Process evaluation of PsyCovidApp, a digital tool for mobile devices aimed at protecting the mental health of healthcare professionals during the COVID-19 pandemic: a mixed method study.

Introduction: PsyCovidApp, a digital intervention aimed at safeguarding the mental health of healthcare workers during the COVID-19 pandemic, demonstrated in a randomized clinical trial to yield significant improvements solely among healthcare workers undergoing psychotherapy or receiving psychotropic medication. Objectives: (1) To identify contextual factors and mechanisms of action that influenced the impact of PsyCovidApp during the aforementioned trial; (2) To pinpoint enhancements for optimizing its efficacy. Materials and methods: For the first objective, a process evaluation was conducted, amalgamating quantitative techniques (surveying 216 healthcare professionals who had utilized PsyCovidApp during the trial) and qualitative methods (in-depth interviews with 16 healthcare workers). The second objective involved a panel of seven experts, utilizing the RAND-UCLA methodology. Results: The quantitative study (response rate = 40%) revealed that 22% of respondents had not fully accessed the content of PsyCovidApp. The average usage time was 22.7 min/day, being higher (p < 0.05) among consumers of psychotropic medications. Contents related to relaxation and mindfulness were most highly rated. Acceptability and usefulness scores ranged between 7.3-7.5/10 points, with higher ratings (p < 0.05) among women and older healthcare workers. The qualitative study uncovered that the primary barriers to using PsyCovidApp were workload, lack of time, and exhaustion. Its primary mechanisms of action included emotion identification, mental health regulation (e.g., insomnia, intense emotions), and learning of techniques and skills. The expert panel reached a consensus on 29 proposals to optimize PsyCovidApp. Conclusion: The knowledge derived from this study could inform the design and implementation of future similar digital tools.

Evaluation of SINERGIAPS, an intervention to improve patient safety in primary healthcare centers in Spain based on patients' perceptions and experiences: a protocol for a hybrid type I randomized clinical trial.

Background: Adverse events in the primary care setting result in a direct cost equivalent to at least 2.5% of total healthcare spending. Across OECD countries, they lead to more than seven million avoidable hospital admissions annually. In this manuscript, we describe the protocol of a trial aimed at evaluating the effectiveness of SinergiAPS (a patient-centered audit and feedback intervention) in reducing avoidable hospital admission and explore the factors that may affect its implementation. Methods: We will conduct a 24-month, parallel, open-label, multicenter, pragmatic, hybrid type 1 randomized clinical trial. 118 primary healthcare centers with wide geographical distribution in Spain will be randomly assigned (ratio 1:1) to two groups. The intervention group will receive two audits (baseline and intermediate at 12 months) based on information collected through the administration of the PREOS-PC questionnaire (a measure of patient-reported patient safety) to a convenience sample of 100 patients per center. The intervention group will receive reports on the results of both audits, along with educational resources aimed at facilitating the design and implementation of safety improvement plans. The control group will receive care as usual. The primary outcome will be the rate of avoidable hospitalizations (administrative data). Secondary outcomes: patient-reported patient safety experiences and outcomes (PREOS-PC questionnaire); patient safety culture as perceived by professionals (MOSPSC questionnaire); adverse events reported by healthcare professionals (ad hoc questionnaire); the number of safety improvement actions which the re has implemented (ad hoc questionnaire). Outcome data will be collected at baseline and 24 months follow-up. For the evaluation of the implementation of the SinergiAPS intervention, we will draw on the Consolidated Framework for Implementation Research (CFIR). We will collect and analyze qualitative and quantitative data (30 individual interviews, implementation logbooks; questionnaires for professionals from intervention centers, and level of use of the SinergiAPS web tool). Discussion: This study will expand the scarce body of evidence existing regarding the effects and implementation of interventions aimed at promoting patient and family engagement in primary healthcare, specifically for enhancing patient safety. The study has the potential to produce an impact on clinical practice, healthcare systems, and population health.Clinical Trial Registration: https://clinicaltrials.gov/study/NCT05958108?term=sinergiAPS&rank=1 (NCT05958108).

Evaluation of the psychometric performance of the Spanish and Catalan versions of the patient reported experiences and Outcomes of Safety in Primary Care (PREOS-PC)-Compact questionnaire.

BACKGROUND: Patients provide a unique, irreplaceable, and essential perspective in evaluating patient safety. The suite of Patient Reported Experiences and Outcomes of Safety in Primary Care (PREOS-PC) tools are a notable exception to the scarcity of patient-reported patient safety measures. Full evaluation of their performance has only been attempted for the English version, thereby limiting its international applicability. OBJECTIVES: To assess the psychometric performance of the Spanish and Catalan versions of the PREOS-PC-Compact. METHODS: Cross-sectional validation study. We used Classical Test Theory methods to examine scale score distribution, internal consistency, and construct validity; and Item Response Theory (IRT) methods to further explore construct validity. RESULTS: 3287 patients completed the Spanish version, and 1007 the Catalan version. Similar results were obtained for both versions. Confirmatory Factor Analysis supported a single construct for each scale. The correlations between PREOS-PC-Compact scales and known group analysis suggested adequate construct validity (inconclusive for known groups at the provider level). All four multi-item scales demonstrated adequate internal consistency reliability (α > 0.7), which was only confirmed for test-retest reliability for 'Practice activation.' A sample between 60-90 patients per practice was estimated sufficient to produce scores with reliability > 0.7 for all scales except for harm scales. IRT models showed disordered thresholds for 'Practice activation' and 'Harm burden' but showed excellent fit after reducing the response categories. CONCLUSION: The Spanish and Catalan versions of the PREOS-PC-Compact are broadly valid and reliable tools to measure patient safety in Spanish primary care centres; confirmation of lower-than-expected test-rest reliability merits further examination .

Feasibility of the SINERGIAPS ("Sinergias entre profesionales y pacientes para una Atención Primaria Segura") intervention for improving patient safety in primary care.

AIM: The primary aim was to examine the feasibility of intervention delivery and of trial procedures. Secondary aims were to study the intervention uptake; its acceptability and perceived utility; and its potential to improve safety culture and avoidable hospital admissions. METHODS: We conducted a 3-month, single-arm feasibility study in 10 primary care (PC) centres in Spain. Centres received information regarding patients' experiences of safety (through the Patient Reported Experiences and Outcomes of Safety in Primary Care [PREOS-PC] questionnaire), and were instructed to plan safety improvements based on that feedback. We used a bespoke online tool to recruit PC professionals, collect patient feedback, and deliver it to the centres, and to collect outcome data (patient safety culture [Medical Office Survey on Patient Safety Culture, MOSPSC questionnaire]). We measured recruitment and follow-up rates and intervention uptake (based on the number of safety improvement plans registered). We conducted semistructured interviews with 9 professionals to explore the intervention acceptability and perceived utility. RESULTS: Of 256 professionals invited, 120 (47%) agreed to participate, and 97 completed baseline and postintervention measures. Of 780 patients invited, 585 (75%) completed the PREOS-PC questionnaire. Five of 10 centres (50%) designed an improvement plan, providing 27 plans in total (range per centre, 1-14). The intervention was perceived as a novel strategy for improving safety, although the healthcare professionals identified several factors limiting its acceptability and utility: lack of feedback at the individual professional level; potentially unrepresentative sample of patients providing feedback; and number of educational materials deemed overwhelming. DISCUSSION: It is feasible to deliver the proposed intervention so long as the identified limitations are addressed.

Cross-Cultural Adaptation, Validation, and Piloting of the Patient Reported Experiences and Outcomes of Safety in Primary Care Questionnaire for Its Use in Spain.

OBJECTIVE: This study aimed to cross-culturally adapt, validate, and pilot the Patient Reported Experiences and Outcomes of Safety in Primary Care questionnaire for its use in Spain. METHODS: After setting up an expert panel to determine its content validity, the questionnaire was translated and back-translated, and subjected to cognitive testing. The questionnaire was piloted in a cross-sectional study in 10 primary health care centers in Spain. Fifty patients per center completed the questionnaire while waiting for an appointment. We estimated (i) the acceptability of the questionnaire (response rate), (ii) scores distribution (floor and ceiling effects), (iii) internal consistency (Cronbach α), and (iv) construct validity (exploratory factor analyses and correlation between scales). To examine patients' evaluations of patient safety, we followed a mixed-methods approach: (i) statistical analyses at the scale and item levels based on responses to standardized items and (ii) qualitative content analysis based on responses to open-ended questions. RESULTS: Complete data were collected from 493 patients (participation rate, 77%). A ceiling effect was observed for 3 scales ("safety problems," "harm severity," "harm needs"). The internal consistency was adequate (α > 0.7) for the majority of scales. Exploratory factor analysis and correlation between scales suggested an appropriate construct validity. Two hundred twenty-six (45.8%) respondents experienced at least 1 safety problem, and 109 (23.2%) reported harm in the previous 12 months. CONCLUSIONS: The multidimensional primary health care patient safety instrument Patient Reported Experiences and Outcomes of Safety in Primary Care is now available for its use in Spain. Initial testing demonstrates its potential for use in primary care. Future developments will further address its use in actual clinical practice.

Impact of Smartphone App-Based Psychological Interventions for Reducing Depressive Symptoms in People With Depression: Systematic Literature Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Depression is a serious, disabling mental disorder that severely affects quality of life. Patients with depression often do not receive adequate treatment. App-based psychotherapy is considered to have great potential to treat depression owing to its reach and easy accessibility. OBJECTIVE: We aim to analyze the impact of app-based psychological interventions for reducing depressive symptoms in people with depression. METHODS: We conducted a systematic literature review and meta-analysis. We searched Medline, Embase, PsycINFO, Web of Science, and Cochrane Central Register of Controlled Trials from inception to December 23, 2020. We selected randomized controlled trials to examine the impact of app-based psychological interventions for reducing depressive symptoms in people with depression. Study selection, data extraction, and critical appraisal (using the Cochrane Risk of Bias tool for randomized studies and the ROBINS-I tool for nonrandomized studies) were conducted independently by 2 reviewers. Where possible, we pooled data using random effects meta-analyses to obtain estimates of the effect size of the intervention. We conducted post hoc meta-regression analyses to explore the factors associated with intervention success. RESULTS: After screening 3468 unique references retrieved from bibliographic searches and assessing the eligibility of 79 full texts, we identified 12 trials (2859 participants) evaluating 14 different interventions. Of 14 trials, 7 (58%) were conducted in the United States; 3 (25%) trials, in Asia (Japan, South Korea, and China); 1 (8%) trial, in Australia; and 1 (8%) trial, in Germany. Of the 12 trials, 5 (42%) trials presented a low risk of bias. The mean duration of the interventions was 6.6 (SD 2.8) weeks. Two-thirds of the interventions were based on cognitive behavioral therapy alone or included it in combination with cognitive control therapy, positive psychology, brief behavioral activation, or mindfulness- and acceptance-based therapy. With no evidence of publication bias, a pooled analysis of 83% (10/12) of the trials and 86% (12/14) of the interventions showed that app-based interventions, compared with a control group receiving usual care or minimal intervention, produced a moderate reduction in depressive symptoms (standardized mean difference [SMD] -0.51, 95% CI -0.69 to -0.33; 2018/2859, 70.58% of the participants; I2=70%). Our meta-regression analyses indicated that there was a greater reduction in symptoms of depression (P=.04) in trials that included participants with moderate to severe depression (SMD -0.67, 95% CI -0.79 to -0.55), compared with trials with participants exhibiting mild to moderate depression (SMD -0.15, 95% CI -0.43 to -0.12). CONCLUSIONS: App-based interventions targeted at people with depression produce moderate reductions in the symptoms of depression. More methodologically robust trials are needed to confirm our findings, determine which intervention features are associated with greater improvements, and identify those populations most likely to benefit from this type of intervention. TRIAL REGISTRATION: PROSPERO CRD42019145689; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=145689.

[Impact of the COVID-19 pandemic on patient-reported patient safety in Primary Care]. / Impacto de la pandemia de COVID-19 en la seguridad del paciente percibida por los pacientes en Atención Primaria.

OBJECTIVE: To evaluate the impact of the changes introduced in response to the pandemic on patient-reported patient safety in Primary Care. DESIGN: Prospective observational panel study (health center) based on two cross-sectional surveys. SETTING: 29 Primary Health Care centers from three Spanish health regions (Mallorca, Catalunya Central and Camp de Tarragona). PARTICIPANTS: Random sample of patients visiting their centers before (n=2199 patients) and during the pandemic (n=1955 patients) MAIN MEASUREMENTS: We used the PREOS-PC questionnaire, a validated instrument which assesses patient-reported patient safety in Primary Care. We compared mean scores of the "experiences of errors" and "harm" scales in both periods, and built multilevel regression analyzes to study the variations in patient and center characteristics associated with worse levels of safety. A qualitative (content) analysis of patients' experiences during the pandemic was also performed. RESULTS: The "experiences of errors" and "harm" scales scores significantly worsened during the COVID-19 period (92.65 to 88.81 (Cohen's d=0.27); and 96.92 to 79.97 (d=0.70), respectively). Patient and center characteristics associated to worsened scores were: women, people with a lower educational level, worse health status, more years assigned to the center, and health region. CONCLUSIONS: During the pandemic, a perceptible worsening in patient safety perceived by patients treated in Primary Care has been observed, which has differentially affected patients according to their sociodemographic characteristics or health center profiles.

Insomnio y calidad del sueño en profesionales sanitarios frente a la Covid-19: una revisión sistemática de la literatura y meta-análisis / Children’s adverse experiences and psychotic chronification

La pandemia de COVID-19 tiene el potencial de afectarsignificativamente la salud mental de los profesionales sanitarios que se encuentran en la primera línea de esta crisis.El insomnio está relacionado con la exposición a situacionesestresantes, como la actual, así como con otros trastornosmentales, patologías físicas y problemas laborales. Los objetivos de esta revisión sistemática fueron: 1) examinar el impacto de la actual pandemia sanitaria producida por COVID-19en el insomnio y la calidad del sueño de los profesionalessanitarios, y 2) identificar los factores de riesgo asociados alinsomnio. Tras una búsqueda bibliográfica en MEDLINE, EMBASE y PsycInfo se identificaron 18 estudios relevantes. Laprevalencia de insomnio autoinformado estimada mediantemeta-análisis de efectos aleatorios fue del 38 % (IC95 %: 37a 39 %), siendo ligeramente superior en mujeres (29 %, IC95%: 27 a 30 %) que en hombres (24 %, IC95 %: 21 a 27 %). Elprincipal factor de riesgo asociado al insomnio fue trabajaren un entorno de alto riesgo, seguido del género femenino yun menor nivel educativo. Las cifras de insomnio y la calidaddel sueño observadas indican la necesidad de desarrollar intervenciones destinadas a mitigar y cuidar la salud mental de los sanitarios al frente de esta pandemia. (AU)

COVID-19 pandemic has the potential to significantlyaffect the mental health of healthcare workers, who standin the frontline of this crisis. Insomnia is often related toexposure to stressful situations, such as the current healthcrisis, as well as other mental disorders, physical conditionsand work-related problems. The objectives of this systematicreview were: 1) to examine the impact of the current health pandemic produced by COVID-19 on insomnia and sleepquality of health professionals, and 2) to identify risk factors associated with insomnia. After a literature search inMEDLINE, EMBASE, and PsycInfo, 18 relevant studies wereidentified. The prevalence of insomnia estimated by randomeffects meta-analysis was 38 % (95 % CI: 37 to 39 %), being slightly higher in women (29 %, 95 % CI: 27 % to 30%) than in men (24 %, 95 % CI: 21 to 27 %). The main riskfactor associated with insomnia was working in a high-riskenvironment, followed by female sex and having a lowereducational level. The figures of self-reported insomnia andworse quality of sleep observed indicate the need to developinterventions aimed at mitigating and caring for the mentalhealth of healthcare workers fighting against this pandemic. (AU)

Assessing the Impact of Multi-Morbidity and Related Constructs on Patient Reported Safety in Primary Care: Generalized Structural Equation Modelling of Observational Data.

We aimed to examine the complex relationships between patient safety processes and outcomes and multimorbidity using a comprehensive set of constructs: multimorbidity, polypharmacy, discordant comorbidity (diseases not sharing either pathogenesis nor management), morbidity burden and patient complexity. We used cross-sectional data from 4782 patients in 69 primary care centres in Spain. We constructed generalized structural equation models to examine the associations between multimorbidity constructs and patient-reported patient safety (PREOS-PC questionnaire). These associations were modelled through direct and indirect (mediated by increased interactions with healthcare) pathways. For women, a consistent association between higher levels of the multimorbidity constructs and lower levels of patient safety was observed via either pathway. The findings for men replicated these observations for polypharmacy, morbidity burden and patient complexity via indirect pathways. However, direct pathways showed unexpected associations between higher levels of multimorbidity and better safety. The consistent association between multimorbidity constructs and worse patient safety among women makes it advisable to target this group for the development of interventions, with particular attention to the role of comorbidity discordance. Further research, particularly qualitative research, is needed for clarifying the complex associations among men.

Effect of a mobile-based intervention on mental health in frontline healthcare workers against COVID-19: Protocol for a randomized controlled trial.

AIM: To evaluate the impact of a psychoeducational, mobile health intervention based on cognitive behavioural therapy and mindfulness-based approaches on the mental health of healthcare workers at the frontline against COVID-19 in Spain. DESIGN: We will carry out a two-week, individually randomized, parallel group, controlled trial. Participants will be individually randomized to receive the PsyCovidApp intervention or control App intervention. METHODS: The PsyCovidApp intervention will include five modules: emotional skills, lifestyle behaviour, work stress and burnout, social support, and practical tools. Healthcare workers having attended patients with COVID-19 will be randomized to receive the PsyCovidApp intervention (intervention group) or a control App intervention (control group). A total of 440 healthcare workers will be necessary to assure statistical power. Measures will be collected telephonically by a team of psychologists at baseline and immediately after the 2 weeks intervention period. Measures will include stress, depression and anxiety (DASS-21 questionnaire-primary endpoint), insomnia (ISI), burnout (MBI-HSS), post-traumatic stress disorder (DTS), and self-efficacy (GSE). The study was funded in May 2020, and was ethically approved in June 2020. Trial participants, outcome assessors and data analysts will be blinded to group allocation. DISCUSSION: Despite the increasing use of mobile health interventions to deliver mental health care, this area of research is still on its infancy. This study will help increase the scientific evidence about the effectiveness of this type of intervention on this specific population and context. IMPACT: Despite the lack of solid evidence about their effectiveness, mobile-based health interventions are already being widely implemented because of their low cost and high scalability. The findings from this study will help health services and organizations to make informed decisions in relation to the development and implementation of this type of interventions, allowing them pondering not only their attractive implementability features, but also empirical data about its benefits. CLINICAL TRIAL REGISTRATION: NCT04393818 (ClinicalTrials.gov identifier). APPROVED FUNDING: May 2020.

Impact of viral epidemic outbreaks on mental health of healthcare workers: a rapid systematic review and meta-analysis.

BACKGROUND: This study aimed at examining the impact of providing healthcare during health emergencies caused by viral epidemic outbreaks on healthcare workers' (HCWs) mental health; to identify factors associated with worse impact, and; to assess the available evidence base regarding interventions to reduce such impact. METHOD: Rapid systematic review. We searched MEDLINE, Embase, and PsycINFO (inception to August 2020). We pooled data using random-effects meta-analyses to estimate the prevalence of specific mental health problems, and used GRADE to ascertain the certainty of evidence. RESULTS: We included 117 studies. The pooled prevalence was higher for acute stress disorder (40% (95%CI 39 to 41%)), followed by anxiety (30%, (30 to 31%)), burnout (28% (26 to 31%)), depression (24% (24 to 25%)), and post-traumatic stress disorder (13% (13 to 14%)). We identified factors associated with the likelihood of developing those problems, including sociodemographic (younger age and female gender), social (lack of social support, stigmatization), and occupational (working in a high-risk environment, specific occupational roles, and lower levels of specialised training and job experience) factors. Four studies reported interventions for frontline HCW: two educational interventions increased confidence in pandemic self-efficacy and in interpersonal problems solving (very low certainty), whereas one multifaceted intervention improved anxiety, depression, and sleep quality (very low certainty). LIMITATIONS: We only searched three databases, and the initial screening was undertaken by a single reviewer. CONCLUSION: Given the very limited evidence regarding the impact of interventions to tackle mental health problems in HCWs, the risk factors identified represent important targets for future interventions.

Exploring primary health care professionals' perceptions about a patient feedback intervention to improve patient safety in Spanish primary health care centres: a qualitative study.

BACKGROUND: Patient feedback interventions are receiving increasing attention given their potential to improve health care provision. However, primary health care (PHC) professionals' acceptability and perceived utility of this type of interventions remain largely unexplored. OBJECTIVES: The aim of this study was to explore PHC professionals' perceptions, opinions and suggestions about a patient feedback intervention currently being designed to improve patient safety in Spanish PHC centres. METHODS: We conducted an exploratory qualitative study with 43 PHC professionals. Information was obtained from three semi-structured interviews and four focus groups. All data were audio-recorded, transcribed and analyzed using content analysis by three analysts. RESULTS: The patient feedback intervention was acceptable to health care professionals, who perceived it as a useful strategy to improve health care processes and activate patients. A number of factors potentially limiting the acceptability and perceived utility of the intervention were identified (low patient safety culture, low patient-centred care orientation and limited credibility of patient feedback data). Recommendations for designing and implementing the proposed intervention in the Spanish PHC centres were identified in relation to the following areas: 'collection and analysis of feedback data'; 'feedback display'; 'feedback delivery' and; 'implementation of safety improvement initiatives'. CONCLUSIONS: Although the proposed intervention was generally perceived as useful and acceptable, our study identified a number of tensions about the practical aspects of using the patient-reported data and the credibility of the data and what actions would arise from its use. The intervention has been adapted to address these tensions before its formal evaluation in a randomized clinical trial.

The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer's disease, improving behavioral motor function and survival.

We have compared the effect of the commonly used ω-3 fatty acid, docosahexaenoic acid ethyl ester (DHA-EE), and of its 2-hydroxylated DHA form (DHA-H), on brain lipid composition, behavior and lifespan in a new human transgenic Drosophila melanogaster model of Alzheimer's disease (AD). The transgenic flies expressed human Aß42 and tau, and the overexpression of these human transgenes in the CNS of these flies produced progressive defects in motor function (antigeotaxic behavior) while reducing the animal's lifespan. Here, we demonstrate that both DHA-EE and DHA-H increase the longer chain fatty acids (≥18C) species in the heads of the flies, although only DHA-H produced an unknown chromatographic peak that corresponded to a non-hydroxylated lipid. In addition, only treatment with DHA-H prevented the abnormal climbing behavior and enhanced the lifespan of these transgenic flies. These benefits of DHA-H were confirmed in the well characterized transgenic PS1/APP mouse model of familial AD (5xFAD mice), mice that develop defects in spatial learning and in memory, as well as behavioral deficits. Hence, it appears that the modulation of brain lipid composition by DHA-H could have remedial effects on AD associated neurodegeneration. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer's disease.

The unfolded protein response (UPR) and autophagy are two cellular processes involved in the clearing of intracellular misfolded proteins. Both pathways are targets for molecules that may serve as treatments for several diseases, including neurodegenerative disorders like Alzheimer's disease (AD). In the present work, we show that 2-hydroxy-DHA (HDHA), a docosahexaenoic acid (DHA) derivate that restores cognitive function in a transgenic mouse model of AD, modulates UPR and autophagy in differentiated neuron-like SH-SY5Y cells. Mild therapeutic HDHA exposure induced UPR activation, characterized by the up-regulation of the molecular chaperone Bip as well as PERK-mediated stimulation of eIF2α phosphorylation. Key proteins involved in initiating autophagy, such as beclin-1, and several Atg proteins involved in autophagosome maturation (Atg3, Atg5, Atg12 and Atg7), were also up-regulated on exposure to HDHA. Moreover, when HDHA-mediated autophagy was studied after amyloid-ß peptide (Aß) stimulation to mimic the neurotoxic environment of AD, it was associated with increased cell survival, suggesting that HDHA driven modulation of this process at least in part mediates the neuroprotective effects of this new anti-neurodegenerative drug. The present results in part explain the pharmacological effects of HDHA inducing full recovery of the cognitive scores in murine models of AD.

Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid - OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-ß (Αß) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aß levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aß-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aß and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aß to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer's disease following 2-hydroxy-DHA treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. In the last years, abnormalities of lipid metabolism and in particular of docosahexaenoic acid (DHA) have been recently linked with the development of the disease. According to the recent studies showing how hydroxylation of fatty acids enhances their biological activity, here we show that chronic treatment with a hydroxylated derivative of DHA, the 2-hydroxy-DHA (2OHDHA) in the 5XFAD transgenic mice model of AD improves performance in the radial arm maze test and restores cell proliferation in the dentate gyrus, with no changes in the presence of beta amyloid (Aß) plaques. These results suggest that 2OHDHA induced restoration of cell proliferation can be regarded as a major component in memory recovery that is independent of Aß load thus, setting the starting point for the development of a new drug for the treatment of AD.

2-hydroxy arachidonic acid: a new non-steroidal anti-inflammatory drug.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies. METHODOLOGY/PRINCIPAL FINDINGS: The analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-α serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the -OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-α levels in vivo. CONCLUSION/SIGNIFICANCE: These findings demonstrate the potential of 2OAA as a NSAID.