into the treatment of T2DM with semaglutide.

Efficacy and Safety of a Diet Enriched with EPA and DHA, Turmeric Extract and Hydrolysed Collagen in Management of Naturally Occurring Osteoarthritis in Cats: A Prospective, Randomised, Blinded, Placebo- and Time-Controlled Study

This study evaluated a therapeutic diet high in eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) of marine source (EPA:DHA ratio 0.69:1), turmeric extract, and hydrolysed collagen in cats (N = 30) with naturally occurring osteoarthritis (OA) over a 13-week (W) period, followed by a 4-W washout, using four previously validated pain/functional outcomes. Compared to the placebo diet, the therapeutic diet significantly improved peak vertical force (p = 0.017; W16, 64% responders), correlating to enhanced weight bearing; stair assay compliance (p < 0.001; W16, 87% responders), reflecting reduced fatigue related to OA pain; night-time actimetry (cohort effect; p = 0.05, 67% responders), suggesting greater spontaneous mobility and comfort; and MI-CAT(V) score (cohort effect; p < 0.001, 80% responders), indicating reduced functional impairments. The earliest therapeutic response was observed at W06, marked by an inflection point between actimetric linear regressions of both cohorts, confirmed by significant MI-CAT(V) differences (p < 0.007; W08; W12; W16). The MI-CAT(V) clinical metrology instrument was validated for inter-rater reliability, minimal placebo effect (<15% responders), and OA severity clustering. Despite baseline differences in biomechanical assessments (p < 0.05), both moderate and severe OA clusters responded equally positively to the therapeutic diet. Based on all outcomes, the therapeutic diet showed promise for the long-term management of feline OA, with no observed side effects.

“I am open to self-belief”: A study examining the impact of open-label effects on postexercise affect and postintervention exercise behaviour

ABSTRACT The contribution of placebo effects can be measured by manipulating psychological factors, such as positive expectations for exercise outcomes, without the need for traditional placebos (such as inert substances). While placebo effects are well known, research has revealed intriguing findings suggesting that placebos can have beneficial effects even when studies are performed without deception. Open-label placebo (OLP) interventions (prescribed honestly), which harness the power of belief, may represent another effective method for enhancing the benefits of exercise effects. This study compared the efficacy of a conventional placebo intervention, an OLP intervention, and a control group among 89 individuals. Participants’ levels of affective response after exercise and exercise behaviour were assessed during the intervention period (4 weeks) and at follow-up (4 weeks). The results revealed similar levels of improvement in all outcomes across the three conditions. Both the conventional placebo and OLP intervention groups exhibited greater enhancements in postexercise enjoyment. OLP interventions demonstrated distinct advantages in terms of remembered affect and expectation fulfilment. Nonetheless, neither intervention directly stimulated postintervention exercise behaviour. Future studies should continue to explore the impact of OLP interventions on adherence to exercise behaviour.

Differential neural activity predicts the long-term stability of the effects of positive and negative expectations on pain.

Expectations modulating pain perception is a well-researched phenomenon, but less is known about the persistence of expectation effects over longer time-courses. In this preregistered study, we examined the persistence of positive (placebo) and negative (nocebo) expectation effects over one week and investigated whether neural activity on day 1 (fMRI) can predict the stability of these effects one week later (n = 41). We tested whether expectations were reflected in EEG oscillatory activity at the second measurement. Both positive and negative pain modulation effects persisted over the tested time-period and did not undergo extinction. Expectations of higher compared to lower pain led to larger theta-to-alpha EEG activity. Most interestingly, differential neural activity in fMRI was correlated with persistent expectations. Individual differences in the persistence of positive expectation effects were related to reduced amygdala activity and enhanced activity in the anterior insula and dorsolateral prefrontal cortex (DLPFC) during the first session. In contrast, persistence of negative expectation effects was predicted by enhanced thalamus activity. Our findings indicate relatively stable placebo and nocebo effects over longer time courses, but this persistence is based on different neural areas for positive and negative expectations.

Development and validation of the General attitude towards Medication Questionnaire (GAMQ)

BackgroundAttitudes towards medication can affect treatment outcomes and adherence through mechanisms such as placebo and nocebo effects. Questionnaires assessing both negative and positive attitudes towards medication in general, which can be used across a variety of settings and in both patient and non-patient samples, are however lacking. To fill this gap, we developed and validated the General Attitude towards Medication Questionnaire (GAMQ).MethodsItems were selected and adapted from existing questionnaires by a group of experts. Validation of the original Dutch version took place in 4 samples: 2 recruited from the general population (n = 508; n = 279) and 2 patient samples (patients with rheumatoid arthritis, n = 121; patients with atopic dermatitis, n = 70). We evaluated the psychometric properties of the GAMQ by determining the factor structure and its stability across samples, internal consistency, and convergent validity.ResultsThe GAMQ contains 6 positive and 6 negatively worded items. A factor structure was observed with three subscales, representing ‘Trust in medication’, ‘Concerns about medication’, and ‘Reluctance to use medication’. The fit of the factor structure was satisfactory across samples, considering classic cut-offs, with an adequate or close to adequate fit. The total scale showed good internal consistency, good convergent validity with related scales (i.e., Beliefs about Medicines Questionnaire - General and a single medication attitude scale), and concurrent validity as reflected in associations with expectations about pain- and itch-relieving medication. It was not consistently or strongly associated with demographic or health-related characteristics.ConclusionsThe newly developed GAMQ showed satisfactory psychometric properties in a variety of populations, although limitations should be considered. The GAMQ is the first scale to assess both positive and negative attitudes towards medication in general, providing indicators of Trust, Concerns, and Reluctance regarding medication. The scale may be an informative measure for predicting treatment outcomes and adherence, as well as placebo and nocebo effects in diverse samples.

Effects of probiotics on selected anthropometrics and biochemical measures in overweight or obese Saudi subjects: a double-blind, placebo-controlled, randomised clinical trial.

This study aimed to assess the effects of multi-strain probiotics on anthropometric and biochemical measures in Saudi adults with overweight or obesity. Single-centre, double-blind, placebo-controlled, randomised clinical trial. Occupational Health Clinics at King Saud University Medical City, Riyadh, Saudi Arabia. Ninety-three Saudi participants with overweight or obesity were randomly assigned to receive twice-daily doses of either placebo (n 49) or 30 × 109 CFU/g of HEXBIO® containing three Lactobacillus and three Bifidobacterium species (n 44) in a double-blind manner over a 12-week period, respectively. Both groups adhered to a hypoenergetic diet. Anthropometric measurements, glycaemic indices and lipid profiles were evaluated at baseline and post-intervention. Following the 12-week intervention, no statistically significant differences were found in all between the probiotic group and placebo group comparisons, except for fat intake, where the group*time interaction showed a significant decrease in favour of the probiotic group (P = 0·02). However, significant within-group reductions were observed in the probiotic group: body weight (-0·9 kg, P = 0·02), HC (-1·5 cm, P = 0·002), energy intake (-387·3 kcal/d, P = 0·002), fasting glucose (-0·7, P = 0·002) and LDL-cholesterol (-0·7, P = 0·02). Consumption of multi-strain probiotic supplementation over 12 weeks significantly decreased fat intake in Saudi adults with overweight or obesity, with the probiotic group highlighting improved anthropometric and biochemical parameters. Further research is needed to evaluate the long-term clinical significance of this dietary practice and whether it has a meaningful impact on overall health beyond the placebo effect.

Limited Potential of Repetitive Transcranial Magnetic Stimulation for Treatment of Essential Tremor: A Systematic Review

Essential tremor (ET) is a prevalent movement disorder characterized by action tremors, predominantly affecting the upper limbs. While various pharmacological and non-pharmacological interventions have shown efficacy in managing ET, the therapeutic role of repetitive transcranial magnetic stimulation (rTMS) remains uncertain. This systematic review synthesizes evidence from clinical trials investigating rTMS as a treatment for ET. Despite some open-label trials reporting reductions in tremor severity, double-blinded studies revealed no significant difference between active and sham rTMS, suggesting a strong placebo effect. The findings indicate that while rTMS can reduce tremor scores, its therapeutic efficacy in ET remains unproven. Future research should focus on improving sham designs and conducting larger, rigorously controlled trials to clarify rTMS’s role in ET management. Current evidence supports considering alternative treatments, such as deep brain stimulation, over rTMS for ET.

Effect of Intravenous Tirofiban Versus Placebo on First-Pass Successful Reperfusion in Endovascular Stroke Thrombectomy: Insights From the RESCUE BT Randomized Clinical Trial.

First-pass successful reperfusion (FPSR), defined as a successful/complete reperfusion achieved after a single thrombectomy pass, is predictive of favorable outcome in patients with acute ischemic stroke with large-vessel occlusion. It is unknown whether intravenous tirofiban is effective in increasing the rate of FPSR in acute anterior large-vessel occlusion stroke. Patients who had acute large-vessel occlusion stroke presenting within 24 hours and underwent endovascular thrombectomy were analyzed from the RESCUE BT (Intravenous Tirofiban for Patients With Large Vessel Occlusion Stroke) clinical trial, of which the main analysis was neutral. The RESCUE BT trial randomized patients to receive either intravenous tirofiban or placebo before endovascular thrombectomy. The primary end point was FPSR, defined as successful reperfusion (extended thrombolysis in cerebral infarction scale 2b50, 2c, or 3) at first thrombectomy attempt. A modified Poisson regression analysis assessed the association between intravenous tirofiban treatment and FPSR. Of 948 enrolled patients, 463 patients were randomized to the tirofiban group and 485 to the placebo group. The mean age was 67 years, and 41.0% of the patients were women. FPSR was achieved more often in the tirofiban group (30.5% versus 23.5%; adjusted risk ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04). FPSR was associated with a favorable shift to lower modified Rankin Scale disability levels at 90 days (common odds ratio, 1.42 [95% CI, 1.08-1.86]; P=0.01). In this post hoc analysis of the RESCUE BT trial, treatment with intravenous tirofiban before endovascular thrombectomy was associated with increased FPSR in patients with acute ischemic stroke due to large-vessel occlusion in the anterior circulation. FPSR was associated with reduced 90-day levels of disability. URL: http://chictr.org; Unique Identifier: ChiCTR-INR-17014167.

Efficacy and Safety of Sotagliflozin in Patients with Type 1 Diabetes and CKD.

This analysis evaluated the efficacy and safety of sotagliflozin, a dual SGLT1&2 inhibitor, added to insulin in patients with type 1 diabetes and chronic kidney disease (CKD). We used data from the 52-week pooled inTandem1&2 trials and the 24-week inTandem3 trial to assess the effects of sotagliflozin (200mg [inTandem 1&2 only] or 400mg daily) versus placebo on glycated hemoglobin (HbA1c; primary endpoint), body weight, systolic blood pressure (BP), insulin dose, and safety endpoints including adjudicated severe hypoglycemia and diabetic ketoacidosis (DKA), stratified by CKD. CKD was identified in 237/1575 of inTandem1&2 participants and 228/1402 of inTandem3 participants. At week-24, significant, placebo-adjusted reductions in HbA1c were observed - inTandem1&2: Non-CKD subgroup (sotagliflozin 200mg: -0.4%, 95% CI -0.4 to -0.3; 400mg: -0.4%, 95% CI -0.5 to -0.3) and CKD subgroup (sotagliflozin 200mg: -0.4%, 95% CI -0.6 to -0.1; 400mg: -0.3%, 95% CI -0.5 to -0.1). For systolic BP, there was a significant reduction at week-24 with sotagliflozin in the non-CKD subgroup but no effect in the CKD subgroup in inTandem1&2. At week-52, the incidence of severe hypoglycemia was lower with sotagliflozin (7% on 200 mg and 4% on 400 mg) compared to placebo (17%) in the CKD subgroup of inTandem1&2, whereas the incidence of severe hypoglycemia was 5-6% across non-CKD subgroups. The incidence of adjudicated DKA at week-52 was 1%, 5%, and 3% for placebo, 200 mg, and 400 mg in the CKD subgroup compared to 0%, 3%, and 4% in the non-CKD subgroup. Results were generally similar in inTandem3 except systolic BP was significantly reduced with sotagliflozin versus placebo in CKD and non-CKD subgroups. In participants with type 1 diabetes and CKD, sotagliflozin treatment had similar HbA1c, body weight, and systolic BP lowering effects as in participants with type 1 diabetes without CKD. Additionaly, sotagliflozin was associated with a lower to neutral risk of severe hypoglycemia and did not significantly increase the risk of DKA among a small number of DKA events.

Good vibes for the brain - Placebo versus real vibration in patients with chronic neck pain: A randomized cross-over study

BackgroundNeck muscle vibration decreases pain and improves sensorimotor impairments in patients with chronic neck pain. However, the impact of placebo on these effects are still unclear. ObjectiveThe aim was to evaluate the effect of neck muscle vibration compared to placebo neck muscle vibration in patients with chronic neck pain. MethodsTwenty-three people with chronic neck pain participated in this double-blinded, randomized crossover study. After baseline assessment at day 1, patients received either neck muscle vibration or placebo neck muscle vibration at day 2. At day 3, patients underwent the other treatment. The primary outcomes assessed at each day were active cervical joint position sense acuity, resting pain, and pressure pain threshold. ResultsCervical joint position sense revealed a significant time effect (F1, 22 = 4.366, p = 0.016, η2 = 0.902). Post-hoc testing revealed significant increases in cervical joint position sense after neck muscle vibration (p = 0.023; d = 0.602) but not after placebo vibration. Resting pain (F1, 22 = 7.550, p = 0.003, η2 = 0.418) displayed significant time effects for neck muscle vibration and placebo vibration. Pressure pain threshold demonstrated a significant time to condition effect (F1, 22 = 6.146; p = 0.008, η2 = 0.369). Post-hoc tests revealed that only neck muscle vibration significantly increased pressure pain threshold (p = 0.043, d = 0.516). ConclusionThe study demonstrates the efficacy of neck muscle vibration to decrease neck pain and improve cervical joint position sense in patients with chronic neck pain. Nevertheless, the influence of placebo effects should not be underestimated as they may contribute to these effects, indicated by similar decreases in resting pain.

A Protocol for the Validation of Novel Sham Acupuncture in Patients Who Have Had a Stroke

Background: A sham control group enhances the quality of clinical trials by controlling for the placebo effect. To ensure rigorous blinding to enhance the quality of clinical trials on acupuncture treatment it is important to develop a more sophisticated sham needle. Discrepancies in perceived needling sensation and treatment expectations between patients and healthy volunteers may affect study outcomes. Thus, it may be inappropriate to generalize the findings of a sham needle validation study in healthy adults to patients who have had a stroke. Therefore, this is a protocol for a clinical trial in patients who have had a stroke to validate a newly developed sham needle to be used in double-blind trials.Methods: Sixty-six patients who have had a stroke will be randomly assigned to the verum or sham needle group using a 1:1 ratio. As the verum and sham needles are identical in appearance, both participants and practitioners will be unaware of the needle type used for acupuncture treatment. After the acupuncture procedure, the participants will be asked whether they believe they received the verum or sham acupuncture treatment and indicate penetration, pain, and de qi sensation for each acupuncture point. A between-group comparison of needle-related adverse events will be performed.Discussion: This double-blind randomized controlled trial will be the first study to validate a newly developed sham acupuncture needle for patients who have had a stroke. The results of this study may inform clinical trial study design for acupuncture treatment of patients who have had a stroke.

Body mass index and clinical outcomes in patients with diabetes and stable coronary artery disease in THEMIS

Abstract Background Physiologic changes due to extremes of body weight may affect the efficacy and tolerability of antiplatelet treatment. However, it remains unclear whether the risks and benefits of intensified antiplatelet therapy among patients with diabetes and stable coronary artery disease (CAD) are affected by body mass index (BMI). Purpose To assess the relationship between baseline BMI and major adverse cardiovascular (CV) events, and to determine if the effects of ticagrelor vs. placebo varied across the BMI spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial of 19,220 individuals aged ≥50 years with type 2 diabetes and stable CAD, randomly allocated to ticagrelor or placebo on top of aspirin. Patients with a prior myocardial infarction (MI) or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of CV death, MI, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BMI using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox regression models with predefined BMI intervals (<25 kg/m2, 25-29.9 kg/m2, and ≥30 kg/m2) adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BMI values (test for interaction). A two-sided P-value <0.01 was considered statistically significant to control the overall chance of type I errors. Results BMI was available in 19,202 (99.9%) participants, with a median of 29 kg/m2 (interquartile range: 26-33). A total of 3352 (17.5%) individuals had a BMI <25 kg/m2, 7644 (39.8%) had a BMI 25-29.9 kg/m2, and 8206 (42.7%) had a BMI ≥30 kg/m2. Median follow-up was 39.9 months (range 0-57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. BMI was not associated with the primary efficacy or safety outcome, or with their individual components. However, BMI was significantly associated with hospitalization for heart failure (HHF) (BMI <25 kg/m2: reference; hazard ratio [HR] for BMI 25-29.9 kg/m2: 1.07, 95% confidence interval [CI], 0.82 to 1.40; HR for BMI ≥30 kg/m2: 1.41, 95% CI, 1.07 to 1.84) and with the composite of HHF or CV death (comparable estimates) after multivariable adjustment (Figure). BMI was also significantly, positively associated with serious adverse events (BMI <25 kg/m2: reference; HR for BMI 25-29.9 kg/m2: 0.99, 95% CI, 0.93 to 1.06; HR for BMI ≥30 kg/m2: 1.20, 95% CI, 1.12 to 1.29). BMI did not modify the risks and benefits of ticagrelor vs. placebo. Conclusions BMI was independently associated with the risk of HHF and the composite of HHF or CV death, but not with other efficacy or safety outcomes, in patients with stable CAD and type 2 diabetes. Ticagrelor was of similar benefit on the primary efficacy outcome vs. placebo across the full range of BMI.

Effect of tranexamic acid in vascular surgery- a sub-study of the POISE-3 randomized clinical trial

Abstract Background/Introduction In the POISE-3 trial involving patients undergoing noncardiac surgery, tranexamic acid (TXA) reduced the incidence of the composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days. Bleeding is a major issue in vascular surgery. However, TXA use may be limited due to concerns about its safety in this high-risk population. With 1,399 participants in POISE-3 undergoing vascular surgery, this is the largest trial assessing TXA's efficacy in this population. Purpose In this post hoc subgroup analysis, we aimed to investigate the interaction between surgery type (vascular/non-vascular) and the effects of TXA vs placebo on bleeding and cardiovascular (CV) safety outcomes in the POISE-3 population. Methods: Eligible patients were ≥45 years, undergoing inpatient noncardiac surgery, and at risk for bleeding and CV complications. Patients were randomised (1:1) to TXA 1 gm IV bolus at start and end of surgery (total 2 gm) or placebo. We used Cox proportional hazards models incorporating tests for interaction to analyse time to the first occurrence of the composite bleeding outcome, and the CV safety outcome (composite of myocardial injury after noncardiac surgery, non-hemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism) at 30 days. Estimates of hazard ratios (HR) with 95% confidence intervals (CI) were calculated for each subgroup with the interaction P value. Results 9,468 of 9535 (99.3%) POISE-3 patients are included in this analysis; 1399 of whom underwent vascular surgery (699 TXA, 700 placebo). Majority (89.8%) of the vascular surgeries were aorto-iliac, peripheral vascular and extracranial surgeries. In the vascular surgery group, 12.6% of patients receiving TXA experienced the composite bleeding outcome versus 14.7% with placebo (HR 0.85, 95% CI 0.64-1.13). For non-vascular surgery patients, these rates were 8.6% with TXA and 11.3% with placebo (HR 0.74, 95% CI 0.65-0.86), with an interaction P value of 0.42. In vascular surgery patients, the CV safety outcome occurred in 20.2% with TXA versus 18.1% with placebo (HR 1.12, 95% CI 0.88-1.42). In the non-vascular surgery group, both TXA and placebo arms showed a 13.1% incidence rate (HR 1.00, 95% CI 0.89-1.13), with an interaction P value of 0.43. Conclusion In vascular surgery patients, there were higher rates of bleeding and cardiovascular events compared to those undergoing non-vascular surgeries; however, there was no significant interaction between the effects of TXA and the type of surgery. The overall POISE-3 trial provides the best estimate of effect with TXA for all patients including those undergoing vascular surgery. The main limitation is that this subgroup analysis was not pre-specified.

The ghrelin receptor agonist AC01 improves cardiac function in non-human primates and in mice with heart failure by increasing cardiomyocyte contractility

Abstract Background Current therapy for Heart Failure (HF) includes neurohormonal antagonist and modulator drugs that improve remodelling, symptoms and clinical outcomes. However, these drugs do not target the underlying problem of reduced contractility. Improving cardiac contractility without harmful consequences is an unmet need in heart failure therapy. The human peptide hormone ghrelin increases cardiac output in HF patients and increases contractility in murine cardiomyocytes. Purpose We aim to study the cardiovascular effects of a novel oral small molecule ghrelin receptor agonist, AC01, in in vivo and ex vivo mouse models and in non-human primates. Methods HF mice (N=11) underwent pressure-volume loops analysis of cardiac functional and hemodynamic to assess the effects of intravenous AC01 (N=7) or placebo (N=4). Primary cardiomyocytes isolated from HF (N=3) and SHAM (N=5) mice, were treated with combinations of vehicle, AC01, ghrelin receptor antagonist (D-Lys-3-GHRP-6) and pertussis toxin (PTX, a Gαi signalling inhibitor). Live cell imaging was performed to assess cardiomyocyte fractional shortening and Ca2+ signalling, while biochemistry assays were employed to measure PKA activity, and phosphorylation of cardiac Troponin I (cTnI). Cynomolgus monkeys (N=6) were instrumented with devices to measure pulse contour, central aortic blood pressure and ECG devices. Cardiovascular effects of AC01 following single oral dosing were assessed through pulse contour hemodynamic modelling and analysis of autonomic system activation. Results In HF mice, AC01 significantly improved cardiac output (p< 0.01), stroke volume (p< 0.001), and ejection fraction (p< 0.001), and increased nominally the end-systolic pressure-volume curve relationship. In cardiomyocytes, AC01 dose-dependently improved fractional shortening (p< 0.01) without increasing Ca2+ transient amplitudes. AC01 reduced PKA activity (p< 0.05) and reduced phosphorylation of cTnI at Serine 23-24 (p< 0.01). These effects were blocked by pre-treatment with either D-Lys-3-GHRP-6 or PTX. In monkeys, oral AC01 sustainably increased cardiac output (p< 0.05) and stroke volume (p< 0.05) and reduced heart rate without altering central systolic blood pressure or causing tachycardia or arrhythmia. Conclusions AC01 improved CO, SV, and EF in HF mice by increasing contractility in a load-independent fashion. AC01 increased cardiomyocyte contractility without affecting Ca2+ transient amplitudes, through ghrelin receptor Gαi signalling, leading to reduced phosphorylation of cTnI. AC01 improved left ventricle systolic function in monkeys. AC01 is a first in class novel inotrope, which improves contractility in different species without harmful mobilization of Ca2+. AC01 should be explored for the treatment of patients with heart failure.graphical abstract

Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: a participant level pooled analysis of CREDENCE and CANVAS

Abstract Background Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalization for heart failure or cardiovascular death and CKD progression among patients with type 2 diabetes at high cardiovascular risk or with concomitant CKD. Purpose To assess the prognostic implications of oral loop diuretic intensification and the treatment effects of canagliflozin versus placebo on loop diuretic use in high-risk patients with type 2 diabetes. Methods This was a post-hoc participant-level pooled analysis of the CANVAS Program and CREDENCE trial which enrolled patients with type 2 diabetes at high cardiovascular risk or with CKD. Oral loop diuretic intensification was defined as a composite of new loop diuretic initiation (among patients not receiving loop diuretics at baseline) or loop diuretic dose increase (among patients receiving loop diuretics at baseline). We assessed the association between the requirement for loop diuretic intensification and the incidence of subsequent all-cause death. The effect of canagliflozin versus placebo on the composite of loop diuretic intensification as well as its components were evaluated. We further examined the effect of canagliflozin on an expanded post hoc composite of cardiovascular death, hospitalization for heart failure or loop diuretic intensification. Results 2,263 (15.6%) of 14,543 patients were treated with loop diuretics at baseline. Over a median follow-up of 2.2 years, 1,264 patients (9.4%) required oral loop diuretic intensification, of which 981 (77.6%) patients required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent mortality that were 3.5-fold higher (5.9[5.4-6.5] per 100 patient-years) than those not requiring oral loop diuretic intensification (1.7[1.6-1.9] per 100 patient-years). Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (HR 0.59; 95%CI: 0.53-0.66) including both new diuretic initiation (HR 0.65; 95%CI: 0.57-0.74) and diuretic dose increase (HR 0.42; 95%CI: 0.33-0.54); Figure 1. Treatment with canagliflozin similarly reduced an expanded composite of worsening heart failure inclusive of cardiovascular death, heart failure hospitalization or diuretic intensification (HR 0.64; 95%CI: 0.58-0.70). Conclusion Among high-risk patients with T2D, new oral loop diuretic intensification was frequent and associated with an increased risk of subsequent mortality. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification.

Initiation response, maximized therapeutic efficacy, and post-treatment effects of biological targeted therapies in myasthenia gravis: a systematic review and network meta-analysis.

As targeted drug development in myasthenia gravis (MG) continues to advance, it is important to compare the efficacy of these drugs for better clinical decision-making. However, due to the varied regimens and dosages used in clinical trials for different drugs, a standardized comparison between them is necessary. This study enrolled participants in phase II and III trials of innovative targeted drugs for MG. The primary outcome was the change in Quantitative Myasthenia Gravis score (MG-QMG) from baseline. The efficacy of all drugs at four time points was separately analyzed at four time points: initiation 1 week, initiation 4 weeks, maximized response, and post last dose 4 weeks. A network meta-analysis was conducted to compare the results of the different drugs. A total of 9 drugs, including Efgartigimod, Rozanolixizumab, Batoclimab, Eculizumab, Belimumab, Zilucoplan, Ravulizumab, Nipocalimab, Rituximab, derived from 12 studies were analyzed. At the initiation 1-week time point, three drugs exhibited significant improvement compared to the placebo effect: Efgartigimod, Zilucoplan, Rozanolixizumab. At the initiation 4-week time point, four drugs showed significant improvement compared to the placebo effect: Efgartigimod, Rozanolixizumab, Batoclimab, Zilucoplan. At the maximized response time point, six drugs achieved significant improvement compared to the placebo effect: Efgartigimod, Rozanolixizumab, Batoclimab, Eculizumab, Zilucoplan, Ravulizumab. At the post last dose 4-week point, all drugs statistically showed no significant difference from the placebo. Although the MG subtypes were not consistent across trials, within the regimen design of each trial, neonatal Fc receptor inhibitors-represented by Efgartigimod, Rozanolixizumab, and Batoclimab-exhibited the most effective response rates when compared to complement and B-cell inhibitor drugs.

Real-World and Patient-Reported Outcomes of Dupilumab and Other Biological Drugs for Chronic Obstructive Pulmonary Disease-A Systematic Review.

Over the last few decades, the efficacy of biological therapies for COPD has been evaluated by different randomized controlled trials (RCTs). Still, the evaluation of real-world data and patient-reported outcome measures (PROMs) have not been performed in this field before. In the current work, we present a systematic literature review of the real-world data and PROMs of biological treatments for COPD. Three large databases (MEDLINE/PubMed, Scopus, and ScienceDirect) were utilized for the systematic literature review. Clinical studies (RCT, cohorts, case series/reports) assessing patients with COPD treated by any biological therapy were included. The review resulted in twelve eligible studies (nine randomized controlled trials and three "real-world" case series/reports). The evaluation of PROMs in the included studies was mainly limited to the severity and burden of respiratory symptoms. Most biological therapies were associated with improved PROMs compared to the baseline, although not for the placebo. Dupilumab was the only biologic therapy with proven efficacy in RCT for both objective and subjective measures. One prior study reported patients' self-perceived drug effects, and none evaluated patients' perceived disease status. Only 25 patients were assessed in a real-world setting for all biologic therapies combined. Real-world data were retrospective in the form of case reports or series. There are limited data on patients' experience with biological therapies for COPD. While real-world data and PROMs are missing, biases such as a placebo effect must be considered, requiring their incorporation with objective outcomes from prospective controlled trials.

Transcranial direct current stimulation (tDCS) and cycling performance on the 3-minute aerobic test (3mAT): placebo and nocebo effects

Transcranial direct current stimulation (tDCS) has been used extensively but research on its efficacy within the sport and exercise science realm has been inconsistent. There may be placebo and nocebo effects present with its use. Our objective was to determine if subjects can be influenced to believe that tDCS will improve cycling performance. Subjects were separated into a belief group (B; 5 women, 6 men) and a disbelief group (DB; 9 women, 3 men). The B group was told that the stimulation would improve performance on a subsequent cycling test. In the DB group, subjects were told that it was not effective and would hinder performance. The cycling test was a 3-minute aerobic test (3mAT) where subjects maintained the highest power output possible for three minutes, after completing a full 20 min warmup. During the warmup, they were given either no stimulation (control) or 2 mA bilateral stimulation over the M1 region. There was a very slight increase in maximal minute power for the B group (0.22%) and a small decrease for the DB group (-1.00%); however, these differences were not significant. No significant differences were found for any of the cycling variables. In conclustion, tDCS was unable to improve performance on the 3mAT. These findings, in conjunction with others, suggest that the acute effect of tDCS is still questionable when aiming to enhance endurance performance.

Psilocybin-assisted neurofeedback for the improvement of executive functions: a randomized semi-naturalistic-lab feasibility study.

Executive function deficits, common in psychiatric disorders, hinder daily activities and may be linked to diminished neural plasticity, affecting treatment and training responsiveness. In this pioneering study, we evaluated the feasibility and preliminary efficacy of psilocybin-assisted frontal-midline theta neurofeedback (NF), a neuromodulation technique leveraging neuroplasticity, to improve executive functions (EFs). Thirty-seven eligible participants were randomized into an experimental group (n = 18) and a passive control group (n = 19). The experimental group underwent three microdose sessions and then three psilocybin-assisted NF sessions, without requiring psychological support, demonstrating the approach's feasibility. NF learning showed a statistical trend for increases in frontal-midline theta from session to session with a large effect size and non-significant but medium effect size dynamical changes within sessions. Placebo effects were consistent across groups, with no tasks-based EF improvements, but significant self-reported gains in daily EFs-working memory, shifting, monitoring and inhibition-showing medium and high effect sizes. The experimental group's significant gains in their key training goals underscored the approach's external relevance. A thorough study with regular sessions and an active control group is crucial to evaluate EFs improvement and their specificity in future. Psilocybin-enhanced NF could offer significant, lasting benefits across diagnoses, improving daily functioning. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.