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To assess the incidence and treatments currently used in clinical practice for the treatment of treatment-resistant depression (TRD) in Scotland.
Patients with major depressive disorder (MDD) who have not responded to at least two successive antidepressant (AD) treatments in a single episode are described as having Treatment-Resistant Depression (TRD). Epidemiological data on TRD in Scotland is lacking. Furthermore, there is no data to our knowledge on therapies prescribed in Scottish clinical practice to treat TRD.
A retrospective, longitudinal cohort study was conducted using Clinical Practice Research Datalink (CPRD) medical records. Adult patients were indexed on AD prescription, requiring MDD diagnosis within 90 days, from Jan 2011-May 2018 with 360-day baseline and 180-day minimum follow-up periods. Failure of ≥2 adequate oral AD regimens following indexing constituted TRD classification. Incidence rates of MDD and TRD (within the MDD cohort) and treatment lines following TRD classification were derived.
The analysis included 20,059 patients with MDD (mean age 44 years, 63% female, median follow-up 59 months); 1,374 (6.8%) were classified as TRD. Median time-to-TRD classification was 25 months. The incidence rate of MDD was 15.9 per 1,000 patient-years and for TRD was 14.7 per 1,000 MDD-patient-years. For all first four post-TRD treatment lines, SSRI monotherapy was the most commonly prescribed therapy, followed by combination (dual/triple) therapy and augmentation therapy (at least one oral AD supplemented with lithium, an antipsychotic or an anticonvulsant therapy). At first-line of TRD treatment, 1,050 (76.4%) patients received monotherapy AD, 212 (15.4%) received combination AD therapy and 112 (8.2%) received augmentation therapy. The most common monotherapy treatments at first-line TRD were sertraline (15.6%), mirtazapine (13.8%), fluoxetine (12.2%) and venlafaxine (11.6%). Among combination therapies, mirtazapine, venlafaxine, sertraline and amitriptyline were frequently used. Among the TRD and MDD cohort, no somatic treatments were coded in CPRD, although the use of these treatments was likely underestimated.
Monotherapy AD treatment was the most common therapy type for all four post-TRD treatment lines. These data support the need for new treatments that can achieve and maintain therapeutic response, and avoid continuous cycling through similar AD therapies.
To understand the long-term climate and glaciological evolution of the ice sheet in the region bordering the Weddell Sea, the British Antarctic Survey has undertaken a series of successful ice core projects drilling to bedrock on Berkner Island, James Ross Island and the Fletcher Promontory. A new project, WACSWAIN, seeks to increase this knowledge by further drilling to bedrock on two further ice rises in this region. In a single-season project, an ice core was recovered to bedrock at 651 m on Skytrain Ice Rise using an ice core drill in a fluid-filled borehole. In a second season, a rapid access drill was used to recover ice chips to 323 m on Sherman Island in a dry borehole, though failing to reach the bedrock which was at an estimated depth of 428 m.
We present an overview of the SkyMapper optical follow-up programme for gravitational-wave event triggers from the LIGO/Virgo observatories, which aims at identifying early GW170817-like kilonovae out to
distance. We describe our robotic facility for rapid transient follow-up, which can target most of the sky at
to a depth of
. We have implemented a new software pipeline to receive LIGO/Virgo alerts, schedule observations and examine the incoming real-time data stream for transient candidates. We adopt a real-bogus classifier using ensemble-based machine learning techniques, attaining high completeness (
) and purity (
) over our whole magnitude range. Applying further filtering to remove common image artefacts and known sources of transients, such as asteroids and variable stars, reduces the number of candidates by a factor of more than 10. We demonstrate the system performance with data obtained for GW190425, a binary neutron star merger detected during the LIGO/Virgo O3 observing campaign. In time for the LIGO/Virgo O4 run, we will have deeper reference images allowing transient detection to
Analyses of macroscopic charcoal, sediment geochemistry (%C, %N, C/N, δ13C, δ15N), and fossil pollen were conducted on a sediment core recovered from Stella Lake, Nevada, establishing a 2000 year record of fire history and vegetation change for the Great Basin. Charcoal accumulation rates (CHAR) indicate that fire activity, which was minimal from the beginning of the first millennium to AD 750, increased slightly at the onset of the Medieval Climate Anomaly (MCA). Observed changes in catchment vegetation were driven by hydroclimate variability during the early MCA. Two notable increases in CHAR, which occurred during the Little Ice Age (LIA), were identified as major fire events within the catchment. Increased C/N, enriched δ15N, and depleted δ13C values correspond with these events, providing additional evidence for the occurrence of catchment-scale fire events during the late fifteenth and late sixteenth centuries. Shifts in the vegetation community composition and structure accompanied these fires, with Pinus and Picea decreasing in relative abundance and Poaceae increasing in relative abundance following the fire events. During the LIA, the vegetation change and lacustrine geochemical response was most directly influenced by the occurrence of catchment-scale fires, not regional hydroclimate.
The analysis presented here was motivated by an objective of describing the interactions between the physical and biological processes governing the responses of tidal wetlands to rising sea level and the ensuing equilibrium elevation. We define equilibrium here as meaning that the elevation of the vegetated surface relative to mean sea level (MSL) remains within the vertical range of tolerance of the vegetation on decadal time scales or longer. The equilibrium is dynamic, and constantly responding to short-term changes in hydrodynamics, sediment supply, and primary productivity. For equilibrium to occur, the magnitude of vertical accretion must be great enough to compensate for change in the rate of sea-level rise (SLR). SLR is defined here as meaning the local rate relative to a benchmark, typically a gauge. Equilibrium is not a given, and SLR can exceed the capacity of a wetland to accrete vertically.
This paper examines the debate over whether Acheulean handaxe shape results from the intentional imposition of a priorly held mental template upon the lithic material substrate or, alternatively, whether a knapper's intentions related to shape ‘emerge’ through the engagement (in action) of human agency and material affordances. We suggest that imposition of form and emergence of form are not mutually exclusive, and use Lave and Wenger's concept of ‘communities of practice’ to knit these opposed views together to explain the consolidation of homogenous handaxe shape at Boxgrove, c. 500,000 years ago. Here we propose that the consistency in handaxe shape found at sites like Boxgrove is a consequence of the emergent actions of individual knappers being simultaneously constrained by the imposition of social norms. Social norms are referred to in action and are negotiated, understood, and adhered to at the wider group level. Therefore, we propose that contextualizing Acheulean handaxe manufacture within its wider social context will show that handaxe shape was both imposed and emergent, not one or the other.
The surface gravity wave pattern that forms behind a steadily moving disturbance is well known to comprise divergent waves and transverse waves, contained within a distinctive $V$-shaped wake. In this paper, we are concerned with a theoretical study of the limit of a slow-moving disturbance (small Froude numbers) in the absence of surface tension, for which the wake is dominated by transverse waves. Three configurations are considered: flow past a submerged source singularity, a submerged doublet and a pressure distribution applied to the surface. We treat the linearised version of these problems and use the method of stationary phase and exponential asymptotics to demonstrate that the apparent wake angle is less than the classical Kelvin angle and to quantify the decrease in apparent wake angle as the Froude number decreases. These results complement a number of recent studies for sufficiently fast-moving disturbances (large Froude numbers) where the apparent wake angle has been also shown to be less than the classical Kelvin angle. As well as shedding light on the issue of apparent wake angle, we also study the fully nonlinear problems for our three configurations under various limits to demonstrate the unique and interesting features of Kelvin wake patterns at small Froude numbers.
Influenza vaccination remains the most effective primary prevention strategy for seasonal influenza. This research explores the percentage of emergency medical services (EMS) clinicians who received the seasonal flu vaccine in a given year, along with their reasons for vaccine acceptance and potential barriers.
A survey was distributed to all EMS clinicians in Virginia during the 2018-2019 influenza season. The primary outcome was vaccination status. Secondary outcomes were attitudes and perceptions toward influenza vaccination, along with patient care behaviors when treating an influenza patient.
Ultimately, 2796 EMS clinicians throughout Virginia completed the survey sufficiently for analysis. Participants were mean 43.5 y old, 60.7% male, and included the full range of certifications. Overall, 79.4% of surveyed EMS clinicians received a seasonal flu vaccine, 74% had previously had the flu, and 18% subjectively reported previous side effects from the flu vaccine. Overall, 54% of respondents believed their agency has influenza or respiratory specific plans or procedures.
In a large, state-wide survey of EMS clinicians, overall influenza vaccination coverage was 79.4%. Understanding the underlying beliefs of EMS clinicians remains a critical priority for protecting these frontline clinicians. Agencies should consider practical policies, such as on-duty vaccination, to increase uptake.
Callery pear (Pyrus calleryana Decne.) is rapidly spreading in the United States, gaining attention in the last two decades as a serious invasive pest. Recommended control methods include foliar, basal bark, cut stump, and hack-and-squirt application of herbicides, but there are few published studies with replicated data on efficacy. Four readily available herbicidal active ingredients and a combination of two active ingredients were tested for control efficacy against P. calleryana in old-field areas and loblolly pine (Pinus taeda L.) understory. Basal bark applications (triclopyr, triclopyr + aminopyralid), foliar applications (glyphosate, imazapyr), and a soil application (hexazinone) effectively killed P. calleryana with the exception of hexazinone at one site, where rainfall may not have been optimal. Foliar application of glyphosate provided the most consistent control. Our results demonstrate efficacy of registered herbicide formulations for P. calleryana control in two geographic locations and two habitat types. The need for development of integrated pest management programs for P. calleryana is discussed.
This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience.
We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression.
Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma.
These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.
Operators are mindful of the balloon-to-aortic annulus ratio when performing balloon aortic valvuloplasty. The method of measurement of the aortic valve annulus has not been standardised.
Methods and results:
Patients who underwent aortic valvuloplasty at two paediatric centres between 2007 and 2014 were included. The valve annulus measured by echocardiography and angiography was used to calculate the balloon-to-aortic annulus ratio and measurements were compared. The primary endpoint was an increase in aortic insufficiency by ≥2 degrees. Ninety-eight patients with a median age at valvuloplasty of 2.1 months (Interquartile range (IQR): 0.2–105.5) were included. The angiographic-based annulus was 8.2 mm (IQR: 6.8–16.0), which was greater than echocardiogram-based annulus of 7.5 mm (IQR: 6.1–14.8) (p < 0.001). This corresponded to a significantly lower angiographic balloon-to-aortic annulus ratio of 0.9 (IQR: 0.9–1.0), compared to an echocardiographic ratio of 1.1 (IQR: 1.0–1.1) (p < 0.001). The degree of discrepancy in measured diameter increased with smaller valve diameters (p = 0.041) and in neonates (p = 0.044). There was significant disagreement between angiographic and echocardiographic balloon-to-aortic annulus ratio measures regarding “High” ratio of >1.2, with angiographic ratio flagging only 2/12 (16.7%) of patients flagged by echocardiographic ratio as “High” (p = 0.012). Patients who had an increase in the degree of aortic insufficiency post valvuloplasty, only 3 (5.5%) had angiographic ratio > 1.1, while 21 (38%) had echocardiographic ratio >1.1 (p < 0.001). Patients with resultant ≥ moderate insufficiency more often had an echocardiographic ratio of >1.1 than angiographic ratio of >1.1 There was no association between increase in balloon-to-aortic annulus ratio and gradient reduction.
Angiographic measurement is associated with a greater measured aortic valve annulus and the development of aortic insufficiency. Operators should use caution when relying solely on angiographic measurement when performing balloon aortic valvuloplasty.
The CDC recommends that consultant pharmacists support antimicrobial stewardship programs (ASPs) in long-term care facilities (LTCFs). We studied CDC-recommended ASP core elements implementation and antibiotic use in LTCFs before and after training consultant pharmacists. Methods: Between August 2017 and October 2017, consultant pharmacists from a regional long-term care pharmacy attended 5 didactic sessions preparing them to assist LTCFs in implementation of CDC-recommended ASP core elements. Training also included creating a process for evaluating appropriateness of all systemic antibiotics and providing prescriber feedback during their monthly mandatory drug-regimen reviews. Once monthly “meet-the-expert” sessions were held with consultant pharmacists throughout the project (November 2017 to December 2018). LTCF enrollment began in November 2017 and >90% of facilities joined by January 2018. After enrollment, consultant pharmacists initiated ASP interventions including antibiotic reviews and feedback using standard templates. They also held regular meetings with infection preventionists to discuss Core Elements implementation and provided various ASP resources to LTCFs (eg, antibiotic policy template, guidance documents and standard assessment and communication tools). Data collection included ASP Core Elements, antibiotic starts, days of therapy (DOT), and resident days (RD). The McNemar test, the Wilcoxon signed-rank test, generalized estimating equation model, and the classic repeated measures approach were used to compare the presence of all 7 core elements and antibiotic use during the baseline (2017) and intervention (2018) year.Results: In total, 9 trained consultant pharmacists assisted 32 LTCFs with ASP implementation. When evaluating 27 LTCFs that provided complete data, a significant increase in presence of all 7 Core Elements after the intervention was noted compared to baseline (67% vs 0; median Core Elements, 7 vs 2; range, 6–7 vs 1–6; P < .001). Median monthly antibiotic starts per 1,000 RD and DOT per 1,000 RD decreased in 2018 compared to 2017: 8.93 versus 9.91 (P < .01) and 106.47 versus 141.59 (P < .001), respectively. However, variations in antibiotic use were detected among facilities (Table 1). When comparing trends, antibiotic starts and DOT were already trending downward during 2017 (Fig. 1A and 1B). On average, antibiotic starts decreased by 0.27 per 1,000 RD (P < .001) and DOT by 1.92 per 1,000 RD (P < .001) each month during 2017. Although antibiotic starts remained mostly stable in 2018, DOT continued to decline further (average monthly decline, 2.60 per 1,000 RD; P < .001). When analyzing aggregated mean, antibiotic use across all sites per month by year, DOT were consistently lower throughout 2018 and antibiotic starts were lower for the first 9 months (Fig. 1C and 1D). Conclusions: Consultant pharmacists can play an important role in strengthening ASPs and in decreasing antibiotic use in LTCFs. Educational programs should be developed nationally to train long-term care consultant pharmacists in ASP implementation.
Funding: Merck & Co., Inc, provided funding for this study.
Disclosures: Muhammad Salman Ashraf and Scott Bergman report receipt of a research grant from Merck.
To investigate the molecular epidemiology of methicillin-susceptible Staphylococcus aureus (MSSA) in infants in a neonatal intensive care unit (NICU) using whole-genome sequencing.
Investigation of MSSA epidemiology in a NICU.
Single-center, level IV NICU.
Universal S. aureus screening was done using a single swab obtained from the anterior nares, axilla, and groin area of infants in the NICU on a weekly basis. Core genome multilocus sequence type (cgMLST) analysis was performed on MSSA isolates detected over 1 year (2018–2019).
In total, 68 MSSA-colonized infants were identified, and cgMLSTs of 67 MSSA isolates were analyzed. Overall, we identified 11 cgMLST isolate groups comprising 39 isolates (58%), with group sizes ranging from 2 to 10 isolates, and 28 isolates (42%) were unrelated to each other or any of the isolate groups. Cases of infants colonized by MSSA were scattered throughout the 1-year study period, and isolates belonging to the same cgMLST group were typically detected contemporaneously, over a few weeks or a few months. Overall, 13 infants (19.7%) developed MSSA infections: bacteremia (n = 3), wound infection (n = 5), conjunctivitis (n = 4), and cellulitis (n = 1). We detected no association between these clinically manifest infections and specific cgMLST groups.
Although MSSA isolates in infants in a NICU showed high diversity, most were related to other isolates, albeit within small groups. cgMLST facilitates an understanding of the complex transmission dynamics of MSSA in NICUs, and these data can be used to inform better control strategies.
To create a reliable radiocarbon calibration curve, one needs not only high-quality data but also a robust statistical methodology. The unique aspects of much of the calibration data provide considerable modeling challenges and require a made-to-measure approach to curve construction that accurately represents and adapts to these individualities, bringing the data together into a single curve. For IntCal20, the statistical methodology has undergone a complete redesign, from the random walk used in IntCal04, IntCal09 and IntCal13, to an approach based upon Bayesian splines with errors-in-variables. The new spline approach is still fitted using Markov Chain Monte Carlo (MCMC) but offers considerable advantages over the previous random walk, including faster and more reliable curve construction together with greatly increased flexibility and detail in modeling choices. This paper describes the new methodology together with the tailored modifications required to integrate the various datasets. For an end-user, the key changes include the recognition and estimation of potential over-dispersion in 14C determinations, and its consequences on calibration which we address through the provision of predictive intervals on the curve; improvements to the modeling of rapid 14C excursions and reservoir ages/dead carbon fractions; and modifications made to, hopefully, ensure better mixing of the MCMC which consequently increase confidence in the estimated curve.
Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.
Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).
At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).
Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.
Carrot weevil, Listronotus oregonensis (LeConte) (Coleoptera: Curculionidae), is a pest of carrot (Daucus carota var. sativus Hoffmann; Apiaceae) throughout eastern Canada. Carrot weevil emergence and oviposition were monitored in commercial carrot fields in Nova Scotia. Cumulative degree days were calculated using a base temperature of 7 °C (DD7), and models were developed to predict cumulative emergence and oviposition using nonlinear regression. Cumulative emergence and oviposition were adequately explained as functions of DD7 by a three-parameter sigmoidal Hill equation. Our emergence model predicted initial and peak adult emergence at 35 and 387 DD7, respectively, with oviposition on carrot baits occurring as early as 42 DD7. Models were then validated to evaluate how well they performed. Oviposition on carrot plants began at the fourth true-leaf stage (342 DD7) and continued until eleventh true-leaf stage. Growers using these models can identify their window of opportunity to manage their carrot weevil populations targeting the majority of emerged adults before oviposition begins in the field.
Are communicators perceived as committed to what they actually say (what is explicit), or to what they mean (including what is implicit)? Some research claims that explicit communication leads to a higher attribution of commitment and more accountability than implicit communication. Here we present theoretical arguments and experimental data to the contrary. We present three studies exploring whether the saying–meaning distinction affects commitment attribution in promises, and, crucially, whether commitment attribution is further modulated by the degree to which the hearer will actually rely on the promise. Our results support the conclusion that people perceive communicators to be committed to ‘what is meant’, and not simply to ‘what is said’. Our findings add to the experimental literature showing that the saying–meaning distinction is not as pivotal to social relations as often assumed, and that its role in commitment attribution might be overestimated. The attribution of commitment is strongly dependent on the (mutually known) relevance of ‘what is meant’.
Death is a universal and profoundly emotive human experience with social and economic implications that extend to communities as a whole. As such, the act of disposing of the dead is typically laden with deep meaning and significance. Archaeological investigations of funerary practices are thus important sources of information on the social contexts and worldviews of ancient societies. Changes in funerary practices are often thought to reflect organisational or cosmological transformations within a society (Carr 1995; Robb 2013). The focus of this volume is the role of cognition and consciousness in the accelerated sociocultural developments of the Neolithic Period in the Near East. In the introduction to this volume, Hodder identifies three commonly cited cognitive changes that can be measured against various archaeological datasets from Çatalhöyük. The funerary remains at Çatalhöyük are an obvious source of data for validating Hodder’s third measure of change: a shift from a fluid and fragmented conception of the body and of selfhood to a greater awareness of an integrated, bounded personal self.
Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction.
Methods and Results:
Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed between 1 January, 1982 and 31 December, 2011, were identified from the Muscular Dystrophy Surveillance Tracking and Research Network database. Two non-mutually exclusive groups were created: patients with ≥2 echocardiograms and non-invasive positive pressure ventilation-compliant patients with ≥1 recorded ejection fraction. Quantitative left ventricular dysfunction was defined as an ejection fraction <55%. Qualitative dysfunction was defined as mild, moderate, or severe. Progression of quantitative left ventricular dysfunction was modelled as a continuous time-varying outcome. Change in qualitative left ventricle function was assessed by the percentage of patients within each category at each age. Forty-one percent (n = 403) had ≥2 ejection fractions containing 998 qualitative assessments with a mean age at first echo of 10.8 ± 4.6 years, with an average first ejection fraction of 63.1 ± 12.6%. Mean age at first echo with an ejection fraction <55 was 15.2 ± 3.9 years. Thirty-five percent (140/403) were non-invasive positive pressure ventilation-compliant and had ejection fraction information. The estimated rate of decline in ejection fraction from first ejection fraction was 1.6% per year and initiation of non-invasive positive pressure ventilation did not change this rate.
In our cohort, we observed that left ventricle function in patients with Duchenne muscular dystrophy declined over time, independent of non-invasive positive pressure ventilation use. Future studies are needed to examine the impact of respiratory support on cardiac function.