Improving chronic pain management with eHealth and mHealth: study protocol for a randomised controlled trial

INTRODUCTION: Chronic pain has become a matter of public health concern due to its high prevalence and because public costs associated with treatment and disability increase each year. Research suggests that limitations in the traditional assessment of chronic pain patients limit the effectiveness of current medical treatments. The use of technology might serve change patient traditional monitoring into ecological momentary assessments, which might be visualised by physicians live. This study describes a randomised control trial designed to test the utility of a technology-based solution for pain telemonitoring consisting of a smartphone app for patients and a web application for physicians. The goal of this study will be to explore whether this combination of eHealth and mHealth improves the effectiveness of existing pain treatments. METHODS AND ANALYSIS: Participants will be 250 patients randomly assigned to one of these two conditions: treatment-as-usual (TAU) and TAU +app+¿web. All participants will receive the usual treatment for their pain. Only the TAU +app+¿web group use Pain Monitor app, which generates alarms that are sent to the physicians in the face of previously established undesired events. Physicians will be able to monitor app reports using a web application, which might result in an adjustment of treatment. We anticipate that the use of Pain Monitor plus the therapist web will result in a reduction of pain intensity and side effects of the medication. Improvements on secondary outcomes, namely fatigue, mood, pain interference, rescue medication use and quality of life, are also expected. Mixed repeated-measure multivariate analyses of variances will be conducted to investigate whether there are differences between preassessment and postassessment scores as a function of the experimental condition. ETHICS AND DISSEMINATION: Ethical approval from the Hospital General Universitari de Castellon was obtained. The findings will be published in peer-reviewed journals

Cell Wall Integrity Pathway Involved in Morphogenesis, Virulence and Antifungal Susceptibility in Cryptococcus neoformans

Due to its location, the fungal cell wall is the compartment that allows the interaction with the environment and/or the host, playing an important role during infection as well as in different biological functions such as cell morphology, cell permeability and protection against stress. All these processes involve the activation of signaling pathways within the cell. The cell wall integrity (CWI) pathway is the main route responsible for maintaining the functionality and proper structure of the cell wall. This pathway is highly conserved in the fungal kingdom and has been extensively characterized in Saccharomyces cerevisiae. However, there are still many unknown aspects of this pathway in the pathogenic fungi, such as Cryptococcus neoformans. This yeast is of particular interest because it is found in the environment, but can also behave as pathogen in multiple organisms, including vertebrates and invertebrates, so it has to adapt to multiple factors to survive in multiple niches. In this review, we summarize the components of the CWI pathway in C. neoformans as well as its involvement in different aspects such as virulence factors, morphological changes, and its role as target for antifungal therapies among others.This work was supported by Grant PID2020-114546RB-100 from the Spanish Ministry for Science and Innovation. De Oliveira H.C. was supported by Inova Fiocruz/Fundação Oswaldo Cruz. Rossi SA is funded by postdoctoral fellowship from Fundacão de Amparo á pesquisa do Estado de São Paulo (reference FAPESP-BEPE 2020/09919-0). García-Barbazán Iwas supported by a FPI fellowship (reference PRE2018-083436). Trevijano-Contador N is funded by a “Ayudas de Atracción de Talento Investigador” Contract of Community of Madrid (reference 2019-T2/BMD-14926).S

Characterizing Breakthrough Cancer Pain Using Ecological Momentary Assessment with a Smartphone App: Feasibility and Clinical Findings

Background: mobile applications (apps) facilitate cancer pain ecological momentary assessment (EMA) and provide more reliable data than retrospective monitoring. The aims of this study are (a) to describe the status of persons with cancer pain when assessed ecologically, (b) to analyze the utility of clinical alarms integrated into the app, and (c) to test the feasibility of implementing an app for daily oncological pain monitoring. Methods: in this feasibility study, 21 patients (mean age = 56.95 years, SD = 10.53, 81.0% men) responded to an app-based evaluation of physical status (baseline and breakthrough cancer pain (BTcP)) and mental health variables (fatigue, mood, and coping) daily during 30 days. Results: cancer pain characterization with the app was similar to data from the literature using retrospective assessments in terms of BTcP duration and perceived medication effectiveness. However, BTcP was less frequent when evaluated ecologically. Pain, fatigue, and mood were comparable in the morning and evening. Passive coping strategies were the most employed daily. Clinical alarms appear to be useful to detect and address adverse events. App implementation was feasible and acceptable. Conclusion: apps reduce recall bias and facilitate a rapid response to adverse events in oncological care. Future efforts should be addressed to integrate EMA and ecological momentary interventions to facilitate pain self-management via apps

Ecological momentary intervention to enhance emotion regulation in healthcare workers via smartphone: a randomized controlled trial protocol

Background: CUIDA-TE is an APP that offers transdiagnostic cognitive behavioral therapy focused on enhancing emotion regulation. As a novelty, it incorporates ecological momentary interventions (EMI), which can provide psychological support in real time, when suffering arises. The main goal of the study is to evaluate the efficacy of CUIDA-TE to improve emotion regulation in healthcare workers, a population that has been particularly emotionally impacted by the COVID-19 pandemic. Methods: In this three-arm, randomized controlled trial (RCT) the study sample will be composed of a minimum of 174 healthcare workers. They will be randomly assigned to a 2-month EMI group (CUIDA-TE APP, n = 58), a 2-month ecological momentary assessment (EMA) only group (MONITOR EMOCIONAL APP, n = 58), or a wait-list control group (no daily monitoring nor intervention, n = 58). CUIDA-TE will provide EMI if EMA reveals emotional problems, poor sleep quality/quantity, burnout, stress, or low perceived self-efficacy when regulating emotions. Depression will be the primary outcome. Secondary outcomes will include emotion regulation, quality of life, and resilience. Treatment acceptance and usability will also be measured. Primary and secondary outcomes will be obtained at pre- and post-intervention measurements, and at the 3-month follow-up for all groups. Discussion: To our knowledge, this is the first RCT that evaluates the efficacy of an APP-based EMI to improve emotion regulation skills in healthcare workers. This type of intervention might ultimately help disseminate treatments and reach a larger number of individuals than traditional face-to-face individual therapies. Trial registration: ClinicalTrial.gov: NCT04958941 Registered 7 Jun 2021. Study status: Participant recruitment has not started

Improving pain treatment with a smartphone app: Study protocol for a randomized controlled trial

Background: Chronic pain has become a major health problem across the world, especially in older adults. Unfortunately, the effectiveness of medical interventions is modest. Some have argued that assessment strategies shouldbe improved if the impact of medical interventions is to be improved. Ecologicalmomentary assessment usingsmartphones is now considered the gold standard in monitoring in health settings, including chronic pain. However, tothe best of our knowledge, there is no randomized controlledtrial to show that telemonitoring using a smartphone appcan indeed improve the effectiveness of medical treatmentsin adults with chronic pain. The goal of this study will be toexplore the effects of using a smartphone app for telemonitoring adults with chronic pain. Methods: The study will be a randomized controlled trial with three groups: treatment as usual (TAU), TAU+app,and TAU+app+alarms. All groups will receive the adequatetreatment for their pain, which will be prescribed thefirst day of study according to clinical guidelines. Assessment in the TAU group will be the usual at the Pain Clinic, thatis, a paper-and-pencil evaluation at the onset of treatment (beginning of study) and at follow up (end of study, 30 dayslater). The other two groups (TAU+app and TAU+app+alarms) will be assessed daily using Pain Monitor, a smartphoneapp developed by our multidisciplinary team. Telemonitoring will only be made in the TAU+app+alarms group. For this group, physicians at the Pain Clinic may decide to adjust pain treatment in response to alarms. Telemonitoring isnot the usual practice at the Pain Clinic and will not occur in the other two groups (TAU and TAU+app), so no changesin treatment are expected in these groups after the first appointment. The total sample size will be 150, with 50 patientsin each group. The assessment protocol will be the same in all groups and will include pain intensity and side effects ofthe medication (primary outcomes), together with several pain-related variables like pain interference, activity level, useof rescue medication, pain catastrophizing, and pain acceptance, among others. Discussion: We believe that the present trial has important clinical implications. We think that telemonitoringusing ecological momentary assessment is crucial to improve current interventions for pain. The armamentarium ofavailable treatments for pain is large, so physicians can turn to different treatments or dosages in the presence of anundesired event. The use of the app for telemonitoring can allow for this rapid detection of unwanted events,thus improving patient safety (i.e., withdrawal of treatment causing side effects)and augmenting treatment effectiveness(i.e., changing an ineffective treatment or dosage). In a time when smartphones are a mainstream technology, we shouldtake advantage of them in the promotion of health care

Neurocognitive Functioning and Suicidal Behavior in Violent Offenders with Schizophrenia Spectrum Disorders

Suicide is one of the main premature causes of death in patients with schizophrenia. However, little is known about the relationship between neurocognitive functioning and suicidality in violent offenders with schizophrenia who have been sentenced to psychiatric treatment after committing violent crimes. We examined the neurocognitive functioning of a sample of 61 violent offenders, most of them murderers with schizophrenia who were classified as suicide attempters (n = 26) and non-attempters (n = 35). We compared the neurocognitive functioning of both groups using a neuropsychological battery. Suicide attempters showed similar performance to non-attempters in a neuropsychological test across all domains of cognitive functioning, memory, attention, verbal fluency, and executive functioning. However, after controlling for demographic and clinical variables, suicide attempters performed better than non-attempters in two planning-related tasks: the Tower of London (p < 0.01) and the Zoo Map (p < 0.01). Suicide attempters were also characterized as having more family histories of suicidality and as displaying more depressive symptoms and negative symptoms of psychopathology on the Positive and Negative Syndrome Scale (PANSS) scale. These results suggest that suicide attempters have a greater ability to formulate plans and initiate goals directed at making a suicide attempt.This research was funded by Universidad de Alicante. Vicerrectorado de Investigación y Transferencia del Conocimiento. Proyectos Emergentes. Project number: GRE-19-17. Marcadores Neurocognitivos de Comportamientos Suicidas y Homicidio en delincuentes Violentos con Esquizofrenia

Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.Ministerio de Economía y CompetitividadInstituto de Salud Carlos II

EMMPRIN-targeted magnetic nanoparticles for In vivo visualization and regression of acute myocardial infarction.

Inhibition of extracellular matrix (ECM) degradation may represent a mechanism for cardiac protection against ischemia. Extracellular matrix metalloproteinase inducer (EMMPRIN) is highly expressed in response to acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including gelatinases MMP-2 and MMP-9. We targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles conjugated with the EMMPRIN binding peptide AP-9 (NAP9), or an AP-9 scrambled peptide as a negative control (NAPSC). We found that NAP9 binds to endogenous EMMPRIN in cultured HL1 myocytes and in mouse hearts subjected to ischemia/reperfusion (IR). Injection of NAP9 at the time of or one day after IR, was enough to reduce progression of myocardial cell death when compared to CONTROL and NAPSC injected mice (infarct size in NAP9 injected mice: 32%±6.59 vs 46%±9.04 or NAPSC injected mice: 48%±7.64). In the same way, cardiac parameters were recovered to almost healthy levels (LVEF NAP9 63% ± 7.24 vs CONTROL 42% ± 4.74 or NAPSC 39% ± 6.44), whereas ECM degradation was also reduced as shown by inhibition of MMP-2 and MMP-9 activation. Cardiac magnetic resonance (CMR) scans have shown a signal enhancement in the left ventricle of NAP9 injected mice with respect to non-injected, and to mice injected with NAPSC. A positive correlation between CMR enhancement and Evans-Blue/TTC staining of infarct size was calculated (R:0.65). Taken together, these results point to EMMPRIN targeted nanoparticles as a new approach to the mitigation of ischemic/reperfusion injury.Ministerio de Economía y CompetitividadInstituto de Salud Carlos II

Cryptococcus neoformans can form titan-like cells in vitro in response to multiple signals

Cryptococcus neoformans is an encapsulated pathogenic yeast that can change the size of the cells during infection. In particular, this process can occur by enlarging the size of the capsule without modifying the size of the cell body, or by increasing the diameter of the cell body, which is normally accompanied by an increase of the capsule too. This last process leads to the formation of cells of an abnormal enlarged size denominated titan cells. Previous works characterized titan cell formation during pulmonary infection but research on this topic has been hampered due to the difficulty to obtain them in vitro. In this work, we describe in vitro conditions (low nutrient, serum supplemented medium at neutral pH) that promote the transition from regular to titan-like cells. Moreover, addition of azide and static incubation of the cultures in a CO2 enriched atmosphere favored cellular enlargement. This transition occurred at low cell densities, suggesting that the process was regulated by quorum sensing molecules and it was independent of the cryptococcal serotype/species. Transition to titan-like cell was impaired by pharmacological inhibition of PKC signaling pathway. Analysis of the gene expression profile during the transition to titan-like cells showed overexpression of enzymes involved in carbohydrate metabolism, as well as proteins from the coatomer complex, and related to iron metabolism. Indeed, we observed that iron limitation also induced the formation of titan cells. Our gene expression analysis also revealed other elements involved in titan cell formation, such as calnexin, whose absence resulted in appearance of abnormal large cells even in regular rich media. In summary, our work provides a new alternative method to investigate titan cell formation devoid the bioethical problems that involve animal experimentation.OZ is funded by grant SAF2014-54336-R and SAF2017-86192-R1 from the Spanish Ministry for Economics, Industry and Competitivity. JA is funded by grants BFU2014-54591-C2-1-P and BFU2017-82574-P (Spanish Ministry for Economics, Industry and Competitivity) and an “Ajut 2014SGR-4” (Generalitat de Catalunya). NT-C was supported by a FPI fellowship (reference BES-2012-051837). SAR was supported by a fellowship from Coordenação de aperfeiçoamento de pessoal de nivel superior, CAPES, program Ciências Sem Fronteiras (202436/2015-2). HCdO is funded by postdoctoral fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-BEPE 2016/20631-3). RG-R is funded by a "Juan de la Cierva" Contract from the Spanish Ministry for Economics, Industry and Competitivity (reference: IJCI-2015-25683). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S