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This study evaluated bone health outcomes of parathyroidectomy in elderly primary hyperparathyroidism (pHPT) patients.A retrospective review was performed of parathyroidectomy patients with pHPT at a single institution from 2010 to 2019. Bone mineral density (BMD) improvements at postoperative dual-energy X-ray absorptiometry (DEXA) scans were analyzed between groups aged ≥75 and 75 years using 1:1 matching on preoperative BMD.Patients ≥75 had BMD improvements through the second postoperative DEXA scans. While mean T-scores slightly improved in the ≥75 group during the study period, T-score improvement was more significant in the75 group at first and third postoperative DEXA scans with +0.7 75 and +0.1 improvements ≥75 by the third DEXA (p = 0.026). Postoperative fragility fracture rates were similar in the ≥75 group, but significantly improved in patients75 (10.4% preoperatively to 1.4% postoperatively, p = 0.020). Both cohorts had low complication rates with recurrent laryngeal nerve injury and permanent hypocalcemia of1% (p = 0.316).Postoperative BMD improvement was similar between the two cohorts with no difference in complication rates suggesting parathyroidectomy is safe and effective in the elderly.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder characterized by loss of motor neurons leading to muscle weakness and atrophy. The United States’ Food and Drug Administration’s (FDA) approval of nusinersen, onasemnogene abeparvovec, and risdiplam for SMA has challenged existing treatment paradigms with multiple treatment options, a new natural history of the disease, and an emerging understanding of the importance of early and pre-symptomatic treatment. The profound impact of early, pre-symptomatic treatment has led to the creation of a neurogenetics urgency for newly identified patients with SMA, a novel problem for neurologists more accustomed to a more methodical approach to diagnosis and care. Implementation of newborn screening programs has helped facilitate early diagnosis and treatment, but challenges remain in overcoming administrative and procedural hurdles that can lead to treatment delays. Herein I discuss two cases that highlight the importance of early treatment, as well as gaps in our understanding of the progression of SMA in pre-symptomatic infants.

Background Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often nonspecific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet‐primed PCR (TP‐PCR) is technically challenging and cost prohibitive for population surveys. Methods Here, we present a high throughput, low‐cost screening tool for CTG repeat expansions using TP‐PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye. Results We determined that multimodal melt profiles from the TP‐PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri‐modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles. Conclusion We demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large‐scale testing programs such as population studies and newborn screening programs., Myotonic dystrophy type 1 is one of the most common forms of muscular dystrophy, caused by a CTG repeat expansion in the DMPK gene. Here, we present a high throughput, low‐cost screening tool to detect an expansion of the CTG repeat using TP‐PCR followed by melt curve analysis with saturating concentrations of SYBR GreenER dye. We demonstrate that accurate and robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots.

Objective:To determine whether the genetic prevalence of the CTG expansion in the DMPK gene associated with myotonic dystrophy (DM1) in an unbiased cohort is higher than previously reported population estimates, ranging from 5-20 per 100,000 individuals.Methods:This study used a cross-sectional cohort of de-identified dried blood spots (DBS) from the newborn screening program in the state of New York, taken from consecutive births from 2013-2014. Blood spots were screened for the CTG repeat expansion in the DMPK gene using triplet-repeat primed PCR and melt curve analysis. Melt curve morphology was assessed by four blinded reviewers to identify samples with possible CTG expansion. Expansion of the CTG repeat was validated by PCR fragment sizing using capillary electrophoresis for samples classified as positive or premutation to confirm the result. Prevalence was calculated as the number of samples with CTG repeat size ≥50 repeats compared to the overall cohort.Results:Out of 50,382 consecutive births, there were 24 with a CTG repeat expansion ≥50, consistent with a diagnosis of DM1. This represents a significantly higher DM1 prevalence of 4.76 per 10,000 births (95%CI 2.86, 6.67) or 1 in every 2,100 births. There were an additional 96 samples (19.1 per 10,000 or 1 in 525 births) with a CTG expansion in the DMPK gene in the premutation range (CTG)35-49.Conclusions:The prevalence of individuals with CTG repeat expansions in DMPK is up to five times higher than previous reported estimates. This suggests DM1, with multisystemic manifestations, is likely underdiagnosed in practice.

Increasing temperatures and drought in desert ecosystems are predicted to cause decreased vegetation density combined with barren ground expansion. It remains unclear how nutrient availability, microbial diversity, and the associated functional capacity vary between the vegetated canopy and gap soils. The specific aim of this study was to characterize canopy versus gap microsite effect on soil microbial diversity, the capacity of gap soils to serve as a canopy soil microbial reservoir, nitrogen (N)-mineralization genetic potential (ureC gene abundance) and urease enzyme activity, and microbial-nutrient pool associations in four arid-hyperarid geolocations of the western Sonoran Desert, Arizona, United States. Microsite combined with geolocation explained 57% and 45.8% of the observed variation in bacterial/archaeal and fungal community composition, respectively. A core microbiome of amplicon sequence variants was shared between the canopy and gap soil communities; however, canopy soils included abundant taxa that were not present in associated gap communities, thereby suggesting that these taxa cannot be sourced from the associated gap soils. Linear mixed-effects models showed that canopy soils have significantly higher microbial richness, nutrient content, and organic N-mineralization genetic and functional capacity. Furthermore, ureC gene abundance was detected in all samples, suggesting that ureC is a relevant indicator of N mineralization in deserts. Additionally, novel phylogenetic associations were observed for ureC, with the majority belonging to Actinobacteria and uncharacterized bacteria. Thus, key N-mineralization functional capacity is associated with a dominant desert phylum. Overall, these results suggest that lower microbial diversity and functional capacity in gap soils may impact ecosystem sustainability as aridity drives open-space expansion in deserts. IMPORTANCE Increasing aridity will drive a shift in desert vegetation and interspace gap (microsite) structure toward gap expansion. To evaluate the impact of gap expansion, we assess microsite effects on soil nutrients, microbiome community composition and functional capacity, and the potential of gap soils to serve as microbial reservoirs for plant root-associated microbiomes in an arid ecosystem. Results indicate that gap soils have significantly lower bioavailable nutrients, microbial richness, and N-mineralization functional capacity. Further, abundance of the bacterial urease gene (ureC) correlates strongly with N availability, and its major phylogenetic association is with Actinobacteria, the dominant phylum found in deserts. This finding is relevant because it identifies an important N-mineralization capacity indicator in the arid soil microbiome. Such indicators are needed to understand the relationships between interplant gap expansion and microbial diversity and functional potential associated with plant sustainability. This will be a critical step in recovery of land degraded by aridity stress.

Biological diversity depends on multiple, cooccurring ecological interactions. However, most studies focus on one interaction type at a time, leaving community ecologists unsure of how positive and negative associations among species combine to influence biodiversity patterns. Using surveys of plant populations in alpine communities worldwide, we explore patterns of positive and negative associations among triads of species (modules) and their relationship to local biodiversity. Three modules, each incorporating both positive and negative associations, were overrepresented, thus acting as "network motifs." Furthermore, the overrepresentation of these network motifs is positively linked to species diversity globally. A theoretical model illustrates that these network motifs, based on competition between facilitated species or facilitation between inferior competitors, increase local persistence. Our findings suggest that the interplay of competition and facilitation is crucial for maintaining biodiversity. ISSN:0027-8424 ISSN:1091-6490

Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.

Introduction The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Materials and Methods A retrospective review of 472 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within six months of death were included. A total of 164 patients were eligible for analysis. Results Overall rates of visceral and distant metastases, including the lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p-value = 0.07). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusion The emergence of new systemic therapies for mPC is changing the natural history of the disease. Visceral metastases are being seen with increasing frequency than in the past. This observation is important for clinicians who are monitoring patients with prostate cancer to maintain a high suspicion for visceral disease.

[Motivation]: Trait data are fundamental to the quantitative description of plant form and function. Although root traits capture key dimensions related to plant responses to changing environmental conditions and effects on ecosystem processes, they have rarely been included in large-scale comparative studies and global models. For instance, root traits remain absent from nearly all studies that define the global spectrum of plant form and function. Thus, to overcome conceptual and methodological roadblocks preventing a widespread integration of root trait data into large-scale analyses we created the Global Root Trait (GRooT) Database. GRooT provides ready to use data by combining the expertise of root ecologists with data mobilization and curation. Specifically, we (a) determined a set of core root traits relevant to the description of plant form and function based on an assessment by experts, (b) maximized species coverage through data standardization within and among traits, and (c) implemented data quality checks., [Main types of variables contained]: GRooT contains 114,222 trait records on 38 continuous root traits.Spatial location and grain: Global coverage with data from arid, continental, polar, temperate and tropical biomes. Data on root traits were derived from experimental studies and field studies., [Time period and grain]: Data were recorded between 1911 and 2019., [Major taxa and level of measurement]: GRooT includes root trait data for which taxonomic information is available. Trait records vary in their taxonomic resolution, with subspecies or varieties being the highest and genera the lowest taxonomic resolution available. It contains information for 184 subspecies or varieties, 6,214 species, 1,967 genera and 254 families. Owing to variation in data sources, trait records in the database include both individual observations and mean values., [Software format]: GRooT includes two csv files. A GitHub repository contains the csv files and a script in R to query the database., The study has been supported by the TRY initiative on plant traits (http://www.try-db.org). The TRY initiative and database are hosted, developed and maintained at the Max Planck Institute for Biogeochemistry, Jena, Germany. TRY is currently supported by DIVERSITAS/Future Earth and the German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig. Open access funding enabled and organized by Projekt DEAL.

Background Trigeminal neuralgia (TN) refractory to medical management is often treated with microvascular decompression (MVD) involving the intracranial placement of Teflon. The placement of Teflon is an effective treatment, but does apply distributed pressure to the nerve and has been associated with pain recurrence. Objective To report the rate of postoperative pain recurrence in TN patients who underwent MVD surgery using a transposition technique with fibrin glue without Teflon. Methods Patients were eligible for our study if they were diagnosed with TN, did not have multiple sclerosis, and had an offending vessel that was identified and transposed with fibrin glue at our institution. All eligible patients were given a follow-up survey. We used a Kaplan-Meier (KM) model to estimate overall pain recurrence. Results A total of 102 patients met inclusion criteria, of which 85 (83%) responded to our survey. Overall, 76 (89.4%) participants responded as having no pain recurrence. Approximately 1-yr pain-free KM estimates were 94.1% (n = 83), 5-yr pain-free KM estimates were 94.1% (n = 53), and 10-yr pain-free KM estimates were 83.0% (n = 23). Conclusion Treatment for TN with an MVD transposition technique using fibrin glue may avoid some cases of pain recurrence. The percentage of patients in our cohort who remained pain free at a maximum of 17 yr follow-up is on the high end of pain-free rates reported by MVD studies using Teflon. These results indicate that a transposition technique that emphasizes removing any compression near the trigeminal nerve root provides long-term pain-free rates for patients with TN.

BACKGROUND: Reduced level of consciousness (LOC) is a common cause of presentation among acutely ill adults in sub-Saharan Africa (SSA) and is associated with high rates of mortality. Although the Full Outline of Unresponsiveness (FOUR) score is often used in clinical practice, its utility in predicting mortality has not been assessed in the region. METHODS: We prospectively enrolled adults presenting with reduced LOC to Mbarara Regional Referral Hospital in Uganda. We recorded clinical and laboratory data and performed the FOUR and Glasgow Coma Scale (GCS) scores at admission. We used survival analysis and fit cox proportional hazards regression models to assess the predictive properties of the two scores and compared their performance using area under the receiver operating characteristic curve (AUROC). RESULTS: We enrolled 359 patients, mean (SD) age was 51 (22.2) years and 58% (210/359) were male. The median (Interquartile range) admission FOUR and GCS scores were 13.0 (3.0–16.0) and 10.0 (3.0–14.0) respectively. Subjects with a FOUR score of 0–11 had a 2.6-fold higher hazard of 30-day mortality (HR 2.6, 95% CI, 1.9 – 3.6, p < 0.001) compared to those with a score of 12–16. Those with a GCS score of 3–8 had a 2.7-fold higher hazard of 30-day mortality (HR 2.7, 95% CI 2.0–3.8, p < 0.001) compared to those with a score of 9–15. The AUROC, (95% CI) for the FOUR score and GCS score were 0.68 (0.62–0.73) and 0.67 (0.62–0.73) respectively (P=0.825). CONCLUSION: The FOUR score is comparable to the GCS score in predicting mortality in Uganda. Our findings support the introduction of FOUR score in guiding the management of patients with reduced LOC in sub-Saharan Africa.

BACKGROUND Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.

The coronavirus disease 2019 (COVID‐19) pandemic has resulted in the reorganization of health‐care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID‐19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon‐skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health‐care provider, considering any geographic or institution‐specific policies and precautions for COVID‐19. We advocate for continuing multidisciplinary care for these patients using telehealth.

The coronavirus disease 2019 (COVID‐19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID‐19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID‐19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic‐ or institution‐specific policies and precautions for COVID‐19.

Background. Neuroanatomic locations of gliomas may influence clinical presentations, molecular profiles, and patients’ prognoses. Methods. We investigated our institutional cancer registry to include patients with glioma over a 10-year period. Statistical tests were used to compare demographic, genetic, and clinical characteristics among patients with gliomas in different locations. Survival analysis methods were then used to assess associations between location and overall survival in the full cohort, as well as in relevant subgroups. Results. 182 gliomas were identified. Of the tumours confined to a single lobe, there were 51 frontal (28.0%), 50 temporal (27.5%), 22 parietal (12.1%), and seven occipital tumours (3.8%) identified. Tumours affecting the temporal lobe were associated with reduced overall survival when compared to all other tumours (11 months vs. 13 months, log-rank p = 0.0068). In subgroup analyses, this result was significant for males [HR (95%CI) 2.05 (1.30, 3.24), p = 0.002], but not for females [HR (95%CI) 1.12 (0.65, 1.93), p = 0.691]. Out of 82 cases tested for IDH-1, 10 were mutated (5.5%). IDH-1 mutation was present in six frontal, two temporal, one thalamic, and one multifocal tumour. Out of 21 cases tested for 1p19q deletions, 12 were co-deleted, nine of which were frontal lobe tumours. MGMT methylation was assessed in 45 cases; 7/14 frontal tumours and 6/13 temporal tumours were methylated. Conclusion. Our results support the hypothesis that the anatomical locations of gliomas influence patients’ clinical courses. Temporal lobe tumours were associated with poorer survival, though this association appeared to be driven by these patients’ more aggressive tumour profiles and higher risk baseline demographics. Independently, female patients who had temporal lobe tumours fared better than males. Molecular analysis was limited by the low prevalence of genetic testing in the study sample, highlighting the importance of capturing this information for all gliomas. Importance of this study. The specific neuroanatomic location of tumours in the brain is thought to be predictive of treatment options and overall prognosis. Despite evidence for the clinical significance of this information, there is relatively little information available regarding the incidence and prevalence of tumours in the different anatomical regions of the brain. This study has more fully characterised tumour prevalence in different regions of the brain. Additionally, we have analysed how this information may affect tumours’ molecular characteristics, treatment options offered to patients, and patients’ overall survival. This information will be informative both in the clinical setting and in directing future research.

The challenges of restoration in dryland ecosystems are growing due to a rise in anthropogenic disturbance and increasing aridity. Plant functional traits are often used to predict plant performance and can offer a window into potential outcomes of restoration efforts across environmental gradients. We analyzed a database including 15 yr of seeding outcomes across 150 sites on the Colorado Plateau, a cold desert ecoregion in the western United States, and analyzed the independent and interactive effects of functional traits (seed mass, height, and specific leaf area) and local biologically relevant climate variables on seeding success. We predicted that the best models would include an interaction between plant traits and climate, indicating a need to match the right trait value to the right climate conditions to maximize seeding success. Indeed, we found that both plant height and seed size significantly interacted with temperature seasonality, with larger seeds and taller plants performing better in more seasonal environments. We also determined that these trait-environment patterns are not influenced by whether a species is native or nonnative. Our results inform the selection of seed mixes for restoring areas with specific climatic conditions, while also demonstrating the strong influence of temperature seasonality on seeding success in the Colorado Plateau region.

Introduction The purpose of this study was to describe and compare the performance of balance and walking tests in relation to self-reported fall history in adults with myotonic dystrophy type 1 (DM1). Methods Twenty-two (13 male) participants with DM1 completed, a 6-month fall history questionnaire, the modified Dynamic Gait Index (mDGI), limits of stability (LoS) testing, and 10-m walking tests. Results Mean (SD) falls in 6 months was 3.7 (3.1), and 19 (86%) participants reported at least 1 fall. Significant differences in mDGI scores (P = 0.006) and 10-m fast walking gait velocity (P = 0.02) were found between those who had been classified as "fallers" and those who had been classified as "nonfallers." Significant correlations were found between mDGI scores and 10-m walking time. Discussion Falls are common in DM1, and the mDGI may have potential to distinguish fallers from nonfallers, whereas the LoS failed to detect such impairment. Future studies should further explore use of the mDGI in DM1. Muscle Nerve 58: 694-699, 2018.

The Colorado Plateau is one of North America's five major deserts, encompassing 340,000 km² of the western United States, and offering many opportunities for restoration relevant to researchers and land managers in drylands around the globe. The Colorado Plateau is comprised of vast tracts of public land managed by local, state, and federal agencies that oversee a wide range of activities (e.g., mineral and energy extraction, livestock grazing, and recreation). About 75% of the Plateau is managed by federal and tribal agencies and tens of millions of people visit the Plateau's public lands each year. However, even in the face of this diverse use, our knowledge of effective ways to restore Plateau ecosystems remains relatively poor. Further, the multiple agencies on the Plateau have mandates that differ greatly in allowable practices, restoration needs, and desired outcomes. The Colorado Plateau is also expected to undergo ecosystem shifts in the face of climate change, further complicating management decisions and potentially limiting some options while creating others. Here, we explore the current state of Colorado Plateau restoration science and underscore key challenges and opportunities for improving our capacity to maintain the myriad of services provided by these desert ecosystems. We highlight past research efforts and future needs related to restoration concepts, including consideration and design of novel ecosystems, mitigation for and adaptation to climate change, use of genetically diverse seed adapted for current and future conditions, and the value of strong multi‐agency and stakeholder collaborations in restoring systems on the Colorado Plateau and beyond.

The sensitivity of plant production to precipitation underlies the functioning of ecosystems. Studies that relate long-term mean annual precipitation and production across multiple sites (spatial relationship) or examine interannual linkages within a site (temporal relationship) can reveal biophysical controls over ecosystem function but have limited ability to infer responses to extreme changes in precipitation that may become more common under climate change. To overcome limitations of using a single approach, we integrated satellite- and ground-based estimates of production with a standardized, multi-site precipitation manipulation experiment across a grassland elevation gradient in the southwestern USA. The responsiveness of production to changes in precipitation followed the order: temporal (0.06–0.13 g m−2 mm−1)

INTRODUCTION Herein we present an exploratory study of orofacial function in children with congenital myotonic dystrophy (CDM) vs. healthy controls. METHODS We evaluated 41 children with CDM and 29 healthy controls for speech and swallow function and for lingual and labial strength. RESULTS The Iowa Oral Performance Instrument (IOPI), measuring tongue strength, and a lip force meter (LFM), measuring lip strength, had excellent interrater reliability with intraclass correlation coefficients (ICCs) of 0.75 (n = 19, P

Congenital muscular dystrophies (CMD) cause progressive muscle weakness resulting in severe motor disabilities. Previous studies focused on the effects of motor disability. Here, we explore other factors affecting health related quality-of-life (HRQOL) in CMD. Qualitative interviews were conducted with participant-parent dyads to identify symptoms having the greatest impact on HRQOL. Symptoms were classified into themes and domains representing physical, mental, social health, and disease specific issues. Social role limitations and specific activity impairment were frequently mentioned. A greater understanding of symptoms impacting HRQOL will provide a framework for improved clinical care and patient centered outcomes as new therapies are developed.

Cardiomyopathy develops in >90% of Duchenne muscular dystrophy (DMD) patients by the second decade of life. We assessed the associations between DMD gene mutations, as well as Latent transforming growth factor-beta-binding protein 4 (LTBP4) haplotypes, and age at onset of myocardial dysfunction in DMD. DMD patients with baseline normal left ventricular systolic function and genotyping between 2004 and 2013 were included. Patients were grouped in multiple ways: specific DMD mutation domains, true loss-of-function mutations (group A) versus possible residual gene expression (group B), and LTBP4 haplotype. Age at onset of myocardial dysfunction was the first echocardiogram with an ejection fraction DMD genotype mutation domains (13.7±4.8 versus 14.3±1.0 versus 14.3±2.9 versus 13.8±2.5, p=0.97), groups A and B (14.4±2.8 versus 12.1±4.4, p=0.09), or LTBP4 haplotypes (14.5±3.2 versus 13.1±3.2 versus 11.0±2.8, p=0.18). DMD gene mutations involving the hinge 3 region, actin-binding domain, and exons 45–49, as well as the LTBP4 IAAM haplotype, were not associated with age of left ventricular dysfunction onset in DMD.

Background In 2005, the American Academy of Pediatrics (AAP) published a policy statement on cardiovascular health supervision for Duchenne Muscular Dystrophy (DMD). Data is lacking on its effect on cardiovascular care. Methods Using the infrastructure of the Muscular Dystrophy Surveillance, Tracking and Research Network, we examined a population-based sample of individuals with DMD, focusing on cardiac testing and prescription of cardiac medication. Comparisons were made pre- (2000–2005) and post- (2006–2011) publication Results 731 cases were studied; mean age of diagnosis 3.8 years and mean duration of follow-up 9.3 years. There was a significant decrease in time from diagnosis to first electrocardiogram (ECG) and echocardiogram (ECHO) from pre- to post-publication; 1047 (95% CI: 905–1188) days to 411 (95% CI: 324–498) days for ECG (p Conclusions Since publication of the AAP statement, DMD patients are having cardiac testing sooner and cardiac medication is prescribed more often. However, the majority are not having testing with recommended frequency. Overcoming barriers to recommended cardiac care may lead to a better understanding of the natural history of cardiomyopathy in DMD and better treatment strategies.

We describe a new assemblage of small carbonaceous fossils (SCFs) from diagenetically 9 minimally altered clays and siltstones of Terreneuvian age from the Lontova and Voosi formations of 10 Estonia, Lithuania and Russia. This is the first detailed account of an SCF assemblage from the 11 Terreneuvian, and includes a number of previously undocumented Cambrian organisms. Recognisably 12 bilaterian-derived SCFs include abundant protoconodonts (total-group Chaetognatha), and distinctive 13 cuticular spines of scalidophoran worms. Alongside these metazoan remains are a range of protistan-14 grade fossils, including Retiranus balticus gen. et sp. nov., a distinctive funnel-shaped or sheet-like 15 problematicum characterized by terminal or marginal vesicles, and Lontohystrichosphaera grandis 16 gen. et sp. nov., a large (100–550 μm) ornamented vesicular microfossil. Together these data offer a 17 fundamentally enriched view of Terreneuvian life in the epicratonic seas of Baltica, from an episode 18 where records of non-biomineralized life are currently sparse. Even so, the recovered assemblages 19 contain a lower diversity of metazoans than SCF biotas from younger (Stage 4) Baltic successions that 20 represent broadly equivalent environments, echoing the diversification signal recorded in the coeval 21 shelly and trace-fossil records. Close comparison to the biostratigraphic signal from Fortunian small 22 shelly fossils (SSFs) supports a late Fortunian age for most of the Lontova/Voosi succession, rather 23 than a younger (wholly Stage 2) range.

Variation in climate has been demonstrated to be a powerful driver of selection and local adaptation among plant populations. Variation in functional traits among populations can also be indicative of the drivers of local adaptation. However, it is not clear to what extent species exhibit consistent patterns of local adaptation as revealed by common, heritable trait–environment relationships among populations. To address this, we conducted a meta-analysis of common garden studies of grass populations to quantify the degree of heritability of several commonly measured functional traits, and whether demonstrated heritability was driven by climate. We found that leaf size, specific leaf area (SLA) and total biomass all displayed strong broad-sense of heritability. Both leaf area and SLA decreased significantly with increasing temperature seasonality among populations within species, while total biomass increased with increasing annual and dry season precipitation, and decreased with increasing precipitation seasonality. These results indicate similar, consistent drivers of local adaptation among species of grasses. Further information on trait–environment relationships within species could greatly improve our ability to predict broad scale patterns in functional diversity across multiple levels of ecological organization. Expanding the range of traits and regions incorporated in common garden research, in the present case by incorporating root traits and Southern Hemisphere taxa, will provide even greater benefits to the fields of restoration, conservation, and global change ecology.

Bedding-plane assemblages of Ediacaran fossils from Mistaken Point, Newfoundland, are among the oldest known records of complex multicellular life on Earth (dated to ~565 Ma). The in situ preservation of these sessile but otherwise deeply enigmatic organisms means that statistical analyses of specimen positions can be used to illuminate their underlying ecological dynamics, including the interactions between taxa.Fossil assemblages on Mistaken Point D and E surfaces were mapped to millimeter accuracy using differentiated GPS. Spatial correlations between 10 well-defined taxa (Bradgatia, Charniid,Charniodiscus,Fractofusus, Ivesheadiomorphs, Lobate Discs,Pectinifrons,Plumeropriscum,Hiemalora, andThectardis) were identified using Bayesian network inference (BNI), and then described and analyzed using spatial point-process analysis. BNI found that the E-surface community had a complex web of interactions and associations between taxa, with all but one taxon (Thectardis) interacting with at least one other. The unique spatial distribution ofThectardissupports previous, morphology-based arguments for its fundamentally distinct nature. BNI revealed that the D-surface community showed no interspecific interactions or associations, a pattern consistent with a homogeneous environment.On the E surface, all six of the abundant taxonomic groups (Fractofusus,Bradgatia, Charniid,Charniodiscus,Thectardis, andPlumeropriscum) were found to have a unique set of interactions with other taxa, reflecting a broad range of underlying ecological responses. Four instances of habitat associations were detected between taxa, of which two (Charniodiscus–PlumeropriscumandPlumeropriscum–Fractofusus) led to weak competition for resources. One case of preemptive competition between Charniid and Lobate Discs was detected. There were no instances of interspecific facilitation. Ivesheadiomorph interactions mirror those ofFractofususandCharniodiscus, identifying them as a form-taxonomic grouping of degradationally homogenized taphomorphs. The absence of increased fossil abundance in proximity to these taphomorphs argues against scavenging or saprophytic behaviors dominating the E-surface community.

IntroductionComputational analysis of genome or exome sequences may improve inherited disease diagnosis, but is costly and time-consuming.MethodsWe describe the use of iobio, a web-based tool suite for intuitive, real-time genome diagnostic analyses.ResultsWe used iobio to identify the disease-causing variant in a patient with early infantile epileptic encephalopathy with prior nondiagnostic genetic testing.ConclusionsIobio tools can be used by clinicians to rapidly identify disease-causing variants from genomic patient sequencing data.

Restoration treatments, such as revegetation with seeding or invasive species removal, have been applied on U.S. public lands for decades. Temporal trends in these management actions have not been extensively summarized previously, particularly in the southwestern United States where invasive plant species, drought, and fire have altered dryland ecosystems. We assessed long-term (1940–2010) trends in restoration using approximately 4,000 vegetation treatments conducted on Bureau of Land Management lands across the southwestern United States. We found that since 1940, the proportions of seeding and vegetation/soil manipulation (e.g. vegetation removal or plowing) treatments have declined, while the proportions of prescribed burn and invasive species treatments have increased. Treatments in pinyon-juniper and big sagebrush communities declined in comparison to treatments in desert scrub, creosote bush, and riparian woodland communities. Restoration-focused treatment objectives increased relative to resource extraction objectives. Species richness and proportion of native species used in seeding treatments also increased. Inflation-adjusted costs per area rose 750% for vegetation/soil manipulation, 600% for seeding, and 400% for prescribed burn treatments in the decades from 1981 to 2010. Seeding treatments were implemented in warmer and drier years when compared to the climate conditions of the entire study period and warmer and wetter years relative to several years before and after the treatment. These results suggest that treatments over a 70-year period on public lands in the southwestern United States are shifting toward restoration practices that are increasingly large, expensive, and related to fire and invasive species control.

Introduction Congenital myotonic dystrophy (CDM) occurs when symptoms of myotonic dystrophy present at birth. In this study we evaluated the relationship between physical function, muscle mass, and age to provide an assessment of the disease and help prepare for therapeutic trials. Methods CDM participants performed timed functional tests (TFTs), the first 2 minutes of 6-minute walk tests (2/6MWTs), and myometry tests, and also performed dual-energy X-ray absorption (DEXA) scans. Healthy controls (HCs) performed TFTs, 6MWTs, and myometry. Results Thirty-seven children with CDM and 27 HCs (age range 3-13 years) participated in the study. There were significant differences in the 10-meter walk (11.3 seconds in CDM vs. 6.8 seconds in HC) and 2MWT (91 meters in CDM vs. 193 meters in HCs). DEXA lean mass of the right arm correlated with grip strength (r = 0.91), and lean mass of the right leg correlated with 6MWT (r = 0.62). Conclusion Children with CDM have significant limitations in strength and mobility. The tests performed were reliable, and lean muscle mass may serve as a useful biomarker. Muscle Nerve 56: 224-229, 2017.

Introduction: Response assessment at day 100 post Autologous Stem Cell Transplant (ASCT) is associated with long-term relapsed free survival (RFS) and overall survival (OS) in multiple myeloma (MM). The International Myeloma Working Group (IMWG) are the preferred criteria to define best response to treatment and define relapse. In the last years, response assessment has incorporated minimal residual disease (MRD) status -associated with improved RFS and OS (Munshi et al); and PET/CT combined with clinical characteristics -also associated with favorable outcomes (Zamagni et al. NCT01910987; MMY3033). The 2016 IMWG MRD criteria, combined imaging (PET/CT) plus next-generation sequencing (NGS) MRD-negative to define complete response (CR). To our knowledge, there is limited data examining the correlation and prognostic value of MRD and FDG-PET/CT at day 100 post ASCT in MM. IN this study, we aimed to determine the prognostic valued of MRD by NGS combined with PET/CT in RFS and OS status after high dose chemotherapy and ASCT in MM. Methods: Patients who underwent ASCT for MM at Mayo Clinic Arizona and had MRD and PET/CT data were included in the study. Clinical data was obtained via retrospective chart review. Cytogenetic risk (CyR) was classified using the mSMART criteria . Disease and ASCT related characteristics were compared by MRD status. MRD was measured by NGS on bone marrow aspirates using the previosly validated clonoSEQ ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) tracking the IgH, IgK and IgL rearrangements at a minimum sensitivity level of 10-5. MRD was defined by residual clonal cells per million nucleated cells as: negative= 0, borderline= 1-5, positive >5. PET/CT scans were performed locally at baseline and at day 100. Comparisons were performed using the chi-square test for categorical variables, Wilcoxon rank-sum test for continuos variables, McNemar's test and Cohens's Kappa for agreement measures. Results: A total of 103 patients had matched MRD and PET/CT assessment around day 100 (+/-9 days) and were included in the analysis. Median age at diagnosis was 62 years (range, 54-66 years), 71 patients (68.9%) were men. CyR was standard risk in 49 (47.6%), high-risk in 39 (37.9%) and unknown in 15 (14.6%) patients. Most 75 (72.8%) patients were MRD positive, 16 (15.5%) were MRD negative, and 12 (11.7%) borderline. The median main MRD clone detected was 64 (range 0-91,874). 70 patients (68%) and 33 (32%) had a negative and positive PET/CT respectively. The median follow-up time was 18 months (range, 13-31 months). At the time of data analysis, 10 patients (9.7%) had relapsed and only 4 (3.9%) had died. There was a high-correlation between MRD status and PET/CT, 31 patients (93.9%) with positive PET/CT were also MRD positive (p=0.0027). There were no statistical differences between PET/CT and CyR (p=0.95). We analyzed the correlation using the FREQ procedure (McNemars's test); there was a strong association between positive PET/CT and positive MRD in 31/33 patients (93.9%, high sensitivity), and low association for negative PET/CT the negative/borderline MRD in 26/70 (37.1%, low specificity; p Conclusions: In conclusion, we demonstrate that the combination of MRD by NGS (clonoSEQ ®) and PET/CT at day 100 are complementary and have a high sensitivity (true positive rate) and fair correlation of agreement but low specificity (true negative rate). PET/CT was the best most sensitive technique to prognosticate RFS and OS. We did not find prognostic correlation of MRD with RFS and OS. However, our findings might be confounded by the low risk of relapse and death, a longer follow-up may demonstrate clinically important differences. Our results add evidence that MRD plus PET/CT improve the definition of CR in MM patients post ASCT. Prospective studies are needed to elucidate the optimal timing and role of combined MRD, PET/CT with other prognostic markers of clinical outcomes. Disclosures Larsen: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fonseca:Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy.

Objective To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). Study design A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. Results Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. Conclusion Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.

Background Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. Objective To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. Methods We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. Results Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). Limitations This is a multicenter but single institution study of a white population. Conclusion Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

Background: Financial distress from medical treatment is an increasing concern. Healthcare organizations may have different levels of organizational commitment, existing programs, and expected outcomes of screening and management of patient financial distress. Patients and Methods: In November 2018, representatives from 17 (63%) of the 27 existing NCCN Member Institutions completed an online survey. The survey focused on screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes about such practices. Due to the lack of a validated questionnaire in this area, survey questions were generated after a comprehensive literature search and discussions among the study team, including NCCN Best Practices Committee representatives. Results: Responses showed that 76% of centers routinely screened for financial distress, mostly with social worker assessment (94%), and that 56% screened patients multiple times. All centers offered programs to help with drug costs, meal or gas vouchers, and payment plans. Charity care was provided by 100% of the large centers (≥10,000 unique annual patients) but none of the small centers that responded (P=.008). Metrics to evaluate the impact of financial advocacy services included number of patients assisted, bad debt/charity write-offs, or patient satisfaction surveys. The effectiveness of institutional practices for screening and management of financial distress was reported as poor/very poor by 6% of respondents. Inadequate staffing and resources, limited budget, and lack of reimbursement were potential barriers in the provision of these services. A total of 94% agreed with the need for better integration of financial advocacy into oncology practice. Conclusions: Three-fourths of NCCN Member Institutions reported screening and management programs for financial distress, although the actual practices and range of services vary. Information from this study can help centers benchmark their performance relative to similar programs and identify best practices in this area.

AIM: Plant communities typically exhibit lagged responses to climate change due to poorly understood effects of colonization and local extinction. Here, we quantify rates of change in mean cold tolerances, and contributions of colonization and local extinction to those rates, recorded in plant macrofossil assemblages from North American hot deserts over the last 30,000 years. LOCATION: Mojave, Sonoran and Chihuahuan Deserts. TIME PERIOD: 30–0 thousand years before present (kybp). MAJOR TAXA STUDIED: Vascular plants. METHODS: Colonization and local extinction dates for 269 plant species were approximated from macrofossils in 15 packrat (Neotoma) midden series. Cold tolerances estimated from contemporary climate were used to quantify assemblage‐mean cold tolerances through time. Rates of colonization and local extinction, and their effects on rates of change in assemblage‐mean cold tolerances, were estimated for 30–20 kybp (Late Pleistocene, no directional warming), 20–10 kybp (deglaciation, rapid warming) and 10–0 kybp (Holocene, no directional warming). RESULTS: Rates of change in all metrics were negligible during the Late Pleistocene. Rates of change in assemblage‐mean cold tolerances (mean 1.0°C × 10⁻⁴/yr) lagged behind warming during deglaciation, and continued at similar rates (1.2°C × 10⁻⁴/yr) throughout the Holocene. Colonization and local extinction contributed equally to delayed responses to warming, but their dynamics differed through time: Colonization by warm‐adapted species predominated during deglaciation, while the most heat‐adapted species exhibited long delays in colonization. Only the most cold‐adapted species went locally extinct during deglaciation, followed by slow repayment of the extinction debt of cool‐adapted species during the Holocene. MAIN CONCLUSIONS: Responses to rapid warming can persist for millennia, even after cessation of warming. Consistent patterns from different midden series across the region support a metacommunity model in which dispersal interacts with environmental filters and buffers against local extinction to drive community–climate disequilibrium during and after periods of warming.

ObjectiveTo examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS).MethodsThis was a 5-year retrospective cross-sectional study (2014–2018) using the NPDS. Demographics, exposure characteristics, and outcomes were described. Univariate logistic regression was used to estimate the odds ratio (OR) for major effect or death. A multivariable logistic regression model with inclusion criteria of p < 0.1 in univariate analysis was implemented with backwards selection.ResultsIn this population (n = 1,489), multiple exposure was most common (n = 1,145). The mean age was 31.2 years and 1,197 (80.4%) participants were female. Major effects from a single exposure were seen in p = 0.004), multiple product exposure (OR 9.50; 95% CI 2.29–39.48; p = 0.002), and concomitant overdose with benzodiazepines (OR 1.71; 95% CI 1.05–2.78; p = 0.032) or tricyclic antidepressants (OR 3.16; 95% CI 1.88–5.31; p < 0.001).ConclusionThe risk of major effect or death was low and predicted by age, multiple product exposure, and concomitant benzodiazepine or tricyclic antidepressant. The triptan toxidrome consists of hypertension, tachycardia, and drowsiness. The toxic effects of ergotamine are acute gastrointestinal syndrome with vertigo and numbness. No cases of serotonin syndrome were seen.