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Purpose | cataract | CATARACT | Compare 12-month (12 M) safety and efficacy of endoscopic cyclophotocoagulation (ECP) + cataract surgery (Group 1) versus ECP + cataract surgery + iStent | PMC10149466 |
Methods | cataract, glaucoma, OAG | ADVERSE EVENTS, CATARACT, SECONDARY, GLAUCOMA, INTRAOCULAR PRESSURE | This prospective, multicenter, comparative case series included patients with OAG and cataract who were randomized to receive treatment in Group 1 or Group 2. Outcomes included mean and percent reduction versus preoperative in intraocular pressure (IOP) and number of glaucoma medications; visual acuity; occurrence of adverse events; and rate of secondary surgeries. | PMC10149466 |
Results | Preoperatively, Groups 1 and 2 had similar mean IOP (mean ± standard deviation 22.1 ± 3.6 and 22.0 ± 2.5 mmHg, respectively) and mean number of medications (3.3 ± 0.6 and 3.4 ± 0.6 medications, respectively). At all follow-up timepoints through 12 M, both groups achieved significant IOP and medication reductions versus preoperative (IOP | PMC10149466 | ||
Conclusion | Both treatment groups (ECP + phacoemulsification, with/without iStent | PMC10149466 | ||
Clinical trial registration (CTR) | CAAE project identification #20053019.5.0000.5078. Protocol #3.587.147. Clinical Trial Database of the Federal University of Goiás, Brazil. Registration Date: September 19, 2019. | PMC10149466 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s10792-022-02563-4. | PMC10149466 | ||
Keywords | PMC10149466 | |||
Introduction | glaucoma, Glaucoma, blindness | GLAUCOMA, INTRAOCULAR PRESSURE, GLAUCOMA, BLINDNESS | Glaucoma is the leading cause of irreversible blindness worldwide [Medical and surgical therapies for treating glaucoma focus on lowering intraocular pressure (IOP), currently the only known modifiable risk factor [In the surgical realm, phacoemulsification alone often is associated with modest IOP reduction due to an increase in outflow facility [The iStent Endoscopic cyclophotocoagulation reduces aqueous production, thereby decreasing the inflow component of the inflow/outflow balance that contributes to IOP [Both ECP and iStent The present prospective multicenter study compares 1 year outcomes following phacoemulsification + ECP (Group 1) or phacoemulsification + ECP + iStent | PMC10149466 |
Material and methods | PMC10149466 | |||
Study design | cataract, hypotensive, glaucoma | CATARACT, ADVERSE EVENTS, HYPOTENSIVE, GLAUCOMA | This was a prospective, comparative, multicenter case series that evaluated ECP with cataract surgery versus ECP plus iStent Once enrolled, patients were prospectively randomized on a 1:1 basis to either phacoemulsification plus ECP or phacoemulsification plus ECP plus iStent This study was pragmatic in nature, with the aim of gathering evidence for real-world treatment of glaucoma. Therefore, no preoperative or postoperative ocular hypotensive medication washout was required. Postoperative management of patients including medication reintroduction, management of adverse events, postoperative visit scheduling, and procedures were managed at the discretion of the treating physician using standard care. | PMC10149466 |
Inclusion criteria | PXG, POAG, pigmentary glaucoma, OAG | PRIMARY OPEN-ANGLE GLAUCOMA, PIGMENTARY GLAUCOMA, PSEUDOEXFOLIATION GLAUCOMA | Adults with OAG [primary open-angle glaucoma (POAG), pseudoexfoliation glaucoma (PXG), or pigmentary glaucoma (PG)] were included. The patients had to be candidates for ECP and iStent | PMC10149466 |
Exclusion criteria | congenital anomalies, thyroid eye disease, glaucoma, traumatic | NEOVASCULAR GLAUCOMA, TUMOR, THYROID EYE DISEASE, GLAUCOMA, ANGLE-CLOSURE GLAUCOMA, STURGE-WEBER SYNDROME | Eyes with prior glaucoma filtration surgery, angle-closure glaucoma, traumatic, malignant, uveitic, or neovascular glaucoma or other discernible congenital anomalies of the anterior chamber angle were not allowed to participate. Patients with retrobulbar tumor, thyroid eye disease, Sturge-Weber Syndrome or any other type of condition that may have caused elevated episcleral venous pressure were excluded. Study participation also was not allowed for any patient having a contraindicated ocular or systemic condition. | PMC10149466 |
Outcome measures | ocular hypotensive, intraoperative or postoperative complications | Outcome measures included IOP, topical ocular hypotensive medication burden, and safety. Data were collected and descriptive analyses were performed using MS Excel. The following measures were analyzed at postoperative study timepoints and compared to preoperative outcomes as appropriate: mean IOP; percentage of eyes with IOP ≤ 18 mmHg and with ≤ 15 mmHg; mean medication burden (number of medications) and percentage of eyes with categorical medication burden; percentage of eyes with more, fewer or the same medication burden at postoperative study timepoints compared to preoperative; Snellen best-corrected visual acuity; and percentage of eyes with intraoperative or postoperative complications. The schedule of visits and assessments through 12 months postoperative is shown in Supplemental Table S1. | PMC10149466 | |
Statistics | Statistical calculations included mean, standard deviation, percentage of total, and categorical counts. Two-tailed | PMC10149466 | ||
Sample size | Given the statistical assumptions (Supplemental Table S2) and a significance level of 0.05, 30 subjects per arm provided 80% power to detect a treatment difference that was statistically significant. | PMC10149466 | ||
Results | PMC10149466 | |||
Glaucoma medications | ocular hypotensive, hypotensive | HYPOTENSIVE | Both treatment groups achieved significant reductions in topical ocular medication use at all postoperative time points (Topical ocular medication use over the course of Year 1. At the preoperative visit in Group 1, no eyes were receiving 0 or 1 medication, while 94.2% of eyes were using 3–4 medications (Fig. Proportion of eyes with categorical ocular hypotensive medication use in group 1 (Phacoemulsification + ECP). Proportion of eyes with categorical ocular hypotensive medication use in group 2 (Phacoemulsification + ECP + iStent Both treatment groups demonstrated high proportions of eyes with reductions in topical ocular hypotensive medication use throughout follow-up (Fig. Change in categorical topical ocular medication use vs preoperative over the course of Year 1 | PMC10149466 |
Discussion | cataract, OAG, glaucoma | CATARACT, GLAUCOMA | A considerable shift from traditional glaucoma surgeries to MIGS procedures has occurred in recent years [The present report provides safety and effectiveness outcomes of phacoemulsification and ECP, either with or without iStent The combination of micro-bypass stent, cataract surgery, and ECP leverages different mechanisms of action in glaucoma management [These findings are consistent with the literature on ECP and trabecular micro-bypass. A retrospective consecutive case series by Ferguson et al. [Favorable trends also were observed in medication reduction in the current study, with the vast majority of eyes in both groups reducing their number of medications through Year 1. As with IOP, the medication reductions were significantly greater in the group undergoing iStent These medication reductions represent significant benefits at the level of each patient, given the well-known personal, physical, social, and financial consequences of chronic medication exposure. For example, the cost of chronic medication can be a financial burden for patients; not surprisingly, numerous studies have shown the cost effectiveness of the iStent device compared with the use of chronic topical medications [Both ECP and iStent These visual acuity findings are consistent with prior evaluations of phacoemulsification + ECP and/or iStent implantation [This study is limited by its modest sample size, 1 year follow-up duration, and inclusion of data from 2 surgeons at 2 sites. Patients with other forms of glaucoma than OAG were excluded, as well as those who had undergone previous glaucoma filtration surgery. The majority of patients in the study population were White, Hispanic, or Black, so results may not be directly applicable to other demographic groups (e.g., Asians). Not all data were available for all parameters at all time points. A future study could include a greater number of patients, longer duration of follow-up, data from more sites, or a broader range of glaucoma subtypes. | PMC10149466 |
Conclusion | cataract | CATARACT | When combined with cataract surgery, both ECP and ECP + iStent | PMC10149466 |
Author contributions | FL, JG, MA guided study design and wrote protocol. FL, JG, MA completed data collection. FL, JG, MA contributed to data analysis and manuscript preparation (including text, figures, and tables). FL, JG, MA reviewed and approved the manuscript. | PMC10149466 | ||
Funding | No monetary nor product support was received for the work in this study. Editorial assistance (Dana M. Hornbeak, MD, MPH) and publication fees were provided by Glaukos Corporation. | PMC10149466 | ||
Data availability | All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. | PMC10149466 | ||
Declarations | PMC10149466 | |||
Conflict of interest | All authors declare that they have no conflict of interest. | PMC10149466 | ||
Consent to participate | Medical writing and editorial support were provided by Julie Crider, PhD (Collaborative Medical Writing, LLC), and Dana Hornbeak, MD, MPH (Glaukos Corporation). | PMC10149466 | ||
Ethical approval | The study was performed according to the tenets of the Declaration of Helsinki; all participants provided their informed consent for enrollment into the study. The study was reviewed and approved by the Ethics Committees of both hospitals involved: Centro Brasileiro De Cirurgia De Olhos (CBCO), Goiânia, GO, Brazil; and Centro Brasileiro Da Visão (CBY), Brasília, DF, Brazil. The study was registered in the Clinical Trial Database of the Federal University of Goiás, Brazil (CAAE ID# 20053019.5.0000.5078, Protocol #3.587.147, registered September 19, 2019). | PMC10149466 | ||
References | PMC10149466 | |||
1. Introduction | sleep disorders, neurodegenerative diseases, behavioral disorders, daytime sleepiness, decline in cognitive functions, dementia, NNG): mean ±, multiple sclerosis, Dementia | MULTIPLE SCLEROSIS, SYNDROME, NEURODEGENERATIVE DISEASES | Dementia is a progressive decline in cognitive functions caused by an alteration in the pattern of neural network connections. There is an inability to create new neuronal connections, producing behavioral disorders. The most evident alteration in patients with neurodegenerative diseases is the alteration of sleep–wake behavior. The aim of this study was to test the effect of two non-pharmacological interventions, therapeutic exercise (TE) and non-invasive neuromodulation through the NESA device (NN) on sleep quality, daytime sleepiness, and cognitive function of 30 patients diagnosed with dementia (non-invasive neuromodulation experimental group (NNG): mean ± SD, age: 71.6 ± 7.43 years; therapeutic exercise experimental group (TEG) 75.2 ± 8.63 years; control group (CG) 80.9 ± 4.53 years). The variables were evaluated by means of the Pittsburg Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Mini-Cognitive Exam Test at four different times during the study: at baseline, after 2 months (after completion of the NNG), after 5 months (after completion of the TEG), and after 7 months (after 2 months of follow-up). Participants in the NNG and TEG presented significant improvements with respect to the CG, and in addition, the NNG generated greater relevant changes in the three variables with respect to the TEG (sleep quality (Dementia is a general term to describe a clinical neurodegenerative syndrome characterized by neuronal and synaptic loss, forming a brain deposit of intra- and/or extracellular insoluble protein aggregates [A high prevalence of sleep disorders in patients with dementia has been identified for more than 30 years. Scientific evidence [Sleep is a basic biological need for the proper functioning of the organism and is essential for memory consolidation [An alteration of the circadian system has an impact on MLT secretion, and this leads to a poor synchronization of biological rhythms such as the sleep–wake cycle. In people with dementia, the suprachiasmatic nucleus (SCN) is impaired and, therefore, this leads to a reduction in melatonin production, causing a disruption of the circadian rhythms, and, therefore, in the quality of life [Currently, pharmacological options in dementia should be used with caution, seriously considering possible side effects before prescribing hypnotic and psychotropic agents [As for non-pharmacological strategies, there is currently a paucity of research in people with dementia, but even so, they are emerging as alternative procedures to improve sleep disorders in patients with dementia because of their minimal risk of side effects. These include sleep hygiene measures, light therapy, physical activity, cognitive stimulation, and auditory stimulation [The need arises for effective non-pharmacological treatments backed by scientific evidence to support their use for the cognitive function and sleep disturbances suffered by this population.In this sense, given that previous studies have shown that TE has demonstrated benefits on these characteristics, albeit in other neurodegenerative diseases [Similarly, some studies have shown positive evidence in the improvement of ANS-related dysfunctions in the field of multiple sclerosis [Therefore, the main objective of this study was to test the effect of two non-pharmacological interventions, on the one hand, therapeutic exercise (TE), and, on the other hand, non-invasive neuromodulation through the NESA device (NN), on sleep quality, daytime sleepiness, and cognitive function in patients with dementia. | PMC10650908 |
2. Materials and Methods | PMC10650908 | |||
2.1. Subjects | Alzheimer’s, dementia, dementias | The sample of this study consists of 30 patients diagnosed with dementia who belong to two associations of Alzheimer’s and other dementias, where they perform daily classes of 1 h of physiotherapy for elderly and cognitive stimulation 5 days a week. During the study, patients in the different groups continued to receive these therapies. The new variation was the introduction of the TE and NN protocols. The inclusion criteria were obtaining a medical diagnosis of dementia equal to or greater than mild according to the Reisberg Global Deterioration Scale (GDS) [ | PMC10650908 | |
2.2. Study Design | Alzheimer’s, daytime sleepiness, dementia, dementias | A randomized, single-blind, multicenter clinical trial was conducted in two associations of Alzheimer’s and other dementias to evaluate the effect of two non-pharmacological treatments, TE and NN, on sleep quality, daytime sleepiness, and cognitive function in patients with dementia. For this purpose, participants were randomly assigned to one of the three study groups (TEG; NNG; CG), using a fixed-size block design generated by the data manager to ensure a balanced randomization for each of the groups and in each of the participating centers. The allocation process was performed using probability convenience sampling [ | PMC10650908 | |
2.3. Procedures | A randomized, multicenter trial was conducted to compare the treatment of NNG and TEG with a CG, and at the same time, both experimental treatments. The 10 participants of the CG received recommendations about sleep habits through an information leaflet but did not perform any active treatment [ | PMC10650908 | ||
2.4. Therapeutic Exercise Protocol | The 10 TEG participants received 52 sessions, from 10:00 am to 11:00 am, of an adapted cardiovascular exercise program in a small group format supervised by a physiotherapist. For the first 16 weeks, 3 weekly one-hour sessions were performed. Then, up to week 20, 1 session per week was followed by a progressive decrease in the load. The structure of the sessions was as follows: 1. active warm-up, 2. strength exercises, 3. balance and coordination exercises, 4. aerobic exercises, and 5. relaxation and return to calm. The sessions were gradually increasing in volume and intensity to achieve moderate intensity exercise. In addition, the participants’ caregivers were instructed to have the patients walk every day, gradually increasing their time, until they reached 30 min daily [ | PMC10650908 | ||
2.5. Nesa Non-Invasive Neuromodulation Protocol | dementia | ADVERSE EFFECTS, NEURODEGENERATION, DYSFUNCTION | The 10 NNG participants completed the protocol NESA [The non-invasive neuromodulation technique, NESA, is a non-invasive and easily transportable monitoring device, which emits low frequency microcurrents (1.3–14.28 Hz, depending on the program), low intensity (0.1–0.9 mA), and low voltage (±3 V) that are introduced into the distal nerve endings of the limbs by means of 24 electrodes (6 electrodes per limb, distributed between both wrists and ankles), producing a circulating bioelectric circuit in the body, for an estimated time to stimulate the autonomic nervous systems and enhance the recovery of those dysfunctional processes of the patient. In our case, dementia, it is known that there is a desynchrony in the wake–sleep cycle due to neurodegeneration, therefore, there is an alteration in the physiological processes of the circadian rhythm, this being a dysfunction in the segregation of melatonin, produced by the pineal gland [The NN protocol, administered by physiotherapists working in their respective centers, consisted of the distribution of 4 phases: The first phase was to avoid adverse effects, 3 sessions with program 1 (P1) 30 min, program 7 (P7) 15 min, and program (P8) 15 min. The second phase was to influence neuronal repolarization, 2 sessions with program 5 (P5) 30 min and P7 another 30 min. The third phase was to introduce the following, P5 15 min, P7 30 min, and P8 15 min. Finally, the fourth phase was to improve sleep quality, 12 sessions with P7 for 45 min and P8 15 min.The microcurrents emitted by the different programs used were symmetrical biphasic low frequency and limited intensity, and therefore imperceptible to the patient. | PMC10650908 |
2.6. Recovery Measures | Daytime sleepiness | LOBO | Sleep quality: This was evaluated using the Pittsburgh Sleep Quality Index (PSQI) [Daytime sleepiness: This was evaluated using the Epworth Sleepiness Scale (ESS) [Cognitive function: This was evaluated by means of the Mini-Cognitive Examination Test (Lobo’s MEC) [ | PMC10650908 |
2.7. Statistical Analysis | dementia | Measurement of the variables was performed in all study participants at 4 different times: at baseline, 2 months (after completion of the NNG), 5 months (after completion of the TEG, and 7 months (after 2 months of follow-up). Self-administered questionnaires were used, but since our trial involved patients diagnosed with dementia, the responses were made by the primary caregiver of each patient.Categorical variables were summarized using percentages and relative frequencies. Equality of proportions of the categories was compared using Pearson’s chi-square statistic. In addition, a one-way ANOVA was performed on the three groups to test whether differences were found as a function of age, and Levene’s test was used to test the homogeneity of variances of the groups.The numerical variables were summarized using descriptive statistics (means, standard deviations pretest, at 2 months, at 5 months, and at 7 months). Since their distributions did not follow a normal law and the sample size was low, we chose to compare the three groups with the nonparametric Kruskal–Wallis H test. If the χ2 statistic was significant, the two-by-two comparison between the groups was performed with the Dwass–Steel–Critchlow–Fligner test to analyze the equality between the groups at each time point. The significance level for all analyses was set at | PMC10650908 | |
2.8. Ethics | dementia | As this was a sample of patients with dementia, their caregivers gave written informed consent before being assigned to a group and evaluated, and the rights of all participants were protected. All experimental protocols respected the fundamental principles established in the 1975 Declaration of Helsinki [ | PMC10650908 | |
3. Results | PMC10650908 | |||
3.1. Sample | A total of 30 participants met the inclusion criteria and were randomized in the data collection process. Ten participants were assigned to the NNG, 10 to the TEG and 10 to the CG. The age of the participants was as follows: NNG 71.6 (SD = 7.43); TEG 75.2 (SD = 8.63), and CG 80.9 (SD = 4.53). ( | PMC10650908 | ||
3.2. Effect of the Intervention on Sleep Quality | When comparing the three groups at each time point for sleep quality, using the Pittsburgh Sleep Quality Index (PSQI), significant differences were found after 5 months (It was found that in the NNG, statistically significant differences were obtained at all measurement moments ( | PMC10650908 | ||
3.3. Effect of Intervention on Daytime Sleepiness | daytime sleepiness | When comparing the three groups at each time point of the variable, statistically significant differences were found at the time points (Likewise, statistically significant differences in daytime sleepiness were found in the NNG at all measurement time points ( | PMC10650908 | |
3.4. Effect of Intervention on Cognitive Function | With respect to the cognitive function of the patients, statistically significant differences were found at the four measurement points. The NNG and TEG obtained improvements in cognitive function reaching 7 months with a score of 30.7 (SD = 3.50) in the NNG, and 27.5 (SD = 2.92) in the TEG. This means that, although both groups improved in the cognitive function scores, it was the NNG patients who showed a better evolution. With respect to the CG, the results showed a small worsening in cognitive function (In the NNG, improvements in cognitive function were significant at all the time points ( | PMC10650908 | ||
4. Discussion | memory loss, drowsiness, dementia, cognitive dysfunction, daytime sleepiness | PATHOLOGY, DYSFUNCTION, NEURODEGENERATIVE DISEASE | The main objective of this study was to test the effect of two non-pharmacological interventions on sleep quality, daytime sleepiness, and cognitive function in patients with dementia. The sample proved to be homogeneous, despite the clinical variability that may present in this type of population and it being a multicenter intervention.In this regard, the results obtained with respect to the sleep quality of patients with dementia showed that the group treated with NESA noninvasive neuromodulation obtained an improvement of 3.3% over the therapeutic exercise group, even from similar values in the pretest with the therapeutic exercise group. Both treatments seemed to be effective for the improvement of sleep quality; however, the efficacy of the treatment in the NNG stands out, obtaining a lower score after 7 months than the TEG. In the study by Cao, S et al. [Similar results were obtained when measuring daytime sleepiness in patients with dementia, highlighting the score of the NNG, which obtained a lower score, and with an improvement of 36.7% over the baseline. The TEG also showed an improvement of 19.17% at the end of the study with respect to the baseline, however, with a smaller effect than the NNG. On the ESS scale, the minimum clinically important improvement in the ESS is estimated [Regarding the cognitive function of patients with dementia, the NNG modality obtained better results than the TEG and CG. The results showed that the no intervention group (CG) did not improve in cognitive function, and the TEG patients also obtained some improvements in the cognitive function of the patients; however, it seemed that the highest effect was in the NNG. In addition, J.S. Andrews et al. [Changes in sleep quality in people with dementia represent an important challenge for the scientific community since, for example, sleep and circadian rhythm disturbances are very common in patients with this pathology and up to 45% of patients experience sleep problems. The clinical presentation is characterized by memory loss and cognitive dysfunction [Non-invasive brain stimulation is of great interest in this context [This is the first study to use the NESA noninvasive neuromodulation with patients with dementia and yields similar results in sleep parameters to those obtained by Garcia et al. [Where benefits in sleep quality like our study were also recorded were in those where the intervention was oriented towards education in sleep habits [Although after the maintenance period, the result was below the level of minimum poor sleep quality; we believe that this could be improved if after further research following this line of treatment, a greater number of treatment sessions were done. Having found an improvement in sleep in both the NNG and TEG we consider that to be a great advance for this current problem. The next future goal should be to recover 100% sleep quality; although, since this is a neurodegenerative disease and there is a dysfunction in melatonin secretion, achieving optimal sleep quality could be a very complex goal [Regarding physical exercise in people with dementia, according to the studies, it appears that systematic exercise, through various mechanisms, can promote brain function and maintain and improve both cognitive and physical functions [Cognitive functions and their influence under noninvasive electrical stimulation in people with dementia have been the subject of study in recent years, reporting results as encouraging as in our study [One of the keys in the possible neurophysiological explanation that we could hypothesize in the improvement of the drowsiness state and cognitive level of our patients, focuses on the influence of the locus coeruleus (LC) [Given that this is the first preliminary study in the world using the NESA noninvasive neuromodulation device in a dementia population with the aim of improving sleep quality, daytime sleepiness, and cognitive function, it would be desirable to conduct further studies using other more objective measurements to corroborate these satisfactory results. In this sense, analyzing sleep–wake parameters by means of an actigraphy could be a reliable and more precise indicator to evaluate the different phases of sleep and the changes during the whole cycle, obtaining additional information on the total duration of sleep, actual time of falling asleep, patient’s sleep conditions, etc. [This study begins an interesting field of research in the neuromodulation of the autonomic system, sleep, and cognitive function as a daily part of the recovery in patients with dementia. | PMC10650908 |
Limitations | fatigue | The study had some limitations that we recommend solving in future interventions. The study had a small sample size and was from a specific area, so the generalizability of the results is limited. Future research should be conducted in a variety of settings with larger samples to determine these measurement pathways in more detail. Since some results were based on self-reports (PSQI, MEC) from face-to-face interviews, the recording model should be further examined using other measures such as actigraphy or polysomnography, although it is known that due to the cognitive limitations of patients these techniques are complicated to perform. The variables included do not explain all the possible variance, so other possible variables may also mediate the relationship, such as fatigue, self-efficacy, stress, or even the influence of their social and/or family environment. | PMC10650908 | |
5. Conclusions | daytime sleepiness | In conclusion, two non-pharmacological treatments, therapeutic exercise, and non-invasive neuromodulation NESA, appear to be effective treatments to improve daytime sleepiness, sleep quality, and cognitive function. | PMC10650908 | |
Author Contributions | Conceptualization, A.G.-C. and S.S.-C.; methodology, A.G.-C. and E.T.-H.; validation, A.G.-C., S.S.-C., R.M.-R. and A.B.-S.; formal analysis, J.A.L.-P. and E.T.-H.; investigation, E.T.-H., S.S.-C. and A.G.-C.; resources, A.B.-S.; data curation, J.A.L.-P. and E.T.-H.; writing—original draft preparation, E.T.-H.; writing—review and editing, A.G.-C., R.M.-R., S.S.-C., J.A.L.-P. and A.B.-S.; visualization, A.G.-C., R.M.-R. and A.B.-S.; supervision A.G.-C., R.M.-R., S.S.-C., J.A.L.-P. and A.B.-S. All authors have read and agreed to the published version of the manuscript. | PMC10650908 | ||
Institutional Review Board Statement | All experimental protocols respected the fundamental principles established in the 1975 Declaration of Helsinki (53) and were approved by the Clinical Research Ethics Committee of the University of Murcia (registration number 3572/2021) and registered in ClinicalTrials.gov with identification number: NCT05715866. | PMC10650908 | ||
Informed Consent Statement | dementia | As this was a sample of patients with dementia, their caregivers gave written informed consent before being assigned to a group and evaluated, and the rights of all participants were protected. | PMC10650908 | |
Data Availability Statement | The raw data supporting the conclusions of this article will be made available by the authors without undue reservation. | PMC10650908 | ||
Conflicts of Interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. | PMC10650908 | ||
References | daytime sleepiness | Study design flowchart.Evolution of sleep quality in different periods.Evolution of daytime sleepiness in different periods.Evolution of cognitive function in different periods.Participant baseline clinical characteristics.Means, standard deviations, effect size, and statistical significance for intergroup and intragroup comparison of sleep quality in the different periods.Two-to-two within-group comparisons of sleep quality at different time points.Means, standard deviations, effect size, and statistical significance for the intergroup and intragroup comparison of daytime sleepiness in the different periods.Two-to-two intragroup comparisons in daytime sleepiness at the different time points.Means, standard deviations, effect size, and statistical significance for intergroup and intragroup comparison in cognitive function in the different periods.Two-to-two intragroup comparisons in cognitive function at the different time points. | PMC10650908 | |
Key Points | PMC10233414 | |||
Question | depression, psychiatric, anxiety | DISORDERS | Is smoking cessation associated with changes in anxiety and depression for adults living with and without psychiatric disorders? | PMC10233414 |
Findings | depression, psychiatric, anxiety | DISORDERS | In this cohort study of 4260 adults, smoking cessation was associated with significant improvements in anxiety and depression among people with and without psychiatric disorders. | PMC10233414 |
Meaning | depression, anxiety | These findings suggest that smoking cessation does not appear to worsen and may improve mental health outcomes.This cohort study assesses changes in anxiety and depression following smoking cessation using 3 confirmatory coprimary analytical approaches. | PMC10233414 | |
Importance | Although many people report a desire to quit smoking, concerns about mental health worsening after quitting are often raised by clinicians and people who smoke. | PMC10233414 | ||
Objective | To assess changes in mental health following smoking cessation using 3 confirmatory coprimary analytical approaches. | PMC10233414 | ||
Design, Setting, and Participants | psychiatric | DISORDER, ADVERSE EVENT, REGRESSIONS, SECONDARY, REGRESSION | This cohort study was conducted using data from a large, randomized clinical trial, the Evaluating Adverse Events in a Global Smoking Cessation Study. Analytical approaches included multivariable Tobit regression, propensity score adjustment, and instrumental variable regressions conducted from August to October 2022. Missing data were imputed for sensitivity analysis. The trial occurred in 16 countries at 140 centers between 2011 and 2015. Only data from participants who completed the trial collected in the US were available for this secondary analysis. Participants included adults with or without a psychiatric disorder who smoked. | PMC10233414 |
Exposure | Smoking abstinence between weeks 9 through 24. | PMC10233414 | ||
Main Outcomes and Measures | depression, Depression, Anxiety | Anxiety and depression scores were measured using the Hospital Anxiety and Depression Scale at 24 weeks, where a lower score indicates better mental health (range, 0-21). | PMC10233414 | |
Results | mental illness, Anxiety, anxiety, depression, Depression | Of the 4260 participants included (mean [SD] age, 46.5 [12.4] years; 2485 women [58.3%]; 3044 White individuals [71.5%]), 2359 (55.4%) had a history of mental illness. The mean (SD) baseline Hospital Anxiety and Depression Scale score was 4.25 (3.68) (median [IQR], 3 [1-6]) for anxiety and 2.44 (2.91) (median [IQR], 1 [0-4]) for depression. After adjustment for demographics and baseline variables, smoking cessation was associated with a decrease in scores for both anxiety (−0.40 point; 95% CI, −0.58 to −0.22 point) and depression (−0.47 point; 95% CI, −0.61 to −0.33 point) compared with continuing smoking. Similarly, propensity score–adjusted models indicated that smoking cessation was associated with reduced scores for anxiety (β = −0.32; 95% CI, −0.53 to −0.11) and depression (β = −0.42; 95% CI, −0.60 to −0.24). Instrumental variable analysis was underpowered, and estimates were imprecise. Findings were robust to planned sensitivity and subgroup analyses, with larger effect sizes in people with a history of mental illness. | PMC10233414 | |
Conclusions and Relevance | psychiatric | DISORDERS | In this cohort study of people with and without psychiatric disorders, smoking cessation, sustained for at least 15 weeks, was associated with improved mental health outcomes in observational analyses, but the instrumental variable analysis provided inconclusive evidence. Findings like these may reassure people who smoke and their clinicians that smoking cessation likely will not worsen and may improve mental health. | PMC10233414 |
Introduction | REGRESSION, REGRESSIONS | Many people who smoke state that they want to quit,A recent Cochrane systematic reviewRandomly assigning people to continue or quit smoking is not feasible; therefore, observational methods are the only way to study the association between smoking cessation and mental health. However, traditional observational epidemiology has a primary issue: determining whether associations are causal. One concern is reverse causality (ie, improved mental health may make successful quitting more likely). A systematic reviewThis study used 3 confirmatory coprimary analyses—multivariable regression models, propensity score–adjusted models, and instrumental variable (IV) regressions—to evaluate the association between smoking cessation and mental health outcomes. The multivariable regression model will have the least control for confounding, propensity score–adjusted modeling will have less susceptibility, | PMC10233414 | |
Methods | This cohort study followed Strengthening the Reporting of Observational Studies in Epidemiology ( | PMC10233414 | ||
Study Design | psychiatric | ADVERSE EVENT, DISORDERS | We used a longitudinal cohort design with individual-level patient data from a double-blind, randomized, placebo-controlled clinical trial of varenicline compared with nicotine replacement therapy, bupropion, or placebo for smoking cessation in people selected because they had or did not have psychiatric disorders (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]). | PMC10233414 |
Data Source | Pfizer and GlaxoSmithKline jointly conducted and funded the EAGLE trials, | PMC10233414 | ||
Participants | People aged 18 to 75 years who smoked 10 or more cigarettes per day during the previous year and were motivated to quit were included. Participants were assessed using the Structured Clinical Interview for the | PMC10233414 | ||
Exposure | Smoking cessation was defined as continuous abstinence between weeks 9 and 24. There were no missing exposure data. | PMC10233414 | ||
Outcome | depression, Depression, Anxiety | Anxiety and depression outcomes were measured using the Hospital Anxiety and Depression Scale (HADS). | PMC10233414 | |
Covariates | diabetes, psychiatric, CVD | CVD, CARDIOVASCULAR DISEASE | Covariates included patients’ age, sex, race, receipt of cessation medication, history of cardiovascular disease (CVD), history of diabetes, psychiatric history, nicotine dependence score, prescription of psychotropics, and body mass index (calculated as weight in kilograms divided by height in meters squared). The method and rationale of racial or ethnic breakdown was not given in the trial report. | PMC10233414 |
Statistical Analysis | REGRESSION | Analyses were conducted using Stata statistical software version 16 (StataCorp) from August to October 2022. We ran 3 main models—multivariable Tobit regression, propensity score matching (PSM), and IV analysis. Owing to regression to the mean when using within-person change scores, we used the 24-week follow-up HADS scores, with adjustment for baseline HADS score. | PMC10233414 | |
Multivariable Tobit Regression | depression, anxiety | REGRESSION | Tobit regression was used because nearly one-third of participants had HADS scores of 0 for depression and almost one-fifth had scores of 0 for anxiety at baseline, making linear regression unfeasible (details are shown in eAppendix 1 in | PMC10233414 |
Propensity Score Matching | REGRESSION | Each participant’s propensity score represents their odds of belonging to the exposure group according to baseline characteristics derived from a logistic regression. | PMC10233414 | |
IV Analysis Procedure | REGRESSION | We ran a 2-stage IV regression. Randomization to placebo or active drug was the instrument, which was associated with increased abstinence in the EAGLES trial. | PMC10233414 | |
Missing Baseline Covariate Data | diabetes | CVD, DIABETES | To increase efficiency and minimize selection bias, we used multivariable multiple imputation to impute data for patients missing values for CVD (4 patients), diabetes (3 patients), and body mass index (39 patients). The imputation procedure produced 20 imputed data sets combined using Rubin rules, | PMC10233414 |
Sensitivity and Subgroup Analysis | People with a missing HADS score at week 24 may have had worse mental health outcomes. Therefore, running only a complete case analysis may have underestimated change in HADS scores. To examine this, we conducted a sensitivity analysis in which we imputed missing outcome data using multivariate multiple imputation. | PMC10233414 | ||
Results | PMC10233414 | |||
Participants | mental illness | We included 4260 participants (mean [SD] age, 46.5 [12.4] years; 2485 women [58.3%]; 3044 White individuals [71.5%]); 2359 (55.4%) had a history of mental illness, and 923 (21.7%) were currently prescribed psychotropic medication ( | PMC10233414 | |
Flow Diagram of Participants Included in Analysis | Depression, Anxiety | CVD, CARDIOVASCULAR DISEASE | BMI indicates body mass index; CVD, cardiovascular disease; and HADS, Hospital Anxiety and Depression Scale. | PMC10233414 |
Baseline Characteristics by Smoking Status at 24-Week Follow-up | Information on breakdown of subcategories included is unavailable.Body mass index is calculated as weight in kilograms divided by height in meters squared. | PMC10233414 | ||
Outcome Data | depression, anxiety | There were 1224 participants (28.7%) with missing HADS scores for week 24. We replaced missing HADS score with the last score recorded after 20 weeks, leaving 1029 participants (24.2%) who had missing outcome data on HADS and were excluded from the complete case analysis. The mean (SD) baseline HADS score was 4.25 (3.68) (median [IQR], 3 [1-6]) for anxiety and 2.44 (2.91) (median [IQR], 1 [0-4]) for depression. | PMC10233414 | |
Complete Case Analysis | We included 3200 people; 2731 continued and 469 stopped smoking. Mental health scores improved in both groups ( | PMC10233414 | ||
Hospital Anxiety and Depression Scale Scores for Participants by Smoking Status and Unadjusted Complete Case Tobit Regression | β = −0.28 (95% CI, −0.41 to −0.14).β = −0.29 (95% CI, −0.4 to −0.19). | PMC10233414 | ||
Change in Hospital Depression and Anxiety Scale Scores for People Who Remained Abstinent Between Weeks 9 and 24 | Abbreviation: PSM, propensity score matching. | PMC10233414 | ||
Unadjusted and Multivariable Adjusted Tobit Regression | Depression, Anxiety | People who stopped smoking had a lower HADS score at week 24 than those who continued smoking. Anxiety was lower by −0.28 point (95% CI, −0.41 −0.14 point) unadjusted and −0.40 point (95% CI, −0.58 to −0.22 point) adjusted. Depression was lower by −0.29 point (95% CI, −0.40 to −0.19 point) unadjusted and −0.47 point (95% CI, −0.61 to −0.33 point) adjusted. There was no evidence of a difference between people who were randomized to active drugs vs those randomized to placebo in mental health outcomes (eTable 1 and eTable 2 in | PMC10233414 | |
PSM Results | The difference in bias was reduced after PSM, and the common support region was large (eAppendix 3 and eFigure in | PMC10233414 | ||
IV Analysis | depression, anxiety | IV analysis suggested that depression increased relative to continuing smoking (β = 1.48; 95% CI, −0.67 to 3.63), as did anxiety (β = 1.60; 95% CI, −1.01 to 4.22), but both estimates were imprecise. Post hoc power analysis suggested that we had very little power to exclude effect sizes like those seen in our observational analyses (eAppendix 4 in | PMC10233414 | |
Sensitivity and Subgroup Analysis | depression, psychiatric, anxiety | SENSITIVITY | Sensitivity analysis removing individuals randomized to bupropion did not materially change the estimates compared with the complete case Tobit model: β = −0.33 (95% CI, −0.53 to −0.12) for anxiety and β = −0.37 (95% CI, −0.53 to −0.21) for depression. Following multiple imputation, there was a difference in adjusted anxiety scores of β = −0.33 (95% CI, −0.53 to −0.12) for the Tobit model and β = −0.54 (95% CI, −0.70 to −0.37) for PSM and adjusted depression scores of −0.97 point (95% CI, −1.15 to −0.78 point) for the Tobit model and −0.53 point (95% CI, −0.67 to −0.40 point) for PSM.Among individuals without a psychiatric history who stopped smoking, the decreases in depression (−0.32 point; 95% CI, −0.48 to −0.15 point) and anxiety (−0.29 point; 95% CI, −0.50 to −0.08 point) scores were smaller than the decreases observed among individuals with a psychiatric history who stopped smoking (depression, −0.60 point; 95% CI, −0.82 to −0.38 point; anxiety, 0.48 point; 95% CI, −0.76 to −0.20 point). | PMC10233414 |
Discussion | PMC10233414 | |||
Main Findings | depression, mental illness, anxiety | SENSITIVITY | In this cohort study, people who stopped smoking showed lower depression and anxiety scores 6 months after stopping smoking than people who continued smoking after adjustment for a range of possible confounding variables or with PSM. Scores were 0.40 point lower for anxiety and 0.47 point lower for depression on the HADS scale. Sensitivity analysis removing people randomly assigned to bupropion left the results unchanged. Sensitivity analyses using multiple imputation showed that effect estimates were in a similar direction of association, but point estimates were somewhat larger than in the complete case analyses. The association between smoking cessation and improvements in mental health was larger when we restricted it to those with a history of mental illness. Our IV analysis was inconclusive but lacked the power to detect an effect of smoking cessation on mental health. | PMC10233414 |
Interpretation | Our analyses suggest that smoking cessation is associated with improved mental health. However, our IV analysis was unable to confirm this. | PMC10233414 | ||
Limitations | chronic obstructive pulmonary disease, psychiatric | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, DISORDERS | Although the instrument of the randomized treatment group is theoretically sound, the instrument was not robust in this data set. Given the low likelihood of detecting an association of the size we observed in the observational data with the IV analysis with our sample size, future work would need a larger sample size. Our results, therefore, do not exclude a causal relationship between smoking cessation and improved mental health for people with and without psychiatric disorders.This study had substantial loss to follow-up, which is common in smoking cessation trials. Evidence suggests that those who fail to attend follow-up are more likely to continue smoking.The EAGLES trialLike many other smoking cessation studies, this study classified people who did not meet the strict definition of abstinence as continuing smoking. Those people who had achieved abstinence but not had 15 weeks of abstinence may have experienced changes in their mental health similar to those who met the 15-week abstinence, as the evidence suggests that the association is of similar strength in people with only 6 weeks of abstinence after several years.Although participants with and without a psychiatric history showed reduced HADS scores, these were less than the minimally clinically important differences suggested by populations with chronic obstructive pulmonary disease and CVD.The EAGLES trial | PMC10233414 |
Conclusions | psychiatric | DISORDERS | In this cohort study of people with and without psychiatric disorders, we found that smoking cessation was associated with improved mental health outcomes. These findings might motivate policy makers and stakeholders to support smoking cessation in people with mental health disorders. | PMC10233414 |
Background | EMA | Ecological momentary assessment (EMA) is increasingly used to evaluate behavioral health processes over extended time periods. The validity of EMA for providing representative, real-world data with high temporal precision is threatened to the extent that EMA compliance drops over time. | PMC10337346 | |
Objective | EMA | This research builds on prior short-term studies by evaluating the time course of EMA compliance over 9 weeks and examines predictors of weekly compliance rates among cigarette-using adults. | PMC10337346 | |
Methods | EMA | A total of 257 daily cigarette-using adults participating in a randomized controlled trial for smoking cessation completed daily smartphone EMA assessments, including 1 scheduled morning assessment and 4 random assessments per day. Weekly EMA compliance was calculated and multilevel modeling assessed the rate of change in compliance over the 9-week assessment period. Participant and study characteristics were examined as predictors of overall compliance and changes in compliance rates over time. | PMC10337346 | |
Results | EMA | Compliance was higher for scheduled morning assessments (86%) than for random assessments (58%) at the beginning of the EMA period ( | PMC10337346 | |
Conclusions | EMA | This study suggests that EMA compliance declines linearly but modestly across lengthy EMA protocols. In general, these data support the validity of EMA for tracking health behavior and hypothesized treatment mechanisms over the course of several months. Future work should target improving compliance among subgroups of participants and investigate the extent to which rapid declines in EMA compliance might prove useful for triggering interventions to prevent study dropout. | PMC10337346 | |
Trial Registration | ClinicalTrials.gov NCT03262662; https://clinicaltrials.gov/ct2/show/NCT03262662 | PMC10337346 | ||
Introduction | EMA | Ecological momentary assessment (EMA) uses digital technologies (eg, smartphones) to gather real-world, real-time data from research participants multiple times per day, thereby overcoming the notable problems with retrospective recall and yielding assessments with excellent temporal resolution and representation of “in the moment” participant experiences [In each of these areas of health behavior research, the use and validity of EMA depend on maintaining EMA compliance across weeks or even months (see Stone and Shiffman [Very little is known about the time course of EMA compliance beyond a few weeks. If compliance declines at a linear rate, the health behavior studies reviewed in the prior paragraph would suggest EMA compliance drops 2%-9% per week. Whereas a 2% per week decline would likely have a modest impact on EMA data [This study seeks to fill this gap in the literature by examining EMA compliance rates over a 9-week period in the context of a randomized controlled clinical trial for smoking cessation among community adults. Based on the work reviewed above, we tested the competing hypotheses that EMA compliance would (1) gradually and linearly decline across weeks or (2) exhibit greater declines in later weeks compared to earlier weeks (ie, accelerating declines tested as a quadratic trend).We also explored candidate predictors of both initial EMA compliance and changes in compliance over time to better understand variables related to assessment completion in clinical EMA samples [We also examined how aspects of the EMA protocol that may have produced a greater burden and less flexibility affected compliance. Specifically, we predicted that initial EMA compliance would be higher, and declines over time would be smaller for (1) participants completing EMA on their own phone compared to a study-provided phone (as the latter often ended up carrying 2 phones, which might have increased burden for completing assessments) [ | PMC10337346 |
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