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Opioids are widely prescribed for pain management, and it is estimated that 40% of adults in the United States use prescription opioids every year. Opioid misuse leads to high mortality, with respiratory depression as the main cause of death. Animal and human studies indicate that opioid use may lead to sleep-disordered breathing. Opioids affect control of breathing and impair upper airway function, causing central apneas, upper airway obstruction, and hypoxemia during sleep. The presence of obstructive sleep apnea (OSA) increases the risk of opioid-induced respiratory depression. However, even if the relationship between opioids and central sleep apnea is firmly established, the question of whether opioids can aggravate OSA remains unanswered. While several reports have shown a high prevalence of OSA and nocturnal hypoxemia in patients receiving a high dose of opioids, other studies did not find a correlation between opioid use and obstructive events. These differences can be attributed to considerable interindividual variability, divergent effects of opioids on different phenotypic traits of OSA, and wide-ranging methodology. This review will discuss mechanistic insights into the effects of opioids on the upper airway and hypoglossal motor activity and the association of opioid use and obstructive sleep apnea. CITATION: Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647–652.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPRb, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPRb positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the NTS of Leprb-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPRb positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPRb signaling in the NTS.

Rationale: North America is currently facing an opioid epidemics. Over 130 Americans die every day from an opioid overdose and the COVID-19 pandemic has increased opioid usage and opioid-related deaths. Respiratory depression is the main cause of morbidity and mortality from opioids. We have previously shown that leptin acts as respiratory stimulant and prevents opioid-induced respiratory depression and upper airway obstruction without reducing analgesia. In this study, we aimed to examine if intranasal (IN) administration of leptin effectively delivers leptin to the brain and prevents opioid-related deaths. Methods: To determine leptin delivery to the brain male C57BL/6J mice, were treated with IN leptin at 1.2 mg/kg in 1% BSA (n=5) or 1% BSA (n=5) and sacrificed 20 min later. Brains were harvested, the olfactory bulbs, medullas and hypotalami were isolated, quick frozen and stored at-80°C. For leptin level measurements, brain tissue was homogenized, protease inhibitors and protein concentrations were determined and ELISA was performed. To determine the survival probability, male C57BL/6J mice, 12 weeks of age, received IN leptin (n=26) or vehicle (n=25) at 1.2 mg/kg and 30 minutes later received a bolus of intraperitoneal (IP) morphine at 400mg/kg. Mice were video monitored for 24 hours and survival time after morphine injection was recorded Results: IN leptin significantly increased leptin levels in the olfactory bulb (from 0 ng/mL to 7.53 ng/mL, p = 0.004) and medulla (from 0.008 ng/mL to 0.107 ng/mL) and presented a trend in the hypothalamus (from 0.018 ng/mL to 0.291 ng/mL, p = 0.1). Mice that received IN leptin had a higher survival rate when compared to mice that received vehicle (69% vs 92%, p = 0.044, Figure). Conclusion: We demonstrated that the intranasal route is effective for the delivery of leptin to the brain and that leptin reduced opioid-induced mortality. (Table Presented).

The use of the Internet and social networks have increased dramatically during the COVID quarantine mainly because several activities were moved online. In education, numerous stakeholders stayed at home and their academic plans were modified and adapted to an entire virtual environment. This was the case of a live event (Science Cafe) whose purpose was to disseminate knowledge through Facebook and YouTube. Thus, this study aimed at verifying if there was knowledge construction in social networks through user interactions by using 1,083 comments posted by the audience. Comments were coded according to validated frameworks for language taxonomy and collaborative knowledge construction. Results show that the predominant interaction is that in which viewers pose questions to speakers. Our analyses also revealed that attendees hardly reached the highest levels of knowledge construction through unguided interaction. Often, user interactions went beyond emotional expressions towards evaluation and therefore, could reach a higher level of knowledge construction. This study shows that social networks may offer informal spaces for deliberation and collaborative interaction with the potential to support learning if guided properly. This research aims to contribute empirical evidence to the growing body of literature that online interactions in informal environments may provide productive learning.

We live in a changing world, where the role of educational institutions is being transformed. The available technologies allow new conditions to access learning; however, as they evolve very fast, sometimes it is challenging to track this evolution regarding the changes that entail to all of us, which may contribute to a digital divide if it is not well addressed. This chapter intends to present distance education as a reliable modality to include students in higher education. For that, it presents the universal design for learning and its crucial role to make inclusive virtual learning environments. Like every modality that exists, there are some challenges that need to be addressed, as well as some benefits that allow to see the potential of this modality to learning, overcoming some adversities that may occur, like the lack of time to go to face-to-face education or even the need of social isolation by risk of getting a disease. info:eu-repo/semantics/publishedVersion

Study Objectives Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. Methods We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. Results Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. Conclusion Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.

Obesity can lead to recurrent upper airway obstruction (obstructive sleep apnea, OSA) during sleep as well as alveolar hypoventilation. We have previously shown that leptin stimulates breathing and treats OSA in leptin-deficientob/obmice and leptin-resistant diet-induced obese mice. Our previous data also suggest that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We selectively expressed leptin receptorLepRbin the DMH neurons of obeseLepRb-deficientdb/dbmice (LepRb-DMH mice), which hypoventilate at baseline, and showed that intracerebroventricular injection of leptin in these animals increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2production. Leptin had no effect on upper airway obstruction inLepRb-DMHanimals. We conclude that leptin stimulates breathing and treats obesity related hypoventilation acting on LepRb-positive neurons in the DMH.

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the μ-opioid receptor agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.

Introduction Obstructive sleep apnea (OSA) is characterized by recurrent periods of upper airway obstruction. The prevalence of OSA exceeds 50% in obese individuals and in 10–20% of obese patients OSA coexists with obesity hypoventilation syndrome (OHS) defined as daytime hypercapnia and hypoventilation during sleep attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Leptin is a potent respiratory stimulant and a potential therapeutic candidate. However, diet-induced obesity (DIO) results in reduced permeability of the blood-brain barrier (BBB) for leptin. Previous studies have shown that the BBB can be penetrated by exosomes, natural nanoparticles that can be used as drug delivery vehicles. In this study, we aimed to determine if exosomes overcome the BBB and treat OSA and OHS in DIO mice. Methods o examine the ability of exosomes to cross the BBB, male, lean (n=5) and DIO (n=5) C57BL/6J mice were injected with fluorescent exosomes or saline into the lateral tail vein. After 4h fluorescent exosomes biodistribution was evaluated by an in vitro imaging system (IVIS). Saline injected mice images were used for background adjustment. A separate subgroup of male, DIO (n=10) and lean (n=10) mice were headmounted with EEG and nuchal EMG leads. Sleep studies were performed in a plethysmography chamber and mice received saline, empty exosomes, free leptin, or leptin-loaded exosomes in a crossover manner. Results Exosomes were successfully delivered to the brain and the transport across the BBB was more efficient in DIO mice with 2-times greater relative fluorescence units measured in DIO when compared to lean mice (p Conclusion We demonstrated that exosomes overcome the BBB and that leptin-loaded exosomes treat OSA and OHS in DIO mice. Support (if any) R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301, FAPESP 2018/08758-3

The present disclosure generally relates to compositions and methods of treating opioid-induced respiratory depression in a subject in need thereof, the method comprising administering leptin.

Obstructive Sleep Apnea (OSA) is a prevalent condition and a major cause of morbidity and mortality in Western Society. The loss of motor input to the tongue and specifically to the genioglossus muscle during sleep is associated with pharyngeal collapsibility and the development of OSA. We applied a novel chemogenetic method to develop a mouse model of sleep disordered breathing Our goal was to reversibly silence neuromotor input to the genioglossal muscle using an adeno-associated viral vector carrying inhibitory designer receptors exclusively activated by designer drugs AAV5-hM4Di-mCherry (DREADD), which was delivered bilaterally to the hypoglossal nucleus in fifteen C57BL/6J mice. In the in vivo experiment, 4 weeks after the viral administration mice were injected with a DREADD ligand clozapine-N-oxide (CNO, i.p., 1mg/kg) or saline followed by a sleep study; a week later treatments were alternated and a second sleep study was performed. Inspiratory flow limitation was recognized by the presence of a plateau in mid-respiratory flow; oxyhemoglobin desaturations were defined as desaturations >4% from baseline. In the in vitro electrophysiology experiment, four males and three females of 5 days of age were used. Sixteen–nineteen days after DREADD injection brain slices of medulla were prepared and individual hypoglossal motoneurons were recorded before and after CNO application. Positive mCherry staining was detected in the hypoglossal nucleus in all mice confirming successful targeting. In sleep studies, CNO markedly increased the frequency of flow limitation n NREM sleep (from 1.9 ± 1.3% after vehicle injection to 14.2 ± 3.4% after CNO, p < 0.05) and REM sleep (from 22.3% ± 4.1% to 30.9 ± 4.6%, respectively, p < 0.05) compared to saline treatment, but there was no significant oxyhemoglobin desaturation or sleep fragmentation. Electrophysiology recording in brain slices showed that CNO inhibited firing frequency of DREADD-containing hypoglossal motoneurons. We conclude that chemogenetic approach allows to silence hypoglossal motoneurons in mice, which leads to sleep disordered breathing manifested by inspiratory flow limitation during NREM and REM sleep without oxyhemoglobin desaturation or sleep fragmentation. Other co-morbid factors, such as compromised upper airway anatomy, may be needed to achieve recurrent pharyngeal obstruction observed in OSA.

The main aim of this study is to explore the underlying factors of the subordinate-supervisor trust relationship and to analyze its impact on the three components of organizational commitment. Data was collected from 192 R&D professionals working at 10 different ICT Portuguese industrial companies. The study confirms the three factors of integrity, benevolence and ability as the basis for the perceived trustworthiness of supervisors by subordinates. In addition, results show that the trust a team member places on his/her leader depends predominantly on his/her perception of integrity. The authors conclude that even in the technological field, where the prevalence of a technical competence-based trust relationship was expected, integrity emerged as important element in the subordinate's trust of his/her supervisor. Integrity was found to correlate significantly with affective, normative and calculative commitment. The authors' findings suggest that organizations can “manage” commitment in ICT industrial enterprises through fostering the perception of integrity by subordinates.

Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent closure of the upper airway during sleep. It has a complex pathophysiology involving four main phenotypes. An abnormal upper airway anatomy is the key factor that predisposes to sleep-related collapse of the pharynx, but it may not be sufficient for OSA development. Non-anatomical traits, including (1) a compromised neuromuscular response of the upper airway to obstruction, (2) an unstable respiratory control (high loop gain), and (3) a low arousal threshold, predict the development of OSA in association with anatomical abnormalities. Current therapies for OSA, such as continuous positive airway pressure (CPAP) and oral appliances, have poor adherence or variable efficacy among patients. The search for novel therapeutic approaches for OSA, including pharmacological agents, has been pursued over the past years. New insights into OSA pharmacotherapy have been provided by preclinical studies, which highlight the importance of appropriate use of animal models of OSA, their applicability, and limitations. In the present review, we discuss potential pharmacological targets for OSA discovered using animal models.

The main purpose of this study is to understand the demographic, personal and situational determining factors leading to academic misconduct among undergraduate students by comparatively analyzing the differences among Economics and Business students and other major students. Two thousand four hundred ninety-two undergraduate students from different Portuguese Public Universities answered a questionnaire regarding their propensity to commit academic fraud, 640 of whom were Economics and Business students. Results concluded that Economics and Business students can be distinguished from others regarding the likelihood of copying from the other Major students. Younger students admit more readily to the possibility of cheating than older students. Results indicate a greater probability of acceptance of dishonest practices outside the area of Economics and Management and a greater probability of condemnation of improper practices by students of Economics and Management. This indicates that students of Economics and Management are aware that their behavior is incorrect and unacceptable; peer-pressure and the learning process itself constitute the main justifications provided by Economics and Business students for their fraudulent actions. Implications for this practice are discussed.

The Bologna Declaration imposed significant changes in European higher education , placing emphasis on teaching methods that promote students’ active learning and the development of skills , including both the skills that are specific to the academic qualification area and the ones that became known as transferable skills . The latter have been considered to be fundamental to the promotion of graduate employability. This chapter presents the specific case of the Transferable Skills Development Programme of a Portuguese public university and analyses the perceptions of 21 graduate students , in the area of Economics and Management , regarding its relevance and contribution to the development of transferable skills. Through the completion of qualitative questionnaires and the interaction established within three focus groups, the respondents acknowledged the innovative profile of the programme in the Portuguese university context and its contribution to the development of transferable competencies, which they believed to be especially relevant to their future job performance . The graduate students involved considered that the Transferable Skills Development Programme should continue to reinforce its commitment to activities and contents which were markedly more practical.

Objective: 1) Evaluate the prevalence of asymmetry of the nasal base in the general population. 2) Quantify among the individuals who carried nasal base asymmetry how many were aware of the fact.Method: Photos of the nasal base of 43 volunteers chosen randomly were taken using a macro lens. Individuals were classified as carriers or noncarriers of nasal base asymmetry. When any asymmetry was present, the image was shown to the carrier, asking whether they were aware or not of the asymmetry.Results: Forty-three individuals between 13 and 70 years old were photographed (16 male and 27 female). The mean age was 43.11 years. Nineteen (44.19%) individuals showed some asymmetry of the nasal basal view. Of these, only 4 (21.05%) individuals were aware of their deformity.Conclusion: Nasal base asymmetry is a prevalent deformity. Most of the individuals (78.95%) are unaware of it. It can generate controversy if the cause of the deformity was or was not a result of surgery. Nasal base asymmetries should always be p...

Patient-Centered Design (PCD) is a particular type of User-Centered Design (UCD), where the end-user is a patient that will use an Information and Communications Technology (ICT) solution for healthcare. It focuses on needs, wants, and skills of the product's primary user and implies involving end-users in the decision-making and development process of the solution. e-Therapy aims to provide support to therapy sessions through ICT solutions. It has grown in the last years, and in the mental health arena is being used for specific therapeutic contexts. It is an especially difficult environment due to specificities of the patients' conditions and the physical access to patients being restricted and, sometimes, not even possible. Thus, a PCD approach can be accomplished through the health professionals involved, applying some of the most well known methods of UCD: interviews, questionnaires, focus groups, and participatory design. eSchi is an e-Therapy tool that complements traditional practices for the cognitive rehabilitation and training of schizophrenic patients. It was successfully developed using a PCD approach.