Lung volume reduction surgery is safe and leads to functional improvement in patients who fail or cannot undergo bronchoscopic lung volume reduction.

Background: Bronchoscopic lung volume reduction (BLVR) has supplanted surgery in the treatment of patients with advanced emphysema, but not all patients qualify for it. Our study aimed to investigate the outcomes of lung volume reduction surgery (LVRS) among patients who either failed BLVR or were not candidates for it. Methods: We conducted a retrospective analysis of patients who underwent LVRS for upper lobe-predominant emphysema at a single tertiary center between March 2018 and December 2022. The main outcomes measures were preoperative and postoperative respiratory parameters, perioperative morbidity, and mortality. Results: A total of 67 LVRS recipients were evaluated, including 10 who had failed prior valve placement. The median patient age was 69 years, and 35 (52%) were male. All procedures were performed thoracoscopically, with 36 patients (53.7%) undergoing bilateral LVRS. The median hospital length of stay was 7 days (interquartile range, 6-11 days). Prolonged air leak (>7 days) occurred in 20 patients. There was one 90-day mortality from a nosocomial pneumonia (non-COVID-related) and no further deaths at 12 months. There were mean improvements of 10.07% in forced expiratory volume in 1 second and 4.74% in diffusing capacity of the lung for carbon monoxide, along with a mean decrease 49.2% in residual volume (P < .001 for all). The modified Medical Research Council dyspnea scale was improved by 1.84 points (P < .001). Conclusions: LVRS can be performed safely in patients who are not candidates for BLVR and those who fail BLVR and leads to significant functional improvement. Long-term follow-up is necessary to ensure the sustainability of LVRS benefits in this patient population.

ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Respiratory Assist Devices in Pulmonary Rehabilitation.

Patients with advanced lung disease, especially patients with COPD, suffer from dyspnea at rest that worsens during the performance of even limited physical activities. The causes of dyspnea are multifactorial and are related to structural changes found in the parenchymal compartment of the lung as well as the airway and pulmonary vasculature. Alterations in any of the lung compartments may have negative consequences for the physiological performance of exercise. Respiratory assist devices that attenuate the pathophysiological derangements induced by the underlying lung disease, and/or unload the increased work of breathing, can enhance the performance of exercise, and help to produce more robust training effects in patients with lung disease. Herein we review the data that examines these approaches using respiratory assist devices to improve exercise outcomes in patients with COPD.

Laparoscopic Versus Open Hemihepatectomy: The ORANGE II PLUS Multicenter Randomized Controlled Trial.

PURPOSE: To compare outcomes after laparoscopic versus open major liver resection (hemihepatectomy) mainly for primary or metastatic cancer. The primary outcome measure was time to functional recovery. Secondary outcomes included morbidity, quality of life (QoL), and for those with cancer, resection margin status and time to adjuvant systemic therapy. PATIENTS AND METHODS: This was a multicenter, randomized controlled, patient-blinded, superiority trial on adult patients undergoing hemihepatectomy. Patients were recruited from 16 hospitals in Europe between November 2013 and December 2018. RESULTS: Of the 352 randomly assigned patients, 332 patients (94.3%) underwent surgery (laparoscopic, n = 166 and open, n = 166) and comprised the analysis population. The median time to functional recovery was 4 days (IQR, 3-5; range, 1-30) for laparoscopic hemihepatectomy versus 5 days (IQR, 4-6; range, 1-33) for open hemihepatectomy (difference, -17.5% [96% CI, -25.6 to -8.4]; P < .001). There was no difference in major complications (laparoscopic 24/166 [14.5%] v open 28/166 [16.9%]; odds ratio [OR], 0.84; P = .58). Regarding QoL, both global health status (difference, 3.2 points; P < .001) and body image (difference, 0.9 points; P < .001) scored significantly higher in the laparoscopic group. For the 281 (84.6%) patients with cancer, R0 resection margin status was similar (laparoscopic 106 [77.9%] v open 122 patients [84.1%], OR, 0.60; P = .14) with a shorter time to adjuvant systemic therapy in the laparoscopic group (46.5 days v 62.8 days, hazard ratio, 2.20; P = .009). CONCLUSION: Among patients undergoing hemihepatectomy, the laparoscopic approach resulted in a shorter time to functional recovery compared with open surgery. In addition, it was associated with a better QoL, and in patients with cancer, a shorter time to adjuvant systemic therapy with no adverse impact on cancer outcomes observed.

Optimizing clinical outcomes for bronchoscopic lung volume reduction with Zephyr® valves.

Bronchoscopic lung volume reduction treatment with Zephyr one-way valves is an effective guideline-based treatment option for patients with severe emphysema and hyperinflation. However, in some cases the treatment response is less than anticipated or there might be a loss of initial treatment effect. Reasons for the lack of response can include incorrect assessment of collateral ventilation, improper valve placement, or patient related factors. Loss of initial benefit can be due to granulation tissue formation and subsequent valve dysfunction, or there may be side effects such as excessive coughing or infectious problems. Careful follow-up after treatment with valves is important and evaluation with a CT scan and/or bronchoscopy is helpful if there is no improvement after treatment or loss of initial benefit. This paper aims to describe the most important causes and provide a strategy of how to approach and manage these patients.

Valid consent in the acute hospital setting: perspectives of patients and members of the public.

BACKGROUND: People who interact with healthcare services have an ethical and legal right to control their own lives, to make informed decisions, and to consent to what happens to them. For consent to be considered ethically and legally valid, three key criteria must be met: consent must be given voluntarily; people must be sufficiently informed of all options; and people should have capacity to make the decision to give or withhold their consent. AIM: This study set out to explore, through the use of surveys, the perspectives of patients and public in relation to consent. METHOD: Surveys were developed for patients and the public and administered paper based (patients) and through social media (public). RESULTS: One hundred and forty surveys were posted to patients, with a 38% response rate; 104 responses were received from the public. Ninety-six percent of patients were satisfied that the decision they made was informed; 100% felt they had made a voluntary decision; 98% felt the clinician seemed knowledgeable about the procedure. What matters most to the public were being informed about the risks associated with the proposed procedure and being assured that whatever choice they make they will receive the best care possible. CONCLUSIONS: The results highlight interesting similarities and differences in relation to consent between members of the public thinking about a possible treatment, surgery, or procedure and those patients who have actually been through the process in the past 12 months. Recommendations have been developed on the basis of these findings to co-design improvements in consent practices.

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities.

Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of "wet-lab" experiments. In this review, we explore the applications of computational approaches in membrane protein oncological characterization, particularly focusing on three prominent membrane protein families: receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and solute carrier proteins (SLCs). We chose these families due to their varying levels of understanding and research data availability, which leads to distinct challenges and opportunities for computational analysis. We discuss the utilization of multi-omics data, machine learning, and structure-based methods to investigate aberrant protein functionalities associated with cancer progression within each family. Moreover, we highlight the importance of considering the broader cellular context and, in particular, cross-talk between proteins. Despite existing challenges, computational tools hold promise in dissecting membrane protein dysregulation in cancer. With advancing computational capabilities and data resources, these tools are poised to play a pivotal role in identifying and prioritizing membrane proteins as personalized anticancer targets.

Pulmonary Vasodilator Therapy Is Associated with Decreased Mortality in Patients with Chronic Lung Disease and Severe Pulmonary Hypertension.

The mortality benefit of PAH-specific therapy for patients with pulmonary hypertension (PH) associated with lung disease is not clear. Our aim was to determine whether pulmonary arterial hypertension (PAH)-specific therapy is associated with reduced mortality among all patients with PH associated with lung disease and in patients with chronic lung disease and severe PH. This was a retrospective cohort study of patients at our institution with chronic lung disease and PH. Survival analysis was performed by comparing patients who received PAH-specific therapy with patients who did not receive pulmonary vasodilators in the entire cohort and in a subgroup of patients with severe PH defined as PVR > 5 WU. We identified 783 patients with chronic lung disease and PH; 246 patients met the new criteria for severe PH. In the entire cohort, a similar survival probability was seen between the treated and untreated PH groups (logrank p = 0.67). In the severe PH subgroup, patients treated with PAH-specific therapy had increased survival probability (logrank p = 0.03). PAH-specific therapy was independently and significantly associated with decreased mortality in severe PH (HR 0.31, 95% CI 0.11-0.88, p = 0.03). PAH-specific therapy may confer a mortality benefit in patients with chronic lung disease and severe PH, which is now defined as PVR > 5 WU, similarly to those with pulmonary arterial hypertension.

Telehealth Cognitive Behavior Therapy to Reduce Anxiety in People Living with Cognitive Impairment: A Randomized Feasibility Pilot Study.

OBJECTIVES: To evaluate the feasibility of telehealth-based cognitive behavior therapy for people living with cognitive impairment experiencing anxiety (Tele-CBT), and to assess whether this leads to improvements in anxiety, depression, and quality of life post-intervention. METHODS: This was a single-blind randomized feasibility pilot trial of the Tele-CBT versus usual care. People living with mild cognitive impairment or dementia experiencing anxiety were recruited and randomized to receive Tele-CBT (n = 5) or continue usual care (n = 5). Feasibility data comprised recruitment uptake and retention, adherence, and ease of use. Outcomes of anxiety (primary outcome - Rating Anxiety in Dementia; RAID), depression, stress, and quality of life were measured pre- and post-intervention. RESULTS: Intervention feasibility was demonstrated through minimal attrition, acceptability, and ease of use via videoconferencing. Both groups showed a decrease of anxiety symptoms (RAID) from baseline to post-assessment. CONCLUSIONS: The Tele-CBT program was acceptable to use via videoconferencing. Reduced anxiety symptoms were observed in both groups at post-. An RCT with a larger sample is required to determine the efficacy and implementation of the intervention. CLINICAL IMPLICATIONS: This study indicates the feasibility of videoconference CBT to address anxiety experienced by people living with cognitive impairment with minimal assistance from support persons.

Design of the STRIVE-IPF Trial- Study of Therapeutic Plasma Exchange, Rituximab, and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AEIPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. Methods: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. Discussion: The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF.Trial Registration ClinicalTrials.gov identifier: NCT03286556.

Design of the STRIVE-IPF trial- study of therapeutic plasma exchange, rituximab, and intravenous immunoglobulin for acute exacerbations of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. METHODS: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. DISCUSSION: The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03286556.

Alzheimer's Disease: A Suitable Case for Treatment with Precision Medicine?

Alzheimer's disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioural disturbance. Owing to evolving research in biomarkers AD can be discovered at early onset, but the disease is currently considered a continuum, which suggests that pharmacotherapy is most efficacious in the preclinical phase, possibly 15 - 20 years before discernible onset. Present developments in AD therapy aim to respond to this understanding and go beyond the drug families that relieve clinical symptoms. Another important factor in this development is the emergence of precision medicine that aims to tailor treatment to specific patients or patient subgroups. This relatively new platform would categorize AD patients on the basis of parameters like clinical aspects, brain imaging, genetic profiling, clinical genetics and epidemiological factors. This review enlarges on recent progress in the design and clinical use of antisense molecules, antibodies, antioxidants, small molecules and gene editing to stop AD progress and possibly reverse the disease on the basis of relevant biomarkers.

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays.

Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target.

Single-session mechanical thrombectomy for iliofemoral deep vein thrombosis using a dual mechanism of action device combining basket and rotational thrombectomy.

OBJECTIVE: Interventional treatments for acute iliofemoral deep vein thrombosis (DVT) remain controversial after publication of the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) study. Interventions have been shown to reduce post-thrombotic syndrome severity and improve quality of life in DVT patients, but have been accompanied by risk of major bleeding from thrombolytics. We describe thrombus removal using a novel combined basket-rotational thrombectomy device that minimizes the need for thrombolytics or repeat procedures. METHODS: The aim of this prospective, nonrandomized, multicenter, first-in-human study of 19 patients with acute iliofemoral DVT was to evaluate the safety and performance of the Pounce venous thrombectomy system ≤12 months after treatment. The primary performance end point was defined as procedural success through achievement of Society of Interventional Radiology (SIR) grade II lysis in treated vessels with freedom from procedural adverse events. Secondary end points included venous disease severity assessments using the Villalta scale and the Venous Clinical Severity Score, patient quality-of-life measurement using the Venous Insufficiency Epidemiological and Economic Study-Quality of Life questionnaire, and calf circumference measurements taken at baseline, 24 hours, and 1 month. RESULTS: The primary end point of complete or near-complete thrombus removal (Society of Interventional Radiology grade II or III) was achieved in all patients. All study device-related safety end points were met, with no major bleeding or device-related adverse events. Of the 19 patients treated, 16 (84.2%) did not receive thrombolytics during the procedure. Post-thrombotic syndrome (Villalta scale >4) was identified in 17 of 19 patients (89.5%) at baseline, 4 of 13 patients (30.8%) available for follow-up at 6 months, and 2 of 11 patients (18.2%) at 12 months. The median Venous Clinical Severity Score decreased (P < .001) from 8.5 (interquartile range [IQR], 7-10) at baseline to 4 (IQR, 2-4) at 1 month after the procedure and was similar at 6 months (2; IQR, 2-5) and 12 months (2; IQR, 1.5-3) after the procedure. The median Venous Insufficiency Epidemiological and Economic Study-Quality of Life questionnaire score improved (P < .001) by 39 from baseline (57; IQR, 53.5-74) to 1 month (96; IQR, 86-101) after the procedure, and remained high at 6 months (99; IQR, 75-103) and 12 months (98; IQR, 94.5-100). The median calf circumference decreased (P = .089) from 39 cm (IQR, 35-47.8 cm) at baseline to 36 cm (IQR, 32.5-40.5 cm) at 24 hours after the procedure and was 34.5 cm (IQR, 33.2-38.5 cm) at 1 month. CONCLUSIONS: The Pounce device is safe and effective for removal the of thrombus in patients with acute iliofemoral DVT. Initial results demonstrate improvements in venous disease severity and patient quality of life.

Reduced Surface Recombination in Extended-Perimeter LEDs toward Electroluminescent Cooling.

III-V semiconductor light-emitting diodes (LEDs) are a promising candidate for demonstrating electroluminescent cooling. However, exceptionally high internal quantum efficiency designs are paramount to achieving this goal. A significant loss mechanism preventing unity internal quantum efficiency in GaAs-based devices is nonradiative surface recombination at the perimeter sidewall. To address this issue, an unconventional LED design is presented, in which the distance from the central current injection area to the device's perimeter is extended while maintaining a constant front contact grid size. This approach effectively moves the perimeter beyond the lateral spread of current at an operating current density of 101-102 A/cm2. In p-i-n GaAs/InGaP double heterojunction LEDs fabricated with varying sizes and perimeter extensions, a 19% relative increase in external quantum efficiency is achieved by extending the perimeter-to-contact distance from 25 to 250 µm for a front contact grid size of 450 × 450 µm2. Utilizing an in-house developed Photon Dynamics model, the corresponding relative increase in internal quantum efficiency is estimated to be 5%. These results are ascribed to a significant reduction in perimeter recombination due to a lower perimeter-to-surface area (P/A) ratio. However, in contrast to lowering the P/A ratio by increasing the front contact grid size of LEDs, the present method enables these improvements without affecting the required maximum current density in the microscopic active LED area under the front contact grid. These findings aid in the advancement of electroluminescent cooling in LEDs and could prove useful in other dedicated semiconductor devices where perimeter recombination is limiting.

Predictors of the placebo response in a nutraceutical randomized controlled trial for depression.

OBJECTIVE: The placebo response in depression studies is the change in symptoms amongst those who receive an inactive treatment. Many well-designed randomized controlled trials (RCTs) of depression have a high proportion of placebo responders, with little understanding as to why. The present study assesses characteristics associated with the placebo response in a nutraceutical trial with a large proportion of placebo responders. METHODS: This is a secondary analysis of a nutraceutical depression RCT which identified no overall treatment benefit relative to placebo (n = 69 in placebo group). We investigated participant characteristics such as socio-demographics, clinical features, and recruitment methods, and their association with the placebo response. Monoaminergic genetic polymorphisms were also assessed. Placebo response was measured based on change in Montgomery-Asberg Depression Rating Scale score. The association of these hypothesis-driven variables of interest and the placebo response was examined using linear mixed effects models. RESULTS: Greater levels of education, particularly pursuing post-high school education, better self-reported general health, marriage/de facto, greater improvement in the first trial week, and more failed antidepressant therapies in the current depressive episode were associated with greater placebo response. An increased placebo response was not found in those recruited via social media nor in those with concomitant antidepressant therapy. Single nucleotide polymorphisms from the tryptophan hydroxylase 1 (TPH1) gene (A779C and A218C) were weakly associated with greater placebo response, although the evidence was attenuated after accounting for multiple comparisons. CONCLUSION: This is, to our knowledge, the first study within nutraceutical research for depression to assess the association between participant characteristics and variation in the placebo response. Several variables appeared to predict the placebo response. Such findings may encourage future trial designs which could dampen placebo response, improve assay sensitivity, and allow for treatment effects to be potentially more detectable. Please cite this article as: Arnold R, Murphy-Smith J, Ng CH, Mischoulon D, Byrne GJ, Bousman CA, Stough C, Berk M, Sarris J. Predictors of the placebo response in a nutraceutical randomized controlled trial for depression. J Integr Med. 2024; 22(1): 46-53.