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Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.

ObjectivesThis analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (Sunosi™) 37.5 (OSA only), 75, 150, or 300 mg/d.MethodsIn two 12-week, randomized, placebo-controlled trials and one 1-year open-label extension study, changes in weight were evaluated from baseline to end of study (week 12 or week 40 of the open-label extension [after up to 52 weeks of solriamfetol treatment]) in participants with OSA or narcolepsy.ResultsAfter 12 weeks of solriamfetol treatment, median percent change in weight from baseline across all solriamfetol doses was -0.84%, compared with 0.54% for placebo, in participants with OSA; and -0.07%, compared with 3.08% for placebo, in participants with narcolepsy. After up to 52 weeks of solriamfetol treatment, overall median percent change in weight from baseline was -1.76%, which showed a dose-dependent pattern (75 mg, 0.57%; 150 mg, -1.2%; 300 mg, -2.5%). Results were similar in subgroups of participants with OSA or narcolepsy, with overall median percent changes in weight of -2.2% and -1.1%, respectively. After up to 52 weeks of solriamfetol treatment, the percentage of participants with weight loss ≥5% relative to baseline was 25.7% overall and increased in a dose-dependent manner (75 mg, 4.5%; 150 mg, 17.3%; 300 mg, 32.4%). Results were similar among subgroups of participants with OSA or narcolepsy, with 26.4% and 24.2% of participants experiencing weight loss ≥5%, respectively. No weight-related treatment-emergent adverse events were serious.ConclusionsSolriamfetol treatment was associated with decreases in body weight in a dose-related manner.

Study objectivesSolriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union for excessive daytime sleepiness in adults with narcolepsy (75-150 mg/day) or obstructive sleep apnea (OSA; 37.5-150 mg/day). In 12-week studies, solriamfetol was associated with improvements in quality of life in participants with narcolepsy or OSA. These analyses evaluated the long-term effects of solriamfetol on quality of life.MethodsParticipants with narcolepsy or OSA who completed previous solriamfetol studies were eligible. A 2-week titration was followed by a maintenance phase ≤ 50 weeks (stable doses: 75, 150, or 300 mg/day). Quality of life assessments included Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-Item Short Form Health Survey version 2. Mean (standard deviation) changes from baseline to end of study were evaluated. Data were summarized descriptively. Adverse events were assessed.ResultsSafety population comprised 643 participants (417 OSA, 226 narcolepsy). Solriamfetol improved Functional Outcomes of Sleep Questionnaire short version Total scores (mean change [standard deviation], 3.7 [3.0]) and 36-Item Short Form Health Survey version 2 Physical and Mental Component Summary scores (3.1 [6.9] and 4.3 [8.4], respectively); improvements were sustained throughout treatment. On Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, solriamfetol reduced (improved) % presenteeism, % overall work impairment, and % activity impairment by a minimum of 25%. Common adverse events (≥ 5%): headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection.ConclusionsLong-term solriamfetol treatment was associated with clinically meaningful, sustained improvements in functional status, work productivity, and quality of life for up to 52 weeks. Adverse events were similar between narcolepsy and OSA.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; Identifier: NCT02348632; URL: https://clinicaltrials.gov/ct2/show/NCT02348632.CitationWeaver TE, Pepin J-L, Schwab R, et al. Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med. 2021;17(10):1995-2007.

The World Health Organization has estimated that air pollution is a major threat to health, causing approximately nine million premature deaths every year. Each individual has, over their lifetime, a unique exposure to air pollution through their habits, working and living conditions. Medical research requires dedicated tools to assess and understand individual exposure to air pollution in view of investigating its health effects. This paper presents portable sensors produced by the Canarin Project that provides accessible, real time personal exposure data to particulate matter. Our primary results demonstrate the use of portable sensors for the assessment of personal exposure to the different micro-environments attended by individuals, and for inspecting the short-term effects of air pollution through the example of sleep apnea. These findings underscore the necessity of obtaining contextual data in determining environmental exposure and give perspectives for the future of air pollution sensors dedicated to medical research.

Purpose of reviewThe purpose of this review is to describe the variability of obstructive sleep apnea (OSA), both from a standpoint of underlying mechanisms and in terms of clinical manifestations.Recent findingsRecent data suggest that not all patients with sleep apnea get their disease for the same reason. As such, no one variable is effective at defining which patients do or do not have sleep apnea. Identifying the mechanism(s) underlying OSA for an individual is helpful as it can help to determine whether personalized therapy could be developed based on an individual's characteristics. In addition, these underlying mechanisms may be helpful in predicting response to therapy and prognosticating regarding future complications.SummaryOSA is a heterogeneous disease with highly varying underlying mechanisms. OSA has variable clinical manifestations with definable subsets having risk of particular complications. Future studies will be helpful to identify mechanisms underlying OSA using clinically accessible tools and then using these data to focus individualized treatment approaches.

Study objectivesTo evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA).MethodsParticipants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study.ResultsIn the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs.ConclusionsThis study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified.Trial registrationNCT02348632.

BackgroundPositive airway pressure (PAP) has become a prominent treatment for children with sleep-disordered breathing. However, there are no large-scale studies to clarify whether PAP is well tolerated in children, and which factors are associated with better adherence to PAP therapy. In this study, we aimed to clarify adherence patterns of PAP therapy in a large paediatric population.MethodsWe did a cross-sectional big-data analysis in children from Oct 1, 2014, to Aug 1, 2018, using existing data derived from PAP devices uploaded nightly in the AirView cloud database. The AirView database is a usage tracking system available to all patients who are assigned PAP therapy, which requires consent from the patient or parent or guardian. All patients older than 4 years and younger than 18 years who used continuous or automated PAP devices were evaluated. Only patients living in the USA and enrolled with a single insurance company were included. If patients were participating in an engagement programme, programme onset must have been within 7 days of therapy onset. Our primary outcome was the proportion of patients who used PAP continuously over 90 days. The primary outcome was assessed in all patients who met the age inclusion criterion and had reliable age data available. Data on missing PAP use were imputed as zero, but data on other metrics were not imputed and excluded from analysis.FindingsWe used data recorded from Oct 1, 2014, to Aug 1, 2018. Of 40 140 children screened, 36 058 (89·8%) were US residents and 20 553 (90·1%) of them met the eligibility criteria and had accessible data (mean age 13·0 years [SD 3·7]). On the basis of 90 days of monitoring data, 12 699 (61·8%) patients continuously used PAP. Factors significantly associated with adherence included age group, residual apnoea-hypopnoea index, use and onset of patient engagement programmes, PAP pressure, and nightly median PAP mask leak, all over the 90-day study period.InterpretationTo our knowledge, our study represents the largest analysis of children using PAP therapy to date. The findings suggest that adherence to PAP therapy is lower than in previous reports from adults. However, numerous actionable factors were associated with improvements in adherence and should be used strategically in clinical decision making to improve PAP adherence in children.FundingResMed.

Reassortment is an evolutionary mechanism by which influenza A viruses (IAV) generate genetic novelty. Reassortment is an important driver of host jumps and is widespread according to retrospective surveillance studies. However, predicting the epidemiological risk of reassortant emergence in novel hosts from surveillance data remains challenging. IAV strains persist and co-occur in the environment, promoting co-infection during environmental transmission. These conditions offer opportunity to understand reassortant emergence in reservoir and spillover hosts. Specifically, environmental RNA could provide rich information for understanding the evolutionary ecology of segmented viruses, and transform our ability to quantify epidemiological risk to spillover hosts. However, significant challenges with recovering and interpreting genomic RNA from the environment have impeded progress towards predicting reassortant emergence from environmental surveillance data. We discuss how the fields of genomics, experimental ecology and epidemiological modelling are well positioned to address these challenges. Coupling quantitative disease models and natural transmission studies with new molecular technologies, such as deep-mutational scanning and single-virus sequencing of environmental samples, should dramatically improve our understanding of viral co-occurrence and reassortment. We define observable risk metrics for emerging molecular technologies and propose a conceptual research framework for improving accuracy and efficiency of risk prediction. This article is part of the theme issue Dynamic and integrative approaches to understanding pathogen spillover.

IntroductionFor patients with obstructive sleep apnoea (OSA) who are initially non-compliant with continuous (automatic) positive airway pressure (CPAP/APAP) therapy, a bilevel PAP (Spont/VAuto) therapy transition pathway is available to improve therapy adherence. The aim of this retrospective study was to compare PAP therapy usage data of patients with non-compliant OSA (ncOSA) on CPAP/APAP who were switched to bilevel PAP.MethodsA PAP telemonitoring database was queried between 1 January 2015 and 31 July 2016 for eligible patients started on CPAP/APAP and non-CMS (United States Center for Medicare and Medicaid Services) compliant and switched to bilevel PAP within 90 days of starting CPAP/APAP therapy. PAP therapy data on all patients were compared before switch (CPAP/APAP) and after switch (VAuto/Spont).ResultsOf the 1496 patients with ncOSA identified, 30.3% used CPAP, 62.3% APAP, and 7.4% both APAP and CPAP before switching to a bilevel mode. 47.8% patients switched to Spont mode and 52.2% to VAuto mode. PAP usage significantly improved by 0.9 h/day (p

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P

Free sugars overconsumption is associated with an increased prevalence of risk factors for metabolic diseases such as the alteration of the blood lipid levels. Natural fruit juices have a free sugar composition quite similar to that of sugar-sweetened beverages. Thus, could fruit juice consumption lead to the same adverse effects on health as sweetened beverages? We attempted to answer this question by reviewing the available evidence on the health effects of both sugar-sweetened beverages and natural fruit juices. We determined that, despite the similarity of fruits juices to sugar-sweetened beverages in terms of free sugars content, it remains unclear whether they lead to the same metabolic consequences if consumed in equal dose. Important discrepancies between studies, such as type of fruit juice, dose, duration, study design, and measured outcomes, make it impossible to provide evidence-based public recommendations as to whether the consumption of fruit juices alters the blood lipid profile. More randomized controlled trials comparing the metabolic effects of fruit juice and sugar-sweetened beverage consumption are needed to shape accurate public health guidelines on the variety and quantity of free sugars in our diet that would help to prevent the development of obesity and related health problems.

BackgroundThe emergence of central sleep apnea (CSA) during positive airway pressure (PAP) therapy has been observed clinically in approximately 10% of obstructive sleep apnea titration studies. This study assessed a PAP database to investigate trajectories of treatment-emergent CSA during continuous PAP (CPAP) therapy.MethodsU.S. telemonitoring device data were analyzed for the presence/absence of emergent CSA at baseline (week 1) and week 13. Defined groups were as follows: obstructive sleep apnea (average central apnea index [CAI] < 5/h in week 1, < 5/h in week 13); transient CSA (CAI ≥ 5/h in week 1, < 5/h in week 13); persistent CSA (CAI ≥ 5/h in week 1, ≥ 5/h in week 13); emergent CSA (CAI < 5/h in week 1, ≥ 5/h in week 13).ResultsPatients (133,006) used CPAP for ≥ 90 days and had ≥ 1 day with use of ≥ 1 h in week 1 and week 13. The proportion of patients with CSA in week 1 or week 13 was 3.5%; of these, CSA was transient, persistent, or emergent in 55.1%, 25.2%, and 19.7%, respectively. Patients with vs without treatment-emergent CSA were older, had higher residual apnea-hypopnea index and CAI at week 13, and more leaks (all P < .001). Patients with any treatment-emergent CSA were at higher risk of therapy termination vs those who did not develop CSA (all P < .001).ConclusionsOur study identified a variety of CSA trajectories during CPAP therapy, identifying several different clinical phenotypes. Identification of treatment-emergent CSA by telemonitoring could facilitate early intervention to reduce the risk of therapy discontinuation and shift to more efficient ventilator modalities.

Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

BackgroundLive-animal markets are a culturally important feature of meat distribution chains in many populations, yet they provide an opportunity for the maintenance and transmission of potentially emergent zoonotic pathogens. The ongoing human outbreak of avian H7N9 in China highlights the need for increased surveillance and control in these live-bird markets (LBMs).DiscussionClosure of retail markets in affected areas rapidly decreased human cases to rare, sporadic occurrence, but little attention has been paid thus far to the role of upstream elements of the poultry distribution chain such as wholesale markets. This could partly explain why transmission in poultry populations has not been eliminated more broadly. We present surveillance data from both wholesale live-bird markets (wLBMs) and rLBMs in Shantou, China (from 2004-2006), and call on disease-dynamic theory to illustrate why closing rLBMs has only minor effects on the overall volume of transmission. We show that the length of time birds stay in rLBMs can severely limit transmission there, but that the system-wide effect may be reduced substantially by high levels of transmission upstream of retail markets.SummaryManagement plans that minimize transmission throughout the entire poultry supply chain are essential for minimizing exposure to the public. These include reducing stay-time of birds in markets to 1 day, standardizing poultry supply chains to limit transmission in pre-retail settings, and monitoring strains with epidemiological traits that pose a high risk of emergence. These actions will further limit human exposure to extant viruses and reduce the likelihood of the emergence of novel strains by decreasing the overall volume of transmission.

Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and (111)In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard (18)F-fluorodeoxyglucose at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope (177)Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology.

Myostatin is a TGFβ family member and negative regulator of muscle size. Due to the complexity of the molecular pathway between myostatin mRNA/protein and changes in transcription, it has been difficult to understand whether myostatin plays a role in resistance exercise-induced skeletal muscle hypertrophy. To circumvent this problem, we determined the expression of a unique myostatin target gene, Mighty, following resistance exercise. Mighty mRNA increased by 6 h (82.9 ± 24.21%) and remained high out to 48 h (56.5 ± 19.67%) after resistance exercise. Further examination of the soleus, plantaris and tibialis anterior muscles showed that the change in Mighty mRNA at 6 h correlated with the increase in muscle size associated with this protocol (R(2) = 0.9996). The increase in Mighty mRNA occurred both independent of Smad2 phosphorylation and in spite of an increase in myostatin mRNA (341.8 ± 147.14% at 3 h). The myostatin inhibitor SKI remained unchanged. However, activated Notch, another potential inhibitor of TGFβ signaling, increased immediately following resistance exercise (83 ± 11.2%) and stayed elevated out to 6 h (78 ± 16.6%). Electroportion of the Notch intracellular domain into the tibialis anterior resulted in an increase in Mighty mRNA (63 ± 13.4%) that was equivalent to the canonical Notch target HES-1 (94.4 ± 7.32%). These data suggest that acute resistance exercise decreases myostatin signaling through the activation of the TGFβ inhibitor Notch resulting in a decrease in myostatin transcriptional activity that correlates well with muscle hypertrophy.

Adaptation is often thought to affect the likelihood that a virus will be able to successfully emerge in a new host species. If so, surveillance for genetic markers of adaptation could help to predict the risk of disease emergence. However, adaptation is difficult to distinguish conclusively from the other processes that generate genetic change. In this Review we survey the research on the host jumps of influenza A, severe acute respiratory syndrome-coronavirus, canine parvovirus and Venezuelan equine encephalitis virus to illustrate the insights that can arise from combining genetic surveillance with microbiological experimentation in the context of epidemiological data. We argue that using a multidisciplinary approach for surveillance will provide a better understanding of when adaptations are required for host jumps and thus when predictive genetic markers may be present.

BackgroundThe genus Cronobacter (formerly called Enterobacter sakazakii) is composed of five species; C. sakazakii, C. malonaticus, C. turicensis, C. muytjensii, and C. dublinensis. The genus includes opportunistic human pathogens, and the first three species have been associated with neonatal infections. The most severe diseases are caused in neonates and include fatal necrotizing enterocolitis and meningitis. The genetic basis of the diversity within the genus is unknown, and few virulence traits have been identified.Methodology/principal findingsWe report here the first sequence of a member of this genus, C. sakazakii strain BAA-894. The genome of Cronobacter sakazakii strain BAA-894 comprises a 4.4 Mb chromosome (57% GC content) and two plasmids; 31 kb (51% GC) and 131 kb (56% GC). The genome was used to construct a 387,000 probe oligonucleotide tiling DNA microarray covering the whole genome. Comparative genomic hybridization (CGH) was undertaken on five other C. sakazakii strains, and representatives of the four other Cronobacter species. Among 4,382 annotated genes inspected in this study, about 55% of genes were common to all C. sakazakii strains and 43% were common to all Cronobacter strains, with 10-17% absence of genes.Conclusions/significanceCGH highlighted 15 clusters of genes in C. sakazakii BAA-894 that were divergent or absent in more than half of the tested strains; six of these are of probable prophage origin. Putative virulence factors were identified in these prophage and in other variable regions. A number of genes unique to Cronobacter species associated with neonatal infections (C. sakazakii, C. malonaticus and C. turicensis) were identified. These included a copper and silver resistance system known to be linked to invasion of the blood-brain barrier by neonatal meningitic strains of Escherichia coli. In addition, genes encoding for multidrug efflux pumps and adhesins were identified that were unique to C. sakazakii strains from outbreaks in neonatal intensive care units.