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Duchenne muscular dystrophy is a devastating neuromuscular disorder characterized by the loss of dystrophin, inevitably leading to cardiomyopathy. Despite publications on prophylaxis and treatment with cardiac medications to mitigate cardiomyopathy progression, gaps remain in the specifics of medication initiation and optimization.
Method:
This document is an expert opinion statement, addressing a critical gap in cardiac care for Duchenne muscular dystrophy. It provides thorough recommendations for the initiation and titration of cardiac medications based on disease progression and patient response. Recommendations are derived from the expertise of the Advance Cardiac Therapies Improving Outcomes Network and are informed by established guidelines from the American Heart Association, American College of Cardiology, and Duchenne Muscular Dystrophy Care Considerations. These expert-derived recommendations aim to navigate the complexities of Duchenne muscular dystrophy-related cardiac care.
Results:
Comprehensive recommendations for initiation, titration, and optimization of critical cardiac medications are provided to address Duchenne muscular dystrophy-associated cardiomyopathy.
Discussion:
The management of Duchenne muscular dystrophy requires a multidisciplinary approach. However, the diversity of healthcare providers involved in Duchenne muscular dystrophy can result in variations in cardiac care, complicating treatment standardization and patient outcomes. The aim of this report is to provide a roadmap for managing Duchenne muscular dystrophy-associated cardiomyopathy, by elucidating timing and dosage nuances crucial for optimal therapeutic efficacy, ultimately improving cardiac outcomes, and improving the quality of life for individuals with Duchenne muscular dystrophy.
Conclusion:
This document seeks to establish a standardized framework for cardiac care in Duchenne muscular dystrophy, aiming to improve cardiac prognosis.
Hypertensive heart disease and hypertrophic cardiomyopathy both lead to left ventricular hypertrophy despite differing in aetiology. Elucidating the correct aetiology of the presenting hypertrophy can be a challenge for clinicians, especially in patients with overlapping risk factors. Furthermore, drugs typically used to combat hypertensive heart disease may be contraindicated for the treatment of hypertrophic cardiomyopathy, making the correct diagnosis imperative. In this review, we discuss characteristics of both hypertensive heart disease and hypertrophic cardiomyopathy that may enable clinicians to discriminate the two as causes of left ventricular hypertrophy. We summarise the current literature, which is primarily focused on adult populations, containing discriminative techniques available via diagnostic modalities such as electrocardiography, echocardiography, and cardiac MRI, noting strategies yet to be applied in paediatric populations. Finally, we review pharmacotherapy strategies for each disease with regard to pathophysiology.
We study the meteorological drivers of melt at two glaciers in Taylor Valley, Antarctica, using 22 years of weather station observations and surface energy fluxes. The glaciers are located only 30 km apart, but have different local climates; Taylor Glacier is generally drier and windier than Commonwealth Glacier, which receives more snowfall due to its proximity to the coast. Commonwealth Glacier shows more inter-annual melt variability, explained by variable albedo due to summer snowfall events. A significant increase in surface melt at Commonwealth Glacier is associated with a decrease in summer minimum albedo. Inter-annual variability in melt at both glaciers is linked to degree-days above freezing during föhn events, occurring more frequently at Taylor Glacier. At Taylor Glacier melt occurs most often with positive air temperatures, but föhn conditions also favour sublimation, which cools the surface and prevents melt for the majority of the positive air temperatures. At Commonwealth Glacier, most of the melt instead occurs with sub-zero air temperatures, driven by strong solar radiative heating. Future melt at Taylor Glacier will likely be more sensitive to changes in föhn events, while Commonwealth Glacier will be impacted more by changes in near coastal weather, where moisture inputs can drive cloud cover, snowfall and change albedo.
In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD.
Methods
Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores.
Results
Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores.
Conclusions
Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.
Ice streams are warmed by shear strain, both vertical shear near the bed and lateral shear at the margins. Warm ice deforms more easily, establishing a positive feedback loop in an ice stream where fast flow leads to warm ice and then to even faster flow. Here, we use radar attenuation measurements to show that the Siple Coast ice streams are colder than previously thought, which we hypothesize is due to along-flow advection of cold ice from upstream. We interpret the attenuation results within the context of previous ice-temperature measurements from nearby sites where hot-water boreholes were drilled. These in-situ temperatures are notably colder than model predictions, both in the ice streams and in an ice-stream shear margin. We then model ice temperature using a 1.5-dimensional numerical model which includes a parameterization for along-flow advection. Compared to analytical solutions, we find depth-averaged temperatures that are colder by 0.7°C in the Bindschadler Ice Stream, 2.7°C in the Kamb Ice Stream and 6.2–8.2°C in the Dragon Shear Margin of Whillans Ice Stream, closer to the borehole measurements at all locations. Modelled cooling corresponds to shear-margin thermal strengthening by 3–3.5 times compared to the warm-ice case, which must be compensated by some other weakening mechanism such as material damage or ice-crystal fabric anisotropy.
To explore associations between maternal pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects.
Design:
This is a population-based, case–control study using maternal responses to a dietary assessment and published arsenic concentration estimates in food items to calculate average daily total and inorganic arsenic exposure during the year before pregnancy. Assigning tertiles of total and inorganic arsenic exposure, logistic regression analysis was used to estimate OR for middle and high tertiles, compared to the low tertile.
Setting:
US National Birth Defects Prevention Study, 1997–2011.
Participants:
Mothers of 10 446 children without birth defects and 14 408 children diagnosed with a non-cardiac birth defect.
Results:
Maternal exposure to total dietary arsenic in the middle and high tertiles was associated with a threefold increase in cloacal exstrophy, with weak positive associations (1·2–1·5) observed either in both tertiles (intercalary limb deficiency) or the high tertile only (encephalocele, glaucoma/anterior chamber defects and bladder exstrophy). Maternal exposure to inorganic arsenic showed mostly weak, positive associations in both tertiles (colonic atresia/stenosis, oesophageal atresia, bilateral renal agenesis/hypoplasia, hypospadias, cloacal exstrophy and gastroschisis), or the high (glaucoma/anterior chamber defects, choanal atresia and intestinal atresia stenosis) or middle (encephalocele, intercalary limb deficiency and transverse limb deficiency) tertiles only. The remaining associations estimated were near the null or inverse.
Conclusions:
This exploration of arsenic in diet and non-cardiac birth defects produced several positive, but mostly weak associations. Limitations in exposure assessment may have resulted in exposure misclassification. Continued research with improved exposure assessment is recommended to identify if these associations are true signals or chance findings.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
A key barrier to translation of biomedical research discoveries is a lack of understanding among scientists regarding the complexity and process of implementation. To address this challenge, the National Science Foundation’s Innovation Corps™ (I-Corps™) program trains researchers in entrepreneurship. We report results from the implementation of an I-Corps™ training program aimed at biomedical scientists from institutions funded by the National Center for Advancing Translational Sciences (NCATS).
Methods:
National/regional instructors delivered 5-week I-Corps@NCATS short courses to 62 teams (150 individuals) across six institutions. Content included customer discovery, value proposition, and validating needs. Teams interviewed real-life customers and presented the value of innovations for specific end-users weekly, culminating in a “Finale” featuring their refined business thesis and business model canvas. Methodology was developed to evaluate the newly adapted program. National mixed-methods evaluation assessed program implementation, reach, effectiveness using observations of training delivery and surveys at Finale (n = 55 teams), and 3–12 months post-training (n = 34 teams).
Results:
Innovations related to medical devices (33%), drugs/biologics (20%), software applications (16%), and diagnostics (8%). An average of 24 interviews was conducted. Teams reported increased readiness for commercialization over time (83%, 9 months; 14%, 3 months). Thirty-nine percent met with institutional technology transfer to pursue licensing/patents and 24% pursued venture capital/investor funding following the short courses.
Conclusions:
I-Corps@NCATS training provided the NCATS teams a rigorous and repeatable process to aid development of a business model based on customer needs. Outcomes of this pilot program support the expansion of I-Corps™ training to biomedical scientists for accelerating research translation.
A simple model using once-daily US National Centers for Environmental Prediction/US National Center for Atmospheric Research (NCEP/NCAR) re-analysis upper-air values estimates winter balance, summer balance and net balance at ten glaciers in Norway and two in Sweden with 0.37 ≤ r2 ≤ 0.90. The October-May Arctic Oscillation (AO), an index of sea-level pressure (SLP) in the Northern Hemisphere, correlates with winter balance and net balance with 0.09 ≤ r2 ≤ 0.82, lower than the model in all but 3 of the 24 cases. The October-May North Atlantic Oscillation (NAO), an SLP gradient in the North Atlantic, has lower correlations than the AO for all but 5 of the 24 cases. At all ten glaciers with records beginning before 1987, net balance became more positive after 1988, owing mainly to increased winter balance, with summer balance changing little. Although winter temperatures increased, they were still well below freezing, so the rain-snow division of the precipitation was only slightly affected. Increase in winter balance was due to increased precipitation caused by a change in atmospheric circulation, resulting in more frequent westerly flow concurrent with the warming. At 850 hPa, westerly flow is ≈2.5˚C warmer than easterly flow; westerly flow warmed by ≈ 0.3 °C, easterly by ≈ 0.7 °C. Both the AO and NAO, with which winter balance is positively correlated at all 12 glaciers, were more positive after 1988.
Six snow-pit records recovered from Siple Dome, West Antarctica, during 1994 are used to study seasonal variations in chemical (major ion and H202), isotopic (deuterium) and physical stratigraphic properties during the 1988-94 period. Comparison of δD measurements and satellite-derived brightness temperature for the Siple Dome area suggests that most seasonal SD maxima occur within ±4 weeks of each 1 January. Several other chemical species (H2O2, non-sea-salt (nss) SO42-, methanesulfonic acid and NO3-) show coeval peaks with SD, together providing an accurate method for identifying summer accumulation. Sea-salt-derived species generally peak during winter/spring, but episodic input is noted throughout some years. No reliable seasonal signal is identified in species with continental sources (nssCa2+ nss Mg2+), NH4+ or nssCl-. Visible strata such as large depth-hoar layers (>5 cm) are associated with summer accumulation and its metamorphosis, but smaller hoar layers and crusts are more difficult to interpret. A multi-parameter approach is found to provide the most accurate dating of these snow-pit records, and is used to determine annual layer thicknesses at each site Significant spatial accumulation variability exists on an annual basis, but mean accumulation in the sampled 10 km2 grid for the 1988-94 period is fairly uniform.
A model using upper-air meteorological variables in the US National Centers for Environmental Prediction and US National Center for Atmospheric Research (NCEP/NCAR) re-analysis database is used to extend net balance bn back to 1948 for seven glaciers in southern Norway. The observational record of another glacier, Storbreen, began in 1948. Over the observational record of each of the seven glaciers, correlation with Storbreen estimates bn more accurately than the upper-air model does for four of them and less accurately for three. In all seven cases, however, an average of the model and the Storbreen correlation is more accurate than either alone, so the average is used to reconstruct bn for years when it was not observed. For the seven glaciers other than Storbreen, a combined series is formed from observations during their period of record and from reconstructed values prior to then back to 1948. There are three distinct sections in all eight bn series: prior to 1989; 1989–1995, when the North Atlantic Oscillation index was strongly positive; and after 1995. The 1989–95 mean bn was anomalously positive because of both decreased ablation and especially increased accumulation. The mean bn since 1995 has been anomalously negative because of increased ablation, whilst accumulation has been nearly the same as over 1948–88. The first principal component of the eight 1949–2005 bn series explains 78% of the total variance, and the second explains 12%. Over 1949–88 there were no substantial shifts in bn or in either winter balance bw or summer balance bs at any of the seven glaciers where observations began after 1948, nor were there in the Storbreen record. There is a distinction between the three glaciers that gained mass over 1948–2005 and the five that lost mass. Each of the three that gained had accumulation-area ratio AAR ≥ 0.64 and <0.7% of its area δS in the lowest tenth of its altitude range, while the five that lost had AAR ≤ 0.46 and 1.9 ≤ δS ≤ 4.4%. Because of these hypsometries, the five glaciers that lost mass now have an especially large ablation area.
Satellite images of Kamb Ice Stream (formerly Ice Stream C), West Antarctica, reveal several long, curved linear features (lineations) oriented sub-parallel to the ice-flow direction. We use ground-based radar to characterize the internal layer stratigraphy of these lineations and the terrains that they bound. Some lineations are relict ice-stream shear margins, identified by hyperbolic diffractors near the surface (interpreted to be buried crevasses) and highly disturbed internal layers at depth. Satellite images show another set of lineations outside the relict margins that wrap around the ends of the surrounding inter-ice-stream ridges. Internal layers beneath these lineations are downwarped strongly into a syncline shape. The internal stratigraphy of the terrain between these lineations and the relict margins is characterized by deep hyperbolic line diffractors. Our preferred hypothesis for the origin of this terrain is that it was floating sometime in the past; the deep hyperbolas are interpreted to be basal crevasses, and the strongly downwarped internal layers mark the position of a relict grounding line. Our study shows that lineations and intervening terrains have different internal layer characteristics implying different origins. Differentiation between these features is not possible using satellite images alone.
Precipitation at 2050 m on Blue Glacier, U.S.A., was measured daily from August 1957 through July 1958. Its correlation with a nearby lowland station with a good, long-term (1914–96) record is used to estimate precipitation on the glacier over that entire period. Average annual precipitation on Blue Glacier is 4500 mm w.e. Snowfall depends on the joint distribution of precipitation and temperature. Over the period 1948–96, for which twice-daily radiosonde observations are available, temperature at any elevation on the glacier is interpolated in the radiosonde profile to partition the precipitation as either rain or snow. Daily partitioning is preferred, especially during spring and autumn storms when averaging over longer periods may substantially under- or overestimate snowfall on the glacier. Prior to 1948, snowfall is estimated from the mean over 1948–96, in a particular month and elevation, of the fraction of the precipitation falling as snow. The standard error in the October–May snowfall at 2100 m is estimated to be 250 mm w.e. during the radiosonde era (1948–96) and 350 mm prior to that. For the first 10 years or so after mass-balance measurements began at Blue Glacier (1957), precipitation increased and winter temperature at 850 mbar (about 1450 m) decreased, but since then the trends have reversed. The combined effect, increasing snowfall until 1965 and decreasing since, closely parallels measured mass changes of Blue Glacier. When the average vertical profile of total annual snowfall is subjected to a hypothetical 1 K warming, the resulting reduction in snowfall is greatest at the glacier terminus and decreases up-glacier; the average over the entire glacier is 300 mm w.e.