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The μ-opioid receptor (μOR) represents an important target of therapeutic and abused drugs. So far, most understanding of μOR activity has focused on a subset of known signal transducers and regulatory molecules. Yet μOR signaling is coordinated by additional proteins in the interaction network of the activated receptor, which have largely remained invisible given the lack of technologies to interrogate these networks systematically. Here we describe a proteomics and computational approach to map the proximal proteome of the activated μOR and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor (GPCR) activity. We demonstrate that distinct opioid agonists exert differences in the μOR proximal proteome mediated by endocytosis and endosomal sorting. Moreover, we identify two new μOR network components, EYA4 and KCTD12, which are recruited on the basis of receptor-triggered G-protein activation and might form a previously unrecognized buffering system for G-protein activity broadly modulating cellular GPCR signaling.

The increasing rates of biodiversity loss and global warming necessitate the implementation of conservation interventions with the highest likelihood of success, given limited resources. Using criteria within the Conservation Excellence Model, the authors comparatively analyzed the core conservation processes of 25 conservation programs in Southeast Asia and identified the factors that influenced program success. Eight key factors emerged: Stakeholder Involvement, Process Selection and Management, Activity and Impact Monitoring Systems, Measurable Goals and Objectives, Evidence-based Approach, Adaptability and Innovativeness, Political Will, and Sustainable Financing. The authors described a management approach that illustrates how identifying measurable goals and objectives enables program success. Additionally, the authors demonstrated the benefits of using both value and technical judgments in developing interventions, shifting from activity to impact monitoring, and integrating learning and innovation into interventions. The authors also found that programs can better overcome operational barriers and increase the likelihood of sustainable outcomes by deepening engagement with conservation partners.

Background: The 'flipped classroom' approach is an innovative approach in educational delivery systems. In a typical flipped class model, work that is typically done as homework in the didactic model is interactively undertaken in the class with the guidance of the teacher, whereas listening to a lecture or watching course-related videos is undertaken at home. The essence of a flipped classroom is that the activities carried out during traditional class time and self-study time are reversed or 'flipped'. Objectives: The primary objectives of this review were to assess the effectiveness of the flipped classroom intervention for undergraduate health professional students on their academic performance, and their course satisfaction. Search Methods: We identified relevant studies by searching MEDLINE (Ovid), APA PsycINFO, Education Resources Information Center (ERIC) as well as several more electronic databases, registries, search engines, websites, and online directories. The last search update was performed in April 2022. Selection Criteria: Included studies had to meet the following criteria: Participants: Undergraduate health professional students, regardless of the type of healthcare streams (e.g., medicine, pharmacy), duration of the learning activity, or the country of study. Intervention: We included any educational intervention that included the flipped classroom as a teaching and learning tool in undergraduate programs, regardless of the type of healthcare streams (e.g., medicine, pharmacy). We also included studies that aimed to improve student learning and/or student satisfaction if they included the flipped classroom for undergraduate students. We excluded studies on standard lectures and subsequent tutorial formats. We also excluded studies on flipped classroom methods, which did not belong to the health professional education(HPE) sector (e.g., engineering, economics). Outcomes: The included studies used primary outcomes such as academic performance as judged by final examination grades/scores or other formal assessment methods at the immediate post-test, as well as student satisfaction with the method of learning. Study design: We included randomised controlled trials (RCTs), quasi-experimental studies (QES), and two-group comparison designs. Although we had planned to include cluster-level RCTs, natural experiments, and regression discontinuity designs, these were not available. We did not include qualitative research. Data Collection and Analysis: Two members of the review team independently screened the search results to assess articles for their eligibility for inclusion. The screening involved an initial screening of the title and abstracts, and subsequently, the full text of selected articles. Discrepancies between the two investigators were settled through discussion or consultation with a third author. Two members of the review team then extracted the descriptions and data from the included studies. Main Results: We found 5873 potentially relevant records, of which we screened 118 of them in full text, and included 45 studies (11 RCTs, 19 QES, and 15 two-group observational studies) that met the inclusion criteria. Some studies assessed more than one outcome. We included 44 studies on academic performance and eight studies on students' satisfaction outcomes in the meta-analysis. The main reasons for excluding studies were that they had not implemented a flipped class approach or the participants were not undergraduate students in health professional education. A total of 8426 undergraduate students were included in 45 studies that were identified for this analysis. The majority of the studies were conducted by students from medical schools (53.3%, 24/45), nursing schools (17.8%, 8/45), pharmacy schools (15.6%, 7/45). medical, nursing, and dentistry schools (2.2%, 1/45), and other health professional education programs (11.1%, 5/45). Among these 45 studies identified, 16 (35.6%) were conducted in the United States, six studies in China, four studies in Taiwan, three in India, two studies each in Australia and Canada, followed by nine single studies from Brazil, German, Iran, Norway, South Korea, Spain, the United Kingdom, Saudi Arabia, and Turkey. Based on overall average effect sizes, there was better academic performance in the flipped class method of learning compared to traditional class learning (standardised mean difference [SMD] = 0.57, 95% confidence interval [CI] = 0.25 to 0.90, [tau][superscript 2]: 1.16; I[superscript 2]: 98%; p < 0.00001, 44 studies, n = 7813). In a sensitivity analysis that excluded eleven studies with imputed data from the original analysis of 44 studies, academic performance in the flipped class method of learning was better than traditional class learning (SMD = 0.54, 95% CI = 0.24 to 0.85, [tau][superscript 2]: 0.76; I[superscript 2]: 97%; p < 0.00001, 33 studies, n = 5924); all being low certainty of evidence. Overall, student satisfaction with flipped class learning was positive compared to traditional class learning (SMD = 0.48, 95% CI = 0.15 to 0.82, [tau][superscript 2]: 0.19, I[superscript 2]:89%, p < 0.00001, 8 studies n = 1696); all being low certainty of evidence. Authors' Conclusions: In this review, we aimed to find evidence of the flipped classroom intervention's effectiveness for undergraduate health professional students. We found only a few RCTs, and the risk of bias in the included non-randomised studies was high. Overall, implementing flipped classes may improve academic performance, and may support student satisfaction in undergraduate health professional programs. However, the certainty of evidence was low for both academic performance and students' satisfaction with the flipped method of learning compared to the traditional class learning. Future well-designed sufficiently powered RCTs with low risk of bias that report according to the CONSORT guidelines are needed. [For the protocol, see EJ1267406.]

[This corrects the article DOI: 10.1371/journal.pone.0230802.].

Targeted mass primaquine treatment (TPT) might be an effective intervention to facilitate elimination of vivax malaria in Myanmar by 2030. In this study, we explored the factors hindering coverage of a TPT campaign conducted in a malarious township of northern Myanmar. From August 2019 to July 2020, a cross-sectional exploratory design including quantitative and qualitative data was conducted in five villages with high P. vivax prevalence following a TPT campaign. Among a targeted population of 2322; 1973 (85.0%) participated in the baseline mass blood survey (MBS) and only 52.0% of the total targeted population (1208, 91.9% of total eligible population) completed the TPT. G6PD deficiency was found among 13.5% of total MBS participants and those were excluded from TPT. Of 1315 eligible samples, farmers and gold miners, males, and those aged 15 to 45 years had higher percentages of non-participation in TPT. Qualitative findings showed that most of the non-participation groups were outside the villages during TPT because of time-sensitive agricultural and other occupational or education-related purposes. In addition to mitigating of some inclusion criteria (i.e. including young children or offering weekly PQ treatment to G6PD deficient individuals), strengthening community awareness and increasing engagement should be pursued to increase community participation.

BackgroundTargeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.MethodsThe open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.ResultsThe most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained.ConclusionsEpacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect.Clinical trial informationA study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).

BackgroundMyanmar bears the heaviest malaria burden in the Greater Mekong Subregion (GMS). This study assessed the spatio-temporal dynamics and environmental predictors of Plasmodium falciparum and Plasmodium vivax malaria in Myanmar.MethodsMonthly reports of malaria cases at primary health centers during 2011-2017 were analyzed to describe malaria distribution across Myanmar at the township and state/region levels by spatial autocorrelation (Moran index) and spatio-temporal clustering. Negative binomial generalized additive models identified environmental predictors for falciparum and vivax malaria, respectively.ResultsFrom 2011 to 2017, there was an apparent reduction in malaria incidence in Myanmar. Malaria incidence peaked in June each year. There were significant spatial autocorrelation and clustering with extreme spatial heterogeneity in malaria cases and test positivity across the nation (P

Nonhuman primates living in proximity to humans increase risks for sylvatic arbovirus transmission. We collected serum samples from nonhuman primates in Hlawga National Park near Yangon, Myanmar, and detected antibodies against chikungunya (33%) and Japanese encephalitis (4%) viruses. Buffer zones between primate and human communities might reduce cross-species arbovirus transmission.

BackgroundAntithyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of thyrotoxicosis. Agranulocytosis is a rare but lethal adverse effect of antithyroid medications. We have reported 2 cases of MMI-induced agranulocytosis with similar risk factors that likely predisposed them to this adverse reaction.Case reportCase 1 involved a 71-year-old woman, with a history of Graves disease, who presented with an altered mental status. She was recently discharged on 40 mg of MMI twice daily, and she continued this dose for 2 months. She was readmitted and found to have neutropenic fever in the setting of MMI-induced agranulocytosis. MMI was discontinued, and she was started on filgrastim. Her cell counts gradually improved, and she was subsequently discharged.Case 2 involved a 68-year-old woman, with a history of Graves disease, who presented with severe back pain, nausea, and vomiting. She was recently discharged on 10 mg of MMI twice daily, which was increased to 10 mg 3 times a day. She was readmitted to the hospital because of a septic shock in the setting of pneumonia, colitis, bacteremia, and MMI-induced agranulocytosis. A bone marrow biopsy showed a polyclonal infiltrate with up to 85% plasma cells. Despite treatment with antibiotics, filgrastim, and continuous renal replacement therapy, she ultimately passed away.DiscussionAlthough these cases had differing outcomes, they shared similar features and risk factors, including older age, female sex, and relatively higher doses of MMI.ConclusionClose follow up and awareness of risk factors, such as age, female sex, and higher doses of MMI, may decrease the risk of MMI-induced agranulocytosis and fatal outcomes.

Artificial Intelligence (AI) has the power to improve our lives through a wide variety of applications, many of which fall into the healthcare space; however, a lack of diversity is contributing to limitations in how broadly AI can help people. The UCSF AI4ALL program was established in 2019 to address this issue by targeting high school students from underrepresented backgrounds in AI, giving them a chance to learn about AI with a focus on biomedicine, and promoting diversity and inclusion. In 2020, the UCSF AI4ALL three-week program was held entirely online due to the COVID-19 pandemic. Thus, students participated virtually to gain experience with AI, interact with diverse role models in AI, and learn about advancing health through AI. Specifically, they attended lectures in coding and AI, received an in-depth research experience through hands-on projects exploring COVID-19, and engaged in mentoring and personal development sessions with faculty, researchers, industry professionals, and undergraduate and graduate students, many of whom were women and from underrepresented racial and ethnic backgrounds. At the conclusion of the program, the students presented the results of their research projects at the final symposium. Comparison of pre- and post-program survey responses from students demonstrated that after the program, significantly more students were familiar with how to work with data and to evaluate and apply machine learning algorithms. There were also nominally significant increases in the students' knowing people in AI from historically underrepresented groups, feeling confident in discussing AI, and being aware of careers in AI. We found that we were able to engage young students in AI via our online training program and nurture greater diversity in AI. This work can guide AI training programs aspiring to engage and educate students entirely online, and motivate people in AI to strive towards increasing diversity and inclusion in this field.

Background and Aims: Interprofessional Education (IPE) is a vital academic blueprint for preparing future doctors to provide patient-centered collaborative approach to care best integrated health services. This study aimed to evaluate the awareness and readiness of Malaysian medical students towards interprofessional education. Materials and methods: A cross-sectional study carried out using a questionnaire survey: The Readiness of Interprofessional Learning Scale (RIPLS). A convenience sampling method was employed. The sample was drawn from undergraduate students enrolled in year 1 to 5 of medical program in two medical universities. Descriptive and inferential statistics were used to analyze the data. Results: The RIPLS was completed by 361 medical students who valued the importance of IPE. The students mentioned that shared learning with other healthcare professional students will increase their ability to understand clinical problems. The students also specified that team-working skills are essential for all healthcare students to learn. However, there were differences between students of different years of study in their perception and readiness toward IPE. Conclusion: Our findings indicate that undergraduate-health-care students have high perception and readiness towards IPE, however important differences in baseline readiness emerged according to year-level. These findings suggest that educators consider baseline attitudes of students when designing interprofessional education curricula. The implication of this awareness and readiness to practice IPL will create a more concert and harmony workspace to the healthcare professionals.

BackgroundRadical cure of the Plasmodium vivax latent liver stage is required to effectively manage vivax malaria. Targeted mass treatment with primaquine may be an effective mechanism for reducing reservoirs of the disease. Since community engagement and high coverage are essential for mass treatment programs, this study aimed to determine the acceptability of mass primaquine treatment in a targeted community in a northern Myanmar township.MethodsA cross-sectional mixed-methods study was deployed among household leaders in July 2019. Face-to-face interviews using structured questionnaires and standardized qualitative guidelines were conducted to gather information. Descriptive and inferential statistics, including logistic regression models, were applied.ResultsAmong 609 study respondents, > 90% agreed to participate in an upcoming targeted mass primaquine treatment (TPT) program. Factors contributing to higher odds of acceptability of the program were older age [adjusted odds ratios (aOR): 2.38, 95% confidence intervals (CI) 1.08-8.96], secondary education level (aOR: 3.99, 95% CI 1.12-20.01), having good knowledge of malaria (aOR: 2.12, 95% CI 1.04-4.76), experiencing malaria within the family (aOR: 1.92, 95% CI 1.14-5.13), and believing eliminating malaria from the village is possible (aOR: 2.83, 95% CI 1.07-4.07). Furthermore, 50 community respondents, 6 midwives, and 4 public health staff (grade II) participated in the qualitative component of the study. Many thought that TPT seemed feasible and stressed that high coverage of underserved groups and health education are needed before commencing the activity.ConclusionsMost respondents agreed to participate in the proposed mass treatment campaign. Older people with secondary education level and those who had experienced malaria within their families were most likely to report willingness to participate. These same individuals may be important in the community engagement process to increase community acceptance of the program.