Resolution doubling in light-sheet microscopy via oblique plane structured illumination.

Structured illumination microscopy (SIM) doubles the spatial resolution of a fluorescence microscope without requiring high laser powers or specialized fluorophores. However, the excitation of out-of-focus fluorescence can accelerate photobleaching and phototoxicity. In contrast, light-sheet fluorescence microscopy (LSFM) largely avoids exciting out-of-focus fluorescence, thereby enabling volumetric imaging with low photobleaching and intrinsic optical sectioning. Combining SIM with LSFM would enable gentle three-dimensional (3D) imaging at doubled resolution. However, multiple orientations of the illumination pattern, which are needed for isotropic resolution doubling in SIM, are challenging to implement in a light-sheet format. Here we show that multidirectional structured illumination can be implemented in oblique plane microscopy, an LSFM technique that uses a single objective for excitation and detection, in a straightforward manner. We demonstrate isotropic lateral resolution below 150 nm, combined with lower phototoxicity compared to traditional SIM systems and volumetric acquisition speed exceeding 1 Hz.

Performance of wet scrubbers to remove VOCs from rubber emissions.

Poor performance of wet scrubbers in rubber processing plants due to breakthrough of specific volatile organic compounds (VOCs) causes odour impact events. The performance of wet scrubbers in the rubber drying process to remove VOCs was investigated in order to determine the responsible odorants. VOC emissions originating at the inlet and outlet of wet scrubbers were quantified using gas chromatography-mass spectrometry/olfactometry (GC-MS/O). Critical VOCs were identified alongside seasonal and daily variations of those VOCs. Altogether, 80 VOCs were detected in rubber emissions with 16 classified as critical VOCs based on their chemical concentration, high odour activity value (OAV) and unpleasant odour. Volatile fatty acids (VFAs) were the dominant VOCs with seasonal variations affecting emission composition. Results demonstrated the ineffectiveness of the wet scrubbers to mitigate odorous VOCs whereas the removal of some VOCs could be improved based on their polarity and solubility. It was found that there is a correlation between the wet scrubber performance and VFAs concentration in the emissions. The findings demonstrated that combining quantitative and sensory analyses improved accuracy in identifying odorous VOCs, which can cause odour annoyance from rubber processing. A VOC identification framework was proposed using both analyses approaches.

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

An Ultra-Microporous Metal-Organic Framework with Exceptional Xe Capacity.

Molecular confinement plays a significant effect on trapped gas and solvent molecules. A fundamental understanding of gas adsorption within the porous confinement provides information necessary to design a material with improved selectivity. In this regard, metal-organic framework (MOF) adsorbents are ideal candidate materials to study confinement effects for weakly interacting gas molecules, such as noble gases. Among the noble gases, xenon (Xe) has practical applications in the medical, automotive and aerospace industries. In this Communication, we report an ultra-microporous nickel-isonicotinate MOF with exceptional Xe uptake and selectivity compared to all benchmark MOF and porous organic cage materials. The selectivity arises because of the near perfect fit of the atomic Xe inside the porous confinement. Notably, at low partial pressure, the Ni-MOF interacts very strongly with Xe compared to the closely related Krypton gas (Kr) and more polarizable CO2 . Further 129 Xe NMR suggests a broad isotropic chemical shift due to the reduced motion as a result of confinement.

Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Modulation of Macrophage Inflammatory Nuclear Factor κB (NF-κB) Signaling by Intracellular Cryptococcus neoformans.

Cryptococcus neoformans (Cn) is a common facultative intracellular pathogen that can cause life-threatening fungal meningitis in immunocompromised individuals. Shortly after infection, Cn is detectable as both extra- and intracellular yeast particles, with Cn being capable of establishing long-lasting latent infections within host macrophages. Although recent studies have shown that shed capsular polysaccharides and intact extracellular Cn can compromise macrophage function through modulation of NF-κB signaling, it is currently unclear whether intracellular Cn also affects NF-κB signaling. Utilizing live cell imaging and computational modeling, we find that extra- and intracellular Cn support distinct modes of NF-κB signaling in cultured murine macrophages. Specifically, in RAW 264.7 murine macrophages treated with extracellular glucuronoxylomannan (GXM), the major Cn capsular polysaccharide, LPS-induced nuclear translocation of p65 is inhibited, whereas in cells with intracellular Cn, LPS-induced nuclear translocation of p65 is both amplified and sustained. Mathematical simulations and quantification of nascent protein expression indicate that this is a possible consequence of Cn-induced "translational interference," impeding IκBα resynthesis. We also show that long term Cn infection induces stable nuclear localization of p65 and IκBα proteins in the absence of additional pro-inflammatory stimuli. In this case, nuclear localization of p65 is not accompanied by TNFα or inducible NOS (iNOS) expression. These results demonstrate that capsular polysaccharides and intact intracellular yeast manipulate NF-κB via multiple distinct mechanisms and provide new insights into how Cn might modulate cellular signaling at different stages of an infection.

Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.

Characterization of the endocrine, digestive and morphological adjustments of the intestine in response to food deprivation and torpor in cunner, Tautogolabrus adspersus.

The cunner, Tautogolabrus adspersus, is a marine teleost endemic to the cold waters of the Northwest Atlantic Ocean. The cunner is non-migratory and is known for its remarkable ability to endure the freezing winter months with little to no food by entering a torpid/dormant state. To evaluate the physiological strategies employed by the cunner's intestinal tract to withstand food deprivation, fish were sampled for their gut after a four-week period of acute food deprivation during their summer (active/feeding) state, as well as after 4months of overwinter fasting. Digestive capacity was evaluated by measuring digestive enzyme activity and related mRNA transcript expression for trypsin, alkaline phosphatase, alanine aminopeptidase and lipase. In order to assess how gut hormones affect/are affected by acute fasting and torpor, we examined the intestinal mRNA expression of several putative appetite regulators, i.e. CCK, apelin, orexin and mTOR. Short-term summer fasting induced a reduction in the activity, but not the transcript expression, of all digestive enzymes examined as well as a reduction in gut apelin mRNA. Torpor induced a reduction in the activity of all enzymes with the exception of alanine aminopeptidase, and a decrease in mRNA levels of alanine aminopeptidase, orexin, CCK and mTOR. Our results suggest that both acute fasting and long-term fasting induce a reduction in the intestinal function of cunner, as evidenced by an overall decrease in the activities of digestive enzymes and mRNA expression of several factors involved in feeding and digestion.

The use of gas chromatography combined with chemical and sensory analysis to evaluate nuisance odours in the air and water environment.

Varieties of gas chromatography (GC) combined with chemical detection (CD) and sensory analysis at the odour detection port (ODP) for the evaluation of environmental odorants has steadily increased in application and sophistication; this has given rise to a plethora of techniques that cater to specific tasks. With this diversity of approaches in mind, there is a need to assess the critical points at which these approaches differ, as well as likely risks and factors that may affect them. These critical points explained within this review include sample preparation, GC separation techniques (with associated co-elution risks), how the elute is separated between CD and sensory analysis, the type of CD, the type of sensory analysis (with particular attention paid to its factors and guidelines), integrative data techniques, as well as how that data may be used. Additionally, this review provides commentary on the current state of the research space and makes recommendations based on how these analyses should be reported, the standardisation of nomenclature, as well as the impediments to the future goals of this research area. By careful consideration of the critical points of varying analytical processes and how best to communicate these findings, the quality of output within this area will improve. This review provides a benchmark for how GC-CD/sensory analysis should be undertaken and reported.

Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp.

Sarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the "Z-Bodies" of sarcomere precursors and the "Z-Lines" of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance. Previous measurements of α-actinin-2 organization have been largely accomplished manually, which is time-consuming and has hampered research progress. Here, we introduce sarcApp, an image analysis tool that quantifies several components of the cardiac sarcomere and their alignment in muscle cells and tissue. We first developed sarcApp to utilize deep learning-based segmentation and real space quantification to measure α-actinin-2 structures and determine the organization of both precursors and sarcomeres/myofibrils. We then expanded sarcApp to analyze "M-Lines" using the localization of myomesin and a protein that connects the Z-Lines to the M-Line (titin). sarcApp produces 33 distinct measurements per cell and 24 per myofibril that allow for precise quantification of changes in sarcomeres, myofibrils, and their precursors. We validated this system with perturbations to sarcomere assembly. We found perturbations that affected Z-Lines and M-Lines differently, suggesting that they may be regulated independently during sarcomere assembly.

Isolation of Hemiketal and Hydroxy Ketone Tautomers of Synthetic Intermediates Each Affording 18-Hydroxycortisol-1,6,7-d3.

During the synthesis of deuterated 18-hydroxycortisol, two of the synthetic intermediates have been found to exist in tautomeric forms as the acyclic 18-hydroxy 20-ketone and the cyclic 18,20-hemiketal corresponding to the previously identified less polar (L) and more polar (M) forms of C-18 hydroxylated steroids, respectively. Specifically, p-chloranil oxidation of 18-hydroxycortisol-17,21-acetonide afforded two isomers of the 6,7-dehydro analogue; separate catalytic reduction of each isomer under deuterium gave a single isomer of acetonide-protected 18-hydroxycortisol-1,6,7-d3 for each, with the more polar isomer giving a more polar product and the less polar isomer giving a less polar product. The more polar product (corresponding to M) was characterized as 18,20-hemiketal; 18-hydroxycortisol-17,21-acetonide-18,20-hemiketal-1,6,7-d3: in the deuterochloroform solution, it was found to slowly convert to a substance consistent with the hydroxy ketone structure with features resembling those of the isolated less polar isomer (corresponding to L). Deacetonidization of each gave 18-hydroxycortisol as a single product, which was characterized as the 18,20-hemiketal. The issues associated with the existence of 18-hydroxysteroids as hydroxy ketones and hemiketals, both in solution and as isolable solids, are discussed.

Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp.

Sarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases, including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the 'Z-Bodies" of sarcomere precursors and the 'Z-Lines' of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance. Previous measurements of α-actinin-2 organization have been largely accomplished manually, which is time-consuming and has hampered research progress. Here, we introduce sarcApp, an image analysis tool that quantifies several components of the cardiac sarcomere and their alignment in muscle cells and tissue. We first developed sarcApp to utilize deep learning-based segmentation and real space quantification to measure α-actinin-2 structures and determine the organization of both precursors and sarcomeres/myofibrils. We then expanded sarcApp to analyze 'M-Lines' using the localization of myomesin and a protein that connects the Z-Lines to the M-Line (titin). sarcApp produces 33 distinct measurements per cell and 24 per myofibril that allow for precise quantification of changes in sarcomeres, myofibrils, and their precursors. We validated this system with perturbations to sarcomere assembly. We found perturbations that affected Z-Lines and M-Lines differently, suggesting that they may be regulated independently during sarcomere assembly.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

A Case Report of Biventricular Arrhythmogenic Cardiomyopathy in a Middle-Aged Female.

Arrhythmogenic cardiomyopathy is an inherited disease in which the normal myocardium is replaced by fibroadipose infiltrates. It is increasingly being recognized as a separate entity to arrhythmogenic right ventricular cardiomyopathy though is rarely diagnosed. We report a 47-year-old female who presented to her local emergency department with a history of presyncope while driving. Electrocardiograph revealed inferolateral ST changes and right bundle branch block. A high burden of premature ventricular contractions and non-sustained ventricular tachycardia was seen on telemetry. Echocardiography showed reduced left ventricular systolic function and cardiac magnetic resonance imaging demonstrated extensive fibrosis involving the left ventricle and the septum of the right ventricle. An inherited cardiac disease genetic panel, including desmosomal gene mutations, was non-contributary. Extensive workup for other potential causes of cardiac fibrosis and reduced left ventricle function including cardiac positron emission tomography (PET) was negative. Based on the presentation and these findings, a diagnosis of biventricular arrhythmogenic cardiomyopathy was made. The patient's condition was complicated by third-degree heart block two weeks after initiation of pharmacological treatment that included amiodarone. An implantable cardiac defibrillator was implanted. She was referred to a tertiary centre specializing in inherited cardiac conditions for familial screening.

Determining the source of unusual xenon isotopes in samples.

Three unusual radioactive isotopes of xenon-125Xe, 127Xe, and 129mXe-have been observed during testing of a new generation radioxenon measurement system at the manufacturing facility in Knoxville, Tennessee. These are possibly the first detections of these isotopes in environmental samples collected by automated radioxenon systems. Unfortunately, the new isotopes detected by the Xenon International sampler can interfere with quantification of the radioactive xenon isotopes used to monitor for nuclear explosions. Xenon International sampling data collected during February through September 2020 were combined with an atmospheric transport model to identify the possible release location. A source-location analyses using sample counts dominated by 125Xe strongly supports the conclusion that the release point is near (within 20 km) the sampler location. Wind patterns are not consistent with releases coming from more distant nuclear power plants. The High Flux Isotope Reactor (HFIR) and the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory are located in the region of most likely source locations. The source-location analysis cannot rule out either facility as a release location, and some of the samples may contain a combination of releases from both facilities. The source-location results using 125Xe are not unexpected because Klingberg et al. (2013) previously published the production rate of radioactive xenon isotopes from neutron activation of stable xenon in the air at the HFIR. Up to 1012 Bq of 125Xe could be produced per operational day and other xenon isotopes would be produced in lesser quantities.

Phase II testing of Xenon International on Mount Schauinsland, Germany.

Station RN33 on Mount Schauinsland near Freiburg, Germany, is part of the International Monitoring System monitoring radioxenon in air (131mXe, 133Xe, 133mXe, and 135Xe) for verification of the Comprehensive Nuclear Test Ban Treaty. Here, we present data from phase II testing of a new system, Xenon International at RN33, July 14th, 2021 to Jan 22nd, 2022, together with SPALAX data from the same time period. Radioxenon could be detected in 473 of 719 samples, among them many multiple isotope detections. Activity concentrations of spiked and selected environmental samples were verified by laboratory reanalysis. The sensitivity of Xenon International for radioxenons is up to one order of magnitude better for the metastable isotopes than that of the SPALAX, with a shorter sampling duration of 6 h.

Deploying the Behavioral and Environmental Sensing and Intervention for Cancer Smart Health System to Support Patients and Family Caregivers in Managing Pain: Feasibility and Acceptability Study.

BACKGROUND: Distressing cancer pain remains a serious symptom management issue for patients and family caregivers, particularly within home settings. Technology can support home-based cancer symptom management but must consider the experience of patients and family caregivers, as well as the broader environmental context. OBJECTIVE: This study aimed to test the feasibility and acceptability of a smart health sensing system-Behavioral and Environmental Sensing and Intervention for Cancer (BESI-C)-that was designed to support the monitoring and management of cancer pain in the home setting. METHODS: Dyads of patients with cancer and their primary family caregivers were recruited from an outpatient palliative care clinic at an academic medical center. BESI-C was deployed in each dyad home for approximately 2 weeks. Data were collected via environmental sensors to assess the home context (eg, light and temperature); Bluetooth beacons to help localize dyad positions; and smart watches worn by both patients and caregivers, equipped with heart rate monitors, accelerometers, and a custom app to deliver ecological momentary assessments (EMAs). EMAs enabled dyads to record and characterize pain events from both their own and their partners' perspectives. Sensor data streams were integrated to describe and explore the context of cancer pain events. Feasibility was assessed both technically and procedurally. Acceptability was assessed using postdeployment surveys and structured interviews with participants. RESULTS: Overall, 5 deployments (n=10 participants; 5 patient and family caregiver dyads) were completed, and 283 unique pain events were recorded. Using our "BESI-C Performance Scoring Instrument," the overall technical feasibility score for deployments was 86.4 out of 100. Procedural feasibility challenges included the rurality of dyads, smart watch battery life and EMA reliability, and the length of time required for deployment installation. Postdeployment acceptability Likert surveys (1=strongly disagree; 5=strongly agree) found that dyads disagreed that BESI-C was a burden (1.7 out of 5) or compromised their privacy (1.9 out of 5) and agreed that the system collected helpful information to better manage cancer pain (4.6 out of 5). Participants also expressed an interest in seeing their own individual data (4.4 out of 5) and strongly agreed that it is important that data collected by BESI-C are shared with their respective partners (4.8 out of 5) and health care providers (4.8 out of 5). Qualitative feedback from participants suggested that BESI-C positively improved patient-caregiver communication regarding pain management. Importantly, we demonstrated proof of concept that seriously ill patients with cancer and their caregivers will mark pain events in real time using a smart watch. CONCLUSIONS: It is feasible to deploy BESI-C, and dyads find the system acceptable. By leveraging human-centered design and the integration of heterogenous environmental, physiological, and behavioral data, the BESI-C system offers an innovative approach to monitor cancer pain, mitigate the escalation of pain and distress, and improve symptom management self-efficacy. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16178.