Structure of the human 20S U5 snRNP.

The 20S U5 small nuclear ribonucleoprotein particle (snRNP) is a 17-subunit RNA-protein complex and a precursor of the U4/U6.U5 tri-snRNP, the major building block of the precatalytic spliceosome. CD2BP2 is a hallmark protein of the 20S U5 snRNP, absent from the mature tri-snRNP. Here we report a high-resolution cryogenic electron microscopy structure of the 20S U5 snRNP, shedding light on the mutually exclusive interfaces utilized during tri-snRNP assembly and the role of the CD2BP2 in facilitating this process.

CEBPA Overexpression Enhances ß-Cell Proliferation and Survival.

A commonality between type 1 and type 2 diabetes is the decline in functional ß-cell mass. The transcription factor Nkx6.1 regulates ß-cell development and is integral for proper ß-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase ß-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 ß-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of ß-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional ß-cell mass by increasing ß-cell proliferation and modulating the unfolded protein response.

Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere.

Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin proteins matching, by molecular weight, the gene sequence predictions were detected in the majority of the TTNtv+ samples. Full-length titin was reduced in TTNtv+ compared with TTNtv- samples. Proteomics analysis of washed myofibrils and stimulated emission depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin was structurally integrated into the sarcomere. Sarcomere length-dependent anti-titin epitope position, shape, and intensity analyses pointed at possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.

An augmented reality-based method to assess precordial electrocardiogram leads: a feasibility trial.

Aims: It has been demonstrated that several cardiac pathologies, including myocardial ischaemia, can be detected using smartwatch electrocardiograms (ECGs). Correct placement of bipolar chest leads remains a major challenge in the outpatient population. Methods and results: In this feasibility trial, we propose an augmented reality-based smartphone app that guides the user to place the smartwatch in predefined positions on the chest using the front camera of a smartphone. A machine-learning model using MobileNet_v2 as the backbone was trained to detect the bipolar lead positions V1-V6 and visually project them onto the user's chest. Following the smartwatch recordings, a conventional 10 s, 12-lead ECG was recorded for comparison purposes. All 50 patients participating in the study were able to conduct a 9-lead smartwatch ECG using the app and assistance from the study team. Twelve patients were able to record all the limb and chest leads using the app without additional support. Bipolar chest leads recorded with smartwatch ECGs were assigned to standard unipolar Wilson leads by blinded cardiologists based on visual characteristics. In every lead, at least 86% of the ECGs were assigned correctly, indicating the remarkable similarity of the smartwatch to standard ECG recordings. Conclusion: We have introduced an augmented reality-based method to independently record multichannel smartwatch ECGs in an outpatient setting.

A Critical Appraisal of Clinicopathological, Imaging, and GeneXpert Profiles of Surgical Referrals with Pediatric Abdominal Tuberculosis.

Aim: To study the clinicopathological, imaging, and GeneXpert profiles of surgical referrals with abdominal tuberculosis (TB) and to compare the utility of GeneXpert versus conventional diagnostic armamentarium. Materials and Methods: This cohort study which was conducted over a study period of 8 years (2011-18) included seventy-seven children operated with a provisional diagnosis of abdominal TB and those who had either histological (n = 58; 75.3%) or GeneXpert (n = 9) confirmation or had miliary tubercles on exploration with supportive clinical and imaging findings (n = 17; 22.1%). GeneXpert testing was added to the diagnostic armamentarium only in the latter half of the study (2016-18, n = 31). Demographic details, symptomatology, prior antitubercular treatment, GeneXpert positivity, imaging, operative, and histological findings were recorded and analyzed using mean, standard deviation, and range for continuous variables and proportion for categorical variables. Results: Perforation peritonitis (n = 26; 33.8%) and unrelieved obstruction (n = 51; 66.2%) were the main surgical indications. The mean age at presentation was 9.5 ± 3.6 years with a distinct female preponderance. The presence of right lower abdomen lump (n = 23; 29.9%), alternate diarrhea and constipation (n = 34; 44.1%), tubercular toxemia (n = 38; 49.4%), positive history of contact (n = 20; 25.9%), tuberculin positivity (n = 38; 49.4%), fibrocavitary pulmonary lesion (5.2%), clumped bowel loops with pulled-up cecum (n = 23; 29.9%), septated ascites (n = 17), mesenteric lymphadenopathy and omental thickening (n:18; 23.4% each) were the supportive tell-tale signs of the disease. The hallmark of pathological diagnosis was caseous necrosis with epithelioid granulomas (n = 43; 55.8%), nongranulomatous caseation (n = 15; 19.5%), and acid-fast bacilli positivity in 27.3% of patients. GeneXpert was positive in only nine patients with an overall sensitivity of 29% as compared to 75.3% for histopathology. Conclusion: Bacteriological and histological confirmation of the disease eluded us in a significant proportion of patients, requiring a very high index of clinical suspicion to clinch the diagnosis. The current version of GeneXpert has low sensitivity in diagnosing pediatric abdominal TB.

Surveillance of Enterobacter cloacae complex colonization and comparative analysis of different typing methods on a neonatal intensive care unit in Germany.

BACKGROUND: Enterobacter cloacae complex is a group of common opportunistic pathogens on neonatal intensive care units. Active microbiological screening to guide empirical antimicrobial treatment or to detect transmission events is recommended in high-risk preterm neonates. A rise in colonization with E. cloacae complex was observed in a German perinatal centre. The aim of this study was to evaluate the performance of different typing techniques using whole genome sequencing (WGS) as a reference. METHODS: Enterobacter cloacae complex isolates from clinical and screening specimens with an epidemiological link to the neonatal intensive care units were further assessed. Identification and antibiotic susceptibility testing was performed by a combination of VITEK2 (bioMérieux) and MALDI-TOF (Bruker Daltonics), followed by RAPD/rep-PCR and PFGE (XbaI). Retrospectively, all isolates were analyzed by Fourier-transform infrared (FTIR) spectroscopy (IR Biotyper, Bruker Daltonics). Whole genome sequencing with SNP-based clustering was used as the reference method. Furthermore, resistome analysis, sequence type and species identification were derived from the WGS data. Transmission analysis was based on epidemiological and typing data. RESULTS: Between September 2017 and March 2018 32 mostly preterm neonates were found to be colonized with E. cloacae complex and 32 isolates from 24 patients were available for further typing. RAPD/rep-PCR and PFGE showed good concordance with WGS whereas FTIR displayed mediocre results [adjusted rand index (ARI) = 0.436]. A polyclonal increase and two dominant and overlapping clonal clusters of two different E. hormaechei subspecies were detected. Overall, four different species were identified. Genotyping confirmed third-generation cephalosporin resistance development in isolates of the same patient. During the six-month period several infection prevention interventions were performed and no E. cloacae complex isolates were observed during the following months. CONCLUSIONS: Interpretation of the microbiological results alone to detect transmission events is often challenging and bacterial typing is of utmost importance to implement targeted infection control measures in an epidemic occurrence of E. cloacae complex. WGS is the most discriminatory method. However, traditional methods such as PFGE or RAPD/rep-PCR can provide reliable and quicker results in many settings. Furthermore, research is needed to quickly identify E. cloacae complex to the species level in the microbiological laboratory.

A Novel Diagnostic Decision Support System for Medical Professionals: Prospective Feasibility Study.

BACKGROUND: Continuously growing medical knowledge and the increasing amount of data make it difficult for medical professionals to keep track of all new information and to place it in the context of existing information. A variety of digital technologies and artificial intelligence-based methods are currently available as persuasive tools to empower physicians in clinical decision-making and improve health care quality. A novel diagnostic decision support system (DDSS) prototype developed by Ada Health GmbH with a focus on traceability, transparency, and usability will be examined more closely in this study. OBJECTIVE: The aim of this study is to test the feasibility and functionality of a novel DDSS prototype, exploring its potential and performance in identifying the underlying cause of acute dyspnea in patients at the University Hospital Basel. METHODS: A prospective, observational feasibility study was conducted at the emergency department (ED) and internal medicine ward of the University Hospital Basel, Switzerland. A convenience sample of 20 adult patients admitted to the ED with dyspnea as the chief complaint and a high probability of inpatient admission was selected. A study physician followed the patients admitted to the ED throughout the hospitalization without interfering with the routine clinical work. Routinely collected health-related personal data from these patients were entered into the DDSS prototype. The DDSS prototype's resulting disease probability list was compared with the gold-standard main diagnosis provided by the treating physician. RESULTS: The DDSS presented information with high clarity and had a user-friendly, novel, and transparent interface. The DDSS prototype was not perfectly suited for the ED as case entry was time-consuming (1.5-2 hours per case). It provided accurate decision support in the clinical inpatient setting (average of cases in which the correct diagnosis was the first diagnosis listed: 6/20, 30%, SD 2.10%; average of cases in which the correct diagnosis was listed as one of the top 3: 11/20, 55%, SD 2.39%; average of cases in which the correct diagnosis was listed as one of the top 5: 14/20, 70%, SD 2.26%) in patients with dyspnea as the main presenting complaint. CONCLUSIONS: The study of the feasibility and functionality of the tool was successful, with some limitations. Used in the right place, the DDSS has the potential to support physicians in their decision-making process by showing new pathways and unintentionally ignored diagnoses. The DDSS prototype had some limitations regarding the process of data input, diagnostic accuracy, and completeness of the integrated medical knowledge. The results of this study provide a basis for the tool's further development. In addition, future studies should be conducted with the aim to overcome the current limitations of the tool and study design. TRIAL REGISTRATION: ClinicalTrials.gov NCT04827342; https://clinicaltrials.gov/ct2/show/NCT04827342.

DNA methylation in blood cells is associated with cortisol levels in offspring of mothers who had prenatal post-traumatic stress disorder.

Maternal stress during pregnancy is associated with differential DNA methylation in offspring and disrupted cortisol secretion. This study aimed to determine methylation signatures of cortisol levels in children, and whether associations differ based on maternal post-traumatic stress disorder (PTSD). Blood epigenome-wide methylation and fasting cortisol levels were measured in 118 offspring of mothers recruited from the Kosovo Rehabilitation Centre for Torture Victims. Mothers underwent clinically administered assessment for PTSD using Diagnostic and Statistical Manual of Mental Disorders. Correlations between offspring methylation and cortisol levels were examined using epigenome-wide analysis, adjusting for covariates. Subsequent analysis focussed on a priori selected genes involved in the hypothalamic-pituitary-adrenal (HPA) axis stress signalling. Methylation at four sites were correlated with cortisol levels (cg15321696, r = -0.33, cg18105800, r = +0.33, cg00986889, r = -0.25, and cg15920527, r = -0.27). In adjusted multivariable regression, when stratifying based on prenatal PTSD status, significant associations were only found for children born to mothers with prenatal PTSD (p < 0.001). Several sites within HPA axis genes were also associated with cortisol levels in the maternal PTSD group specifically. There is evidence that methylation is associated with cortisol levels, particularly in offspring born to mothers with prenatal PTSD. However, larger studies need to be carried out to independently validate these findings.

A comprehensive review of dye-sensitized solar cell optimal fabrication conditions, natural dye selection, and application-based future perspectives.

Dye-sensitized solar cells (DSSC) constructed using natural dyes possess irreplaceable advantages in energy applications. The main reasons are its performance, environmentally benign dyes, impressible performance in low light, ecologically friendly energy production, and versatile solar product integration. Though DSSCs using natural dyes as sensitizers have many advantages, they suffer from poor efficiency compared to conventional silicon solar cells. Moreover, the difficulty in converting them to practical devices for the day-to-day energy needs has to be addressed. This review will outline the optimization of conditions to be followed for better efficiency in DSSCs using natural dyes as sensitizers. This review has taken into account the importance of the first step towards the fabrication of DSSC, i.e. the selection process. The selection of plant parts has a noticeable impact on the overall efficiency of the device. Accordingly, a proper study has been done to analyse the plant's parts that have shown better results in terms of device efficiency. In addition to this, a wide range of techniques and factors such as extraction methods, the solvent used, coating techniques, immersing time, and co-sensitization have been taken into consideration from the studies done over the period of 10 years to examine their influence on the overall performance of the DSSC device. These results have been addressed to stipulate the best suitable condition that will help supplement the efficiency of the device even further. Also, the future perspectives, such as the DSSCs use in wearable devices, incorporating various approaches to enhance the power conversion efficiency of DSSCs using natural dyes, and thermochromism ability for DSSCs have been discussed.

Comparison of the condyle-fossa relationship and resorption between patients with and without Juvenile Idiopathic Arthritis (JIA).

PURPOSE: The purpose of this study was 1) to compare condyle - fossa relationships in the temporomandibular joint (TMJ), and 2) to score condylar resorption by using a TMJ indexing system in patients with JIA and without JIA. METHODS: The present retrospective cross-sectional study included cone-beam computed tomography (CBCT) images obtained from the sagittal, coronal, and axial slices. In the multidisciplinary Pediatric Rheumatology Outpatient Clinic at The University of Alabama at Birmingham (UAB) children with JIA are also examined by a group of orthodontists working in the same institute from October 2018 to July 2019. The predictor variable consists of patients with JIA and without JIA. The primary outcome variables are the depth of the mandibular fossa, joint spaces, axial angles, medio-lateral width, and condyle resorption. Other study variables were age and sex. In this study, the measurements obtained from 2 different groups (with JIA and without JIA) are compared using a t-test, where Tukey is utilized to adjust for multiple comparisons. The left and right joints are analyzed separately as the paired t test conducted showed a significant difference between the 2 joints (P < .05). RESULTS: The study was comprised of 34 patients diagnosed with JIA and 34 healthy subjects. The depth of the mandibular fossa, the anterior joint spaces, the axial angles, and the resorption index showed statistically significant differences between the JIA and healthy groups in both left and right sides (P < .05). However, there was no statistically significant difference in the posterior joint spaces and mediolateral width between JIA and healthy groups in both sides (P > .05). CONCLUSIONS: The results of our study presented the destructive potential of juvenile idiopathic arthritis by using CBCT. CBCT scanning is a helpful tool in the evaluation of the radiographic result of TMJ.

Therapeutic Benefit of Galectin-1: Beyond Membrane Repair, a Multifaceted Approach to LGMD2B.

Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients.

Validation of Diagnostic Methods for European Foulbrood on Commercial Honey Bee Colonies in the United States.

One of the most serious bacterial pathogens of Western honey bees (Apis mellifera Linnaeus [Hymenoptera: Apidae]) is Melissococcus plutonius, the cause of the disease European foulbrood. Because European foulbrood is highly variable, with diverse outcomes at both the individual and colony levels, it is difficult to diagnose through visual inspection alone. Common lab diagnostic techniques include microscopic examination and molecular detection through PCR. In 2009, a lateral flow device was developed and validated for field diagnosis of European foulbrood. At the time, M. plutonius was thought to be genetically homogenous, but we have subsequently learned that this bacterium exists as multiple strains, including some strains that are classified as 'atypical' for which the lateral flow device is potentially less effective. These devices are increasingly used in the United States, though they have never been validated using strains from North America. It is essential to validate this device in multiple locations as different strains of M. plutonius circulate in different geographical regions. In this study, we validate the field use of the lateral flow device compared to microscopic examination and qPCR on larval samples from 78 commercial honey bee colonies in the United States with visual signs of infection. In this study, microscopic diagnosis was more sensitive than the lateral flow device (sensitivity = 97.40% and 89.47%, respectively), and we found no false positive results with the lateral flow device. We find high concurrence between the three diagnostic techniques, and all three methods are highly sensitive for diagnosing European foulbrood.

An Improved Scalable Hydrogel Dish for Spheroid Culture.

Research in fields studying cellular response to surface tension and mechanical forces necessitate cell culture tools with tunability of substrate stiffness. We created a scalable hydrogel dish design to facilitate scaffold-free formation of multiple spheroids in a single dish. Our novel design features inner and outer walls, allowing efficient media changes and downstream experiments. The design is easily scalable, accommodating varying numbers of microwells per plate. We report that non-adherent hydrogel stiffness affects spheroid morphology and compaction. We found that spheroid morphology and viability in our hydrogel dishes were comparable to commercially available Aggrewell™800 plates, with improved tunability of surface stiffness and imaging area. Device function was demonstrated with a migration assay using two investigational inhibitors against EMT. We successfully maintained primary-derived spheroids from murine and porcine lungs in the hydrogel dish. These features increase the ability to produce highly consistent cell aggregates for biological research.

IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice.

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.

Fully automated cognitive screening tool based on assessment of speech and language.

INTRODUCTION: Recent years have seen an almost sevenfold rise in referrals to specialist memory clinics. This has been associated with an increased proportion of patients referred with functional cognitive disorder (FCD), that is, non-progressive cognitive complaints. These patients are likely to benefit from a range of interventions (eg, psychotherapy) distinct from the requirements of patients with neurodegenerative cognitive disorders. We have developed a fully automated system, 'CognoSpeak', which enables risk stratification at the primary-secondary care interface and ongoing monitoring of patients with memory concerns. METHODS: We recruited 15 participants to each of four groups: Alzheimer's disease (AD), mild cognitive impairment (MCI), FCD and healthy controls. Participants responded to 12 questions posed by a computer-presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification. RESULTS: CognoSpeak could distinguish between participants in the AD or MCI groups and those in the FCD or healthy control groups with a sensitivity of 86.7%. Patients with MCI were identified with a sensitivity of 80%. DISCUSSION: Our fully automated system achieved levels of accuracy comparable to currently available, manually administered assessments. Greater accuracy should be achievable through further system training with a greater number of users, the inclusion of verbal fluency tasks and repeat assessments. The current data supports CognoSpeak's promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.

Blood DNA methylation signatures to detect dementia prior to overt clinical symptoms.

INTRODUCTION: This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. METHODS: DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow-up in 25 dementia cases, and 24 controls. RESULTS: Cases and controls differed in DNAm (unadjusted P < .01) at the time of diagnosis (n = 28,787 probes), and pre-diagnosis (n = 15,111 probes), with cg01404610 (General transcription factor IIA subunit 1 gene) significant after correction for multiple testing. Overall, 1150 probes overlapped between analyses (methylation differences from -10.6% to +11.0%), and effect sizes increased from pre-diagnosis to diagnosis. DISCUSSION: Discernible blood DNAm signatures are in dementia cases before the appearance of overt clinical symptoms. Blood-based methylation may serve as a potential biomarker of dementia, but further investigation is needed to determine their true clinical utility.

Supporting Self-Management of Cardiovascular Diseases Through Remote Monitoring Technologies: Metaethnography Review of Frameworks, Models, and Theories Used in Research and Development.

BACKGROUND: Electronic health (eHealth) is a rapidly evolving field informed by multiple scientific disciplines. Because of this, the use of different terms and concepts to explain the same phenomena and lack of standardization in reporting interventions often leaves a gap that hinders knowledge accumulation. Interventions focused on self-management support of cardiovascular diseases through the use of remote monitoring technologies are a cross-disciplinary area potentially affected by this gap. A review of the underlying frameworks, models, and theories that have informed projects at this crossroad could advance future research and development efforts. OBJECTIVE: This research aimed to identify and compare underlying approaches that have informed interventions focused on self-management support of cardiovascular diseases through the use of remote monitoring technologies. The objective was to achieve an understanding of the distinct approaches by highlighting common or conflicting principles, guidelines, and methods. METHODS: The metaethnography approach was used to review and synthesize researchers' reports on how they applied frameworks, models, and theories in their projects. Literature was systematically searched in 7 databases: Scopus, Web of Science, EMBASE, CINAHL, PsycINFO, Association for Computing Machinery Digital Library, and Cochrane Library. Included studies were thoroughly read and coded to extract data for the synthesis. Studies were mainly related by the key ingredients of the underlying approaches they applied. The key ingredients were finally translated across studies and synthesized into thematic clusters. RESULTS: Of 1224 initial results, 17 articles were included. The articles described research and development of 10 different projects. Frameworks, models, and theories (n=43) applied by the projects were identified. Key ingredients (n=293) of the included articles were mapped to the following themes of eHealth development: (1) it is a participatory process; (2) it creates new infrastructures for improving health care, health, and well-being; (3) it is intertwined with implementation; (4) it integrates theory, evidence, and participatory approaches for persuasive design; (5) it requires continuous evaluation cycles; (6) it targets behavior change; (7) it targets technology adoption; and (8) it targets health-related outcomes. CONCLUSIONS: The findings of this review support and exemplify the numerous possibilities in the use of frameworks, models, and theories to guide research and development of eHealth. Participatory, user-centered design, and integration with empirical evidence and theoretical modeling were widely identified principles in the literature. On the contrary, less attention has been given to the integration of implementation in the development process and supporting novel eHealth-based health care infrastructures. To better integrate theory and evidence, holistic approaches can combine patient-centered studies with consolidated knowledge from expert-based approaches. TRIAL REGISTRATION: PROSPERO CRD42018104397; https://tinyurl.com/y8ajyajt. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/13334.

The effect of torso elevation on minimum effective continuous positive airway pressure for treatment of obstructive sleep apnea.

BACKGROUND: Continuous positive airway pressure (CPAP) is considered the gold standard treatment of obstructive sleep apnea (OSA). However, it can be a challenge in some patients to find an effective CPAP setting that is well tolerated. A lower CPAP setting may improve patient tolerance of the treatment. The objective of this study was to evaluate the effect of approximately 30° torso elevation on minimum effective CPAP for the treatment of OSA. METHODS: A retrospective chart review was performed to determine the effective CPAP setting required to treat OSA in patients who underwent CPAP titration with torso elevation using a wedge cushion, after having failed during the same titration study to achieve therapeutic results at CPAP of 20 cm H2O without torso elevation. RESULTS: Thirty-nine patients who underwent CPAP titration with and without torso elevation utilizing a wedge cushion had statistically significant lowering of the minimum effective CPAP setting with torso elevation, with a mean CPAP reduction of 4.7 (p < 0.001) compared to ineffective treatment at CPAP of 20 cm H2O without torso elevation. Apnea hypopnea index (AHI), respiratory disturbance index (RDI), and lowest oxygen saturation (SpO2) were all improved with torso elevation, with a mean AHI difference of 4.4 (p = 0.03), mean RDI difference of 14.2 (p = 0.001), and mean SpO2 difference of 5.9% (p = 0.002). Age and BMI were inversely correlated, and gender had no correlation with therapeutic CPAP settings with use of torso elevation. CONCLUSION: Torso elevation of approximately 30° resulted in effective CPAP treatment at settings significantly lower than 20 cm H2O in all reviewed OSA patients, who had been ineffectively treated without torso elevation at the maximum tested setting of 20 cm H2O. This intervention may be a useful adjunct during in-lab titration studies for patients who are not effectively treated at or cannot tolerate high CPAP settings.

Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.

GIGYF (Grb10-interacting GYF [glycine-tyrosine-phenylalanine domain]) proteins coordinate with 4EHP (eIF4E [eukaryotic initiation factor 4E] homologous protein), the DEAD (Asp-Glu-Ala-Asp)-box helicase Me31B/DDX6, and mRNA-binding proteins to elicit transcript-specific repression. However, the underlying molecular mechanism remains unclear. Here, we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6. A 2.4 Å crystal structure of the GIGYF-Me31B complex reveals that this motif arranges into a coil connected to a ß hairpin on binding to conserved hydrophobic patches on the Me31B RecA2 domain. Structure-guided mutants indicate that 4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA, thus revealing the molecular principles of translational repression.

Frameworks, Models, and Theories Used in Electronic Health Research and Development to Support Self-Management of Cardiovascular Diseases Through Remote Monitoring Technologies: Protocol for a Metaethnography Review.

BACKGROUND: Electronic health (eHealth) is a multidisciplinary and rapidly evolving field, and thus requires research focused on knowledge accumulation, curation, and translation. Cardiovascular diseases constitute a global health care crisis in which eHealth can provide novel solutions to improve the efficiency and reach of self-management support for patients where they most need it: their homes and communities. A holistic understanding of eHealth projects focused on such case is required to bridge the multidisciplinary gap formed by the wide range of aims and approaches taken by the various disciplines involved. OBJECTIVE: The primary objective of this review is to facilitate a holistic interpretation of eHealth projects aimed at providing self-management support of cardiovascular diseases in the natural setting of patients, thus priming the use of remote monitoring technologies. The review aims to synthesize the operationalization of frameworks, models, and theories applied to the research and development process of eHealth. METHODS: We will use Noblit and Hare's metaethnography approach to review and synthesize researchers' and practitioners' reports on how they applied frameworks, models, and theories in their projects. We will systematically search the literature in 7 databases: Scopus, Web of Science, EMBASE, CINAHL, PsycINFO, ACM Digital Library, and the Cochrane Library. We will thoroughly read and code selected studies to extract both raw and contextual data for the synthesis. The relation of the studies will be determined according to the elements of the frameworks, models, or theories the studies applied. We will translate these elements between each other and intend to synthesize holistic principles for eHealth development for the case at hand. RESULTS: The search strategy has been completed, data extraction is almost finalized, and the first synthesis approaches are underway. The search yielded 1224 citations and, after we applied the selection criteria, 17 articles remained. We expect to submit the final results for publication in 2019. CONCLUSIONS: This review is important because it aims to create a holistic understanding of a multidisciplinary topic at the crossroads of eHealth, cardiovascular diseases, and self-management. The value of metaethnography in contrast to other systematic review methods is that its synthesis approach seeks to generate a new understanding of a topic, while preserving the social and theoretical contexts in which findings emerge. Our results will show how useful this method can be in bridging the multidisciplinary gap of eHealth research and development, to inform and advance the importance of holistic approaches, while showcasing this approach for the case of self-management in cardiovascular diseases. TRIAL REGISTRATION: PROSPERO CRD42018104397; https://www.crd.york.ac.uk/PROSPERO/display_record.php? RecordID=104397 (Archived by WebCite at http://www.webcitation.org/75H1kP1Mm). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13334.