Publications by authors named "Kathleen Brown"

265 Publications

National characteristics of non-transported children by Emergency Medical Services (EMS) in the United States.

Prehosp Emerg Care 2021 Sep 27:1-15. Epub 2021 Sep 27.

Division of Emergency Medicine, Children's National Hospital, Washington DC, United States.

Most 911 calls result in ambulance transport to an emergency department. In some cases, transport is refused or deemed unnecessary. The frequency of pediatric non-transport is unknown. Our primary objective was to describe the proportion of pediatric EMS activations resulting in non-transport. Our secondary objective was to identify patient, community, and EMS agency factors associated with pediatric non-transport. We conducted a cross-sectional study using 2019 data from the National EMS Information System registry. We compared non-transport rates for children (< 18 y/o), adults (18 - 60 y/o) and elderly (>60 y/o) patients. We then used generalized estimating equations to identify factors associated with pediatric non-transport while accounting for geographical clustering. There were 21,931,490 EMS activations, including 1,403,454 pediatric 911 responses. 30% of pediatric 911 responses resulted in non-transport. Non-transport was less likely for adults (19%, OR 0.54 [0.54, 0.55]) and elderly patients (13%, OR 0.35 [0.35, 0.36]). The most common pediatric non-transport dispositions were: refused evaluation/care, and treated/released. Non-transport was associated with: pulmonary (aOR 3.84 [3.30, 4.48]) and musculoskeletal chief complaints (aOR 3.75 [3.22, 4.36]). Non-transport was more likely for: rural EMS calls (aOR 1.28 [1.24, 1.32]); calls classified by EMS as Lower Acuity (aOR 7.88 [5.98, 10.38]); and Tribal EMS agencies (aOR 3.49 [3.09, 3.94]). Almost one-third of pediatric 911 activations result in non-transport. Although very few children have been included in pilots of alternate transport processes to date, non-transport is actually more common in children than adults. More work is needed to understand better the patient safety and economic implications of this practice.
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http://dx.doi.org/10.1080/10903127.2021.1985666DOI Listing
September 2021

Practicing What We Teach: Increasing Inhaler Use for Mild Asthma in the Pediatric Emergency Department.

J Healthc Qual 2021 Sep 9. Epub 2021 Sep 9.

Introduction: Asthma is a leading cause of pediatric emergency department (ED) visits. A metered-dose inhaler and spacer (MDI-S) device is equivalent to and more cost effective than delivery by nebulization in the ED management of mild asthma exacerbations. We aimed to increase the use of albuterol MDI-S among patients with mild asthma exacerbations using a quality improvement framework.

Methods: We evaluated albuterol use for mild asthma exacerbations between January 2019 and March 2020 in our pediatric EDs.

Results: Our primary outcome was the proportion of albuterol delivered through an MDI-S. Our process measure was the use of a new electronic order set. Balancing measures included ED length of stay, admission rates, and the use of intravenous magnesium. Interventions included forging multidisciplinary partnerships, revising clinical practice guidelines, establishing an electronic order set, and leading educational initiatives for clinicians. We demonstrated a center line shift of MDI-S use from 34.4% to 47.7%. The average length of stay, hospital admissions, and magnesium use were not affected by our interventions.

Conclusion: Forging multidisciplinary partnerships, creating an electronic order set prioritizing albuterol MDI-S use, and educational initiatives led to a sustained increase in albuterol MDI-S use for mild asthma in our pediatric EDs.
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http://dx.doi.org/10.1097/JHQ.0000000000000326DOI Listing
September 2021

Soil penetration by maize roots is negatively related to ethylene-induced thickening.

Plant Cell Environ 2021 Aug 28. Epub 2021 Aug 28.

School of Biosciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, UK.

Radial expansion is a classic response of roots to a mechanical impedance that has generally been assumed to aid penetration. We analysed the response of maize nodal roots to impedance to test the hypothesis that radial expansion is not related to the ability of roots to cross a compacted soil layer. Genotypes varied in their ability to cross the compacted layer, and those with a steeper approach to the compacted layer or less radial expansion in the compacted layer were more likely to cross the layer and achieve greater depth. Root radial expansion was due to cortical cell size expansion, while cortical cell file number remained constant. Genotypes and nodal root classes that exhibited radial expansion in the compacted soil layer generally also thickened in response to exogenous ethylene in hydroponic culture, that is, radial expansion in response to ethylene was correlated with the thickening response to impedance in soil. We propose that ethylene insensitive roots, that is, those that do not thicken and can overcome impedance, have a competitive advantage under mechanically impeded conditions as they can maintain their elongation rates. We suggest that prolonged exposure to ethylene could function as a stop signal for axial root growth.
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http://dx.doi.org/10.1111/pce.14175DOI Listing
August 2021

Association of Inclusion of More Black Individuals in Lung Cancer Screening With Reduced Mortality.

JAMA Netw Open 2021 Aug 2;4(8):e2119629. Epub 2021 Aug 2.

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California.

Importance: The potential to achieve greater reductions in lung cancer mortality than originally estimated by the National Lung Screening Trial with the inclusion of more Black participants stresses the importance of improving access to lung cancer screening for Black current and former smokers, a population presently with the highest lung cancer morbidity and mortality.

Objective: To estimate lung cancer and all-cause mortality reductions achievable with lung cancer screening via low-dose computed tomography (LDCT) of the chest in populations with greater proportions of Black screening participants than seen in the original NLST cohort.

Design, Setting, And Participants: This cohort study was conducted as a secondary analysis of existing data from the National Lung Screening Trial, a large national randomized clinical trial conducted from 2002 through 2009. NLST participants were current or former smokers, aged between 55 and 74 years, with at least 30 pack-years of smoking history and less than 15 years since quitting. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs of lung cancer mortality and all-cause mortality according to LDCT screening compared with chest radiograph screening. Using a transportability formula, we estimated outcomes for LDCT screening among hypothetical populations by varying the distributions of Black individuals, women, and current smokers. Data were analyzed between September 2020 and March 2021.

Exposures: Lung screening with LDCT of the chest compared with chest radiography.

Main Outcomes And Measures: Lung cancer mortality and all-cause mortality.

Results: This study included a total of 53 452 participants enrolled in the NLST. Of 2376 Black individuals and 51 076 non-Black individuals, 21 922 (41.0%) were women and the mean (SD) age was 61.4 (5.0) years. Over a median (interquartile range) follow-up of 6.7 (6.2-7.0) years, LDCT screening among the synthesized population with a higher proportion of Black individuals (13.4%, mirroring US Census data) was associated with a greater relative reduction of lung cancer mortality (eg, Black individuals: HR, 0.82; 95% CI, 0.72-0.92; vs entire NLST cohort: HR, 0.84; 95% CI, 0.76-0.96). Further reductions in lung cancer mortality by LDCT screening were found among a hypothetical population with a higher proportion of men or current smokers, along with a higher proportion of Black individuals (ie, 60% Black participants; 20% to 40% women) (HR, 0.68; 95% CI, 0.48-0.97).

Conclusions And Relevance: The potential to achieve greater reductions in lung cancer mortality than originally estimated by the NLST with the inclusion of more Black participants stresses the critical importance of improving access to lung cancer screening for Black current and former smokers.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.19629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385597PMC
August 2021

Serum Sodium Concentration and Mental Status in Children With Diabetic Ketoacidosis.

Pediatrics 2021 09 9;148(3). Epub 2021 Aug 9.

Department of Psychology, University of California, Davis, Davis, California.

Objectives: Diabetic ketoacidosis (DKA) is typically characterized by low or low-normal serum sodium concentrations, which rise as hyperglycemia resolves. In retrospective studies, researchers found associations between declines in sodium concentrations during DKA and cerebral injury. We prospectively investigated determinants of sodium concentration changes and associations with mental status alterations during DKA.

Methods: Using data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in Diabetic Ketoacidosis Trial, we compared children who had declines in glucose-corrected sodium concentrations with those who had rising or stable concentrations. Children were randomly assigned to 1 of 4 intravenous fluid protocols that differed in infusion rate and sodium content. Data from the first 4, 8, and 12 hours of treatment were analyzed for 1251, 1086, and 877 episodes, respectively.

Results: In multivariable analyses, declines in glucose-corrected sodium concentrations were associated with higher sodium and chloride concentrations at presentation and with previously diagnosed diabetes. Treatment with 0.45% (vs 0.9%) sodium chloride fluids was also associated with declines in sodium concentration; however, higher rates of fluid infusion were associated with declines in sodium concentration only at 12 hours. Frequencies of abnormal Glasgow Coma Scale scores and clinical diagnoses of cerebral injury were similar in patients with and without declines in glucose-corrected sodium concentrations.

Conclusions: Changes in glucose-corrected sodium concentrations during DKA treatment are influenced by the balance of free-water loss versus sodium loss at presentation and the sodium content of intravenous fluids. Declines in glucose-corrected sodium concentrations are not associated with mental status changes during treatment.
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http://dx.doi.org/10.1542/peds.2021-050243DOI Listing
September 2021

Delineating the genotypic and phenotypic spectrum of -related neurodevelopmental disorders.

J Med Genet 2021 Jul 28. Epub 2021 Jul 28.

GeneDx, Gaithersburg, Maryland, USA.

Background: Variants in have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.

Methods: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a related neurodevelopmental disorder.

Results: We identified 13 novel missense variants in in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.

Conclusion: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of disorders, aiding future molecular and clinical diagnosis and management.
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http://dx.doi.org/10.1136/jmedgenet-2021-107871DOI Listing
July 2021

Managing Incidental Findings on Thoracic CT: Lung Findings. A White Paper of the ACR Incidental Findings Committee.

J Am Coll Radiol 2021 Sep 8;18(9):1267-1279. Epub 2021 Jul 8.

Director, MGH Institute for Technology Assessment, Massachusetts General Hospital, Boston, Massachusetts; Associate Chair, Integrated Imaging & Imaging Sciences, MGH Radiology, Massachusetts General Hospital, Boston, Massachusetts; Executive Director, Clinical Enterprise Integration, Mass General Brigham (MGB) Radiology, Massachusetts General Hospital, Boston, Massachusetts; Associate Professor of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

The ACR Incidental Findings Committee presents recommendations for managing incidentally detected lung findings on thoracic CT. The Chest Subcommittee is composed of thoracic radiologists who endorsed and developed the provided guidance. These recommendations represent a combination of current published evidence and expert opinion and were finalized by informal iterative consensus. The recommendations address commonly encountered incidental findings in the lungs and are not intended to be a comprehensive review of all pulmonary incidental findings. The goal is to improve the quality of care by providing guidance on management of incidentally detected thoracic findings.
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http://dx.doi.org/10.1016/j.jacr.2021.04.014DOI Listing
September 2021

Adolescent alcohol use predicts cannabis use over a three year follow-up period.

Subst Abus 2021 Jul 8:1-6. Epub 2021 Jul 8.

Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Background: Alcohol and cannabis use frequently co-occur, which can result in problems from social and academic impairment to dependence (i.e., alcohol use disorder [AUD] and/or cannabis use disorder [CUD]). The Emergency Department (ED) is an excellent site to identify adolescents with alcohol misuse, conduct a brief intervention, and refer to treatment; however, given time constraints, alcohol use may be the only substance assessed due to its common role in unintentional injury. The current study, a secondary data analysis, assessed the relationship between adolescent alcohol and cannabis use by examining the National Institute of Alcohol Abuse and Alcoholism (NIAAA) two question screen's (2QS) ability to predict future CUD at one, two, and three years post-ED visit. At baseline, data was collected via tablet self-report surveys from medically and behaviorally stable adolescents 12-17 years old ( = 1,689) treated in 16 pediatric EDs for non-life-threatening injury, illness, or mental health condition. Follow-up surveys were completed via telephone or web-based survey. Logistic regression compared CUD diagnosis odds at one, two, or three-year follow-up between levels constituting a single-level change in baseline risk categorization on the NIAAA 2QS (nondrinker versus low-risk, low- versus moderate-risk, moderate- versus high-risk). Receiver operating characteristic curve methods examined the predictive ability of the baseline NIAAA 2QS cut points for CUD at one, two, or three-year follow-up. Adolescents with low alcohol risk had significantly higher rates of CUD versus nondrinkers (OR range: 1.94-2.76, < .0001). For low and moderate alcohol risk, there was no difference in CUD rates (OR range: 1.00-1.08). CUD rates were higher in adolescents with high alcohol risk versus moderate risk (OR range: 2.39-4.81, < .05). Even low levels of baseline alcohol use are associated with risk for a later CUD. The NIAAA 2QS is an appropriate assessment measure to gauge risk for future cannabis use.
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http://dx.doi.org/10.1080/08897077.2021.1949665DOI Listing
July 2021

A Novel Use of NEMSIS to Create a PECARN-Specific EMS Patient Registry.

Prehosp Emerg Care 2021 Jul 27:1-8. Epub 2021 Jul 27.

Research networks need access to EMS data to conduct pilot studies and determine feasibility of prospective studies. Combining data across EMS agencies is complicated and costly. Leveraging the National EMS Information System (NEMSIS) to extract select agencies' data may be an efficient and cost-effective method of providing network-level data. Describe the process of creating a Pediatric Emergency Care Applied Research Network (PECARN) specific NEMSIS data set and determine if these data were nationally representative. We established data use agreements (DUAs) with EMS agencies participating in PECARN to allow for agency identification through NEMSIS. Using 2019 NEMSIS version 3.4.0 data for EMS events with patients 18 years old and younger, we compared PECARN NEMSIS data to national NEMSIS data. Analyzed variables were selected for their ability to characterize events. No statistical analyses were utilized due to the large sample, instead, differences of ±5% were deemed clinically meaningful. DUAs were established for 19 EMS agencies, creating a PECARN data set with 305,188 EMS activations of which 17,478 (5.7%) were pediatric. Of the pediatric activations, 17,140 (98.1%) were initiated through 9-1-1 and 9,487 (55.4%) resulted in transport by the documenting agency. The national data included 36,288,405 EMS activations of which 2,152,849 (5.9%) were pediatric. Of the pediatric activations 1,704,141 (79.2%) were initiated through 9-1-1 and 1,055,504 (61.9%) were transported by the documenting agency. Age and gender distributions were similar between the two groups, but the PECARN-specific data under-represents Black and Latinx patients. Comparison of EMS provider primary impressions revealed that three of the five most common were similar with injury being the most prevalent for both data sets along with mental/behavioral health and seizure. We demonstrated that NEMSIS can be leveraged to create network specific data sets. PECARN's EMS data were similar to the national data, though racial/ethnic minorities and some primary impressions may be under-represented. Additionally, more EMS activations in PECARN study areas originated through 9-1-1 but fewer were transported by the documenting agency. This is likely related to the type of participating agencies, their ALS response level, and the diversity of the communities they serve.
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http://dx.doi.org/10.1080/10903127.2021.1951407DOI Listing
July 2021

Effects of Fluid Rehydration Strategy on Correction of Acidosis and Electrolyte Abnormalities in Children With Diabetic Ketoacidosis.

Diabetes Care 2021 Sep 29;44(9):2061-2068. Epub 2021 Jun 29.

Department of Pediatrics, University of California Davis Health, University of California, Davis, School of Medicine, Sacramento.

Objective: Fluid replacement to correct dehydration, acidosis, and electrolyte abnormalities is the cornerstone of treatment for diabetic ketoacidosis (DKA), but little is known about optimal fluid infusion rates and electrolyte content. The objective of this study was to evaluate whether different fluid protocols affect the rate of normalization of biochemical derangements during DKA treatment.

Research Design And Methods: The current analysis involved moderate or severe DKA episodes ( = 714) in children age <18 years enrolled in the Fluid Therapies Under Investigation in DKA (FLUID) Trial. Children were assigned to one of four treatment groups using a 2 × 2 factorial design (0.90% or 0.45% saline and fast or slow rate of administration).

Results: The rate of change of pH did not differ by treatment arm, but Pco increased more rapidly in the fast versus slow fluid infusion arms during the initial 4 h of treatment. The anion gap also decreased more rapidly in the fast versus slow infusion arms during the initial 4 and 8 h. Glucose-corrected sodium levels remained stable in patients assigned to 0.90% saline but decreased in those assigned to 0.45% saline at 4 and 8 h. Potassium levels decreased, while chloride levels increased more rapidly with 0.90% versus 0.45% saline. Hyperchloremic acidosis occurred more frequently in patients in the fast arms (46.1%) versus the slow arms (35.2%).

Conclusions: In children treated for DKA, faster fluid administration rates led to a more rapid normalization of anion gap and Pco than slower fluid infusion rates but were associated with an increased frequency of hyperchloremic acidosis.
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http://dx.doi.org/10.2337/dc20-3113DOI Listing
September 2021

Root angle in maize influences nitrogen capture and is regulated by calcineurin B-like protein (CBL)-interacting serine/threonine-protein kinase 15 (ZmCIPK15).

Plant Cell Environ 2021 Jun 25. Epub 2021 Jun 25.

Department of Plant Science, The Pennsylvania State University, University Park, Pennsylvania, USA.

Crops with reduced nutrient and water requirements are urgently needed in global agriculture. Root growth angle plays an important role in nutrient and water acquisition. A maize diversity panel of 481 genotypes was screened for variation in root angle employing a high-throughput field phenotyping platform. Genome-wide association mapping identified several single nucleotide polymorphisms (SNPs) associated with root angle, including one located in the root expressed CBL-interacting serine/threonine-protein kinase 15 (ZmCIPK15) gene (LOC100285495). Reverse genetic studies validated the functional importance of ZmCIPK15, causing a approximately 10° change in root angle in specific nodal positions. A steeper root growth angle improved nitrogen capture in silico and in the field. OpenSimRoot simulations predicted at 40 days of growth that this change in angle would improve nitrogen uptake by 11% and plant biomass by 4% in low nitrogen conditions. In field studies under suboptimal N availability, the cipk15 mutant with steeper growth angles had 18% greater shoot biomass and 29% greater shoot nitrogen accumulation compared to the wild type after 70 days of growth. We propose that a steeper root growth angle modulated by ZmCIPK15 will facilitate efforts to develop new crop varieties with optimal root architecture for improved performance under edaphic stress.
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http://dx.doi.org/10.1111/pce.14135DOI Listing
June 2021

Targeted mutation of transcription factor genes alters metaxylem vessel size and number in rice roots.

Plant Direct 2021 Jun 15;5(6):e00328. Epub 2021 Jun 15.

Department of Plant Science The Pennsylvania State University University Park PA USA.

Root metaxylem vessels are responsible for axial water transport and contribute to hydraulic architecture. Variation in metaxylem vessel size and number can impact drought tolerance in crop plants, including rice, a crop that is particularly sensitive to drought. Identifying and validating candidate genes for metaxylem development would aid breeding efforts for improved varieties for drought tolerance. We identified three transcription factor candidate genes that potentially regulate metaxylem vessel size and number in rice based on orthologous annotations, published expression data, and available root and drought-related QTL data. Single gene knockout mutants were generated for each candidate using CRISPR-Cas9 genome editing. Root metaxylem vessel area and number were analyzed in 6-week-old knockout mutants and wild-type plants under well-watered and drought conditions in the greenhouse. Compared with wild type, () mutants had fewer, smaller metaxylem vessels in shallow roots and more, larger vessels in deep roots in drought conditions, indicating that may be a repressor of drought-induced metaxylem plasticity. The mutants showed fewer but larger metaxylem vessel area in well-watered conditions, but phenotypes were inconsistent under drought treatment. () mutants had fewer, smaller metaxylem vessels in well-watered conditions with greater effects on xylem number than size. mutants had larger shoots and more, deeper roots than the wild type in well-watered conditions, but there were no differences in performance under drought between mutants and wild type. Though these candidate gene mutants did not exhibit large phenotypic effects, the identification and investigation of candidate genes related to metaxylem traits in rice deepen our understanding of metaxylem development and are needed to facilitate incorporation of favorable alleles into breeding populations to improve drought stress tolerance.
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http://dx.doi.org/10.1002/pld3.328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204146PMC
June 2021

Using a consumer-based wearable activity tracker for physical activity goal setting and measuring steps in pregnant women with gestational diabetes mellitus: exploring acceptance and validity.

BMC Pregnancy Childbirth 2021 Jun 8;21(1):420. Epub 2021 Jun 8.

The University of Tennessee, Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN, 37920, USA.

Background: Activity monitoring devices may be used to facilitate goal-setting, self-monitoring, and feedback towards a step-based physical activity (PA) goal. This study examined the performance of the wrist-worn Fitbit Charge 3™ (FC3) and sought opinions on walking and stepping-in-place from women with gestational diabetes (GDM).

Methods: Participants completed six 2-min metronome-assisted over ground bouts that varied by cadence (67, 84, or 100 steps per minute) and mode (walking or stepping-in-place; N = 15), with the sequence randomized. Steps were estimated by FC3 and measured, in duplicate, by direct observation (hand-tally device, criterion). Equivalence testing by the two one-sided tests (TOST) method assessed agreement within ± 15%. Mean absolute percent error (MAPE) of steps were compared to 10%, the accuracy standard of the Consumer Technology Association (CTA)™. A subset (n = 10) completed a timed, 200-m self-paced walk to assess natural walking pace and cadence. All participants completed semi-structured interviews, which were transcribed and analyzed using descriptive and interpretive coding.

Results: Mean age was 27.0 years (SD 4.2), prepregnancy BMI 29.4 kg/m (8.3), and gestational age 32.8 weeks (SD 2.6). The FC3 was equivalent to hand-tally for bouts of metronome-assisted walking and stepping-in-place at 84 and 100 steps per minute (i.e., P < .05), although walking at 100 steps per minute (P = .01) was no longer equivalent upon adjustment for multiple comparisons (i.e., at P < .007). The FC3 was equivalent to hand-tally during the 200-m walk (i.e., P < .001), in which mean pace was 68.2 m per minute (SD 10.7), or 2.5 miles per hour, and mean cadence 108.5 steps per minute (SD 6.5). For walking at 84 and 100 steps per minute, stepping-in-place at 100 steps per minute, and the 200-m walk, MAPE was within 10%, the accuracy standard of the CTA™. Interviews revealed motivation for PA, that stepping-in-place was an acceptable alternative to walking, and competing responsibilities made it difficult to find time for PA.

Conclusions: The FC3 appears to be a valid step counter during the third trimester, particularly when walking or stepping-in-place at or close to women's preferred cadence.
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http://dx.doi.org/10.1186/s12884-021-03900-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188700PMC
June 2021

Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.

Nat Commun 2021 05 11;12(1):2678. Epub 2021 May 11.

Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
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http://dx.doi.org/10.1038/s41467-021-22888-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113450PMC
May 2021

Access to Optimal Emergency Care for Children.

Ann Emerg Med 2021 05;77(5):523-531

Emergency Nurses Association, Schaumburg, Illinois.

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http://dx.doi.org/10.1016/j.annemergmed.2021.03.034DOI Listing
May 2021

Access to Optimal Emergency Care for Children.

Pediatrics 2021 05;147(5)

Emergency Nurses Association, Schaumburg, Illinois.

Every year, millions of pediatric patients seek emergency care. Significant barriers limit access to optimal emergency services for large numbers of children. The American Academy of Pediatrics, American College of Emergency Physicians, and Emergency Nurses Association have a strong commitment to identifying these barriers, working to overcome them, and encouraging, through education and system changes, improved access to emergency care for all children.
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http://dx.doi.org/10.1542/peds.2021-050787DOI Listing
May 2021

Feline and Canine Rabies in New York State, USA.

Viruses 2021 03 10;13(3). Epub 2021 Mar 10.

Wadsworth Center, New York State Department of Health, Slingerlands, NY 12159, USA.

In New York State, domestic animals are no longer considered rabies vector species, but given their ubiquity with humans, rabies cases in dogs and cats often result in multiple individuals requiring post-exposure prophylaxis. For over a decade, the New York State rabies laboratory has variant-typed these domestic animals to aid in epidemiological investigations, determine exposures, and generate demographic data. We produced a data set that outlined vaccination status, ownership, and rabies results. Our data demonstrate that a large percentage of felines submitted for rabies testing were not vaccinated or did not have a current rabies vaccination, while canines were largely vaccinated. Despite massive vaccination campaigns, free clinics, and education, these companion animals still occasionally contract rabies. Barring translocation events, we note that rabies-positive cats and dogs in New York State have exclusively contracted a raccoon variant. While the United States has made tremendous strides in reducing its rabies burden, we hope these data will encourage responsible pet ownership including rabies vaccinations to reduce unnecessary animal mortality, long quarantines, and post-exposure prophylaxis in humans.
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http://dx.doi.org/10.3390/v13030450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998993PMC
March 2021

Lung Cancer Screening in African Americans: The Time to Act Is Now.

Radiol Imaging Cancer 2020 09 21;2(5):e200107. Epub 2020 Aug 21.

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, Calif (A.P., K.B., B.S., D.A.); and Department of Radiology, Ronald Reagan UCLA Medical Center, Los Angeles, Calif (B.S.).

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http://dx.doi.org/10.1148/rycan.2020200107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983712PMC
September 2020

Nodal root diameter and node number in maize ( L.) interact to influence plant growth under nitrogen stress.

Plant Direct 2021 Mar 16;5(3):e00310. Epub 2021 Mar 16.

Department of Plant Science The Pennsylvania State University University Park PA USA.

Under nitrogen limitation, plants increase resource allocation to root growth relative to shoot growth. The utility of various root architectural and anatomical phenotypes for nitrogen acquisition are not well understood. Nodal root number and root cross-sectional area were evaluated in maize in field and greenhouse environments. Nodal root number and root cross-sectional area were inversely correlated under both high and low nitrogen conditions. Attenuated emergence of root nodes, as opposed to differences in the number of axial roots per node, was associated with substantially reduced root number. Greater root cross-sectional area was associated with a greater stele area and number of cortical cell files. Genotypes that produced few, thick nodal roots rather than many, thin nodal roots had deeper rooting and better shoot growth in low nitrogen environments. Fewer nodal roots offset the respiratory and nitrogen costs of thicker diameter roots, since total nodal root respiration and nitrogen content was similar for genotypes with many, thin and few, thick nodal roots. We propose that few, thick nodal roots may enable greater capture of deep soil nitrogen and improve plant performance under nitrogen stress. Synergistic interactions between an architectural and anatomical trait may be an important strategy for nitrogen acquisition. Understanding trait interactions among different root nodes has important implications in for improving crop nutrient uptake and stress tolerance.
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http://dx.doi.org/10.1002/pld3.310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963125PMC
March 2021

Priorities for Prehospital Evidence-Based Guideline Development: A Modified Delphi Analysis.

Prehosp Emerg Care 2021 Mar 16:1-10. Epub 2021 Mar 16.

Few areas of prehospital care are supported by evidence-based guidelines (EBGs). We aimed to identify gaps in clinical and operational prehospital EBGs to prioritize future EBG development and research funding. Using modified Delphi methodology, we sought consensus among experts in prehospital care and EBG development. Five rounds of surveys were administered between October 2019 and February 2020. Round 1 asked participants to list the top three gaps in prehospital clinical guidelines and top three gaps in operational guidelines that should be prioritized for guideline development and research funding. Based on responses, 3 reviewers performed thematic analysis to develop a list of prehospital EBG gaps, with participant feedback in Round 2. In Round 3, participants rated each gap's importance using a 5-point Likert scale, and participants' responses were averaged. In Round 4, participants rank-ordered 10 gaps with the highest mean scores identified in Round 3. In Round 5, participants indicated their agreement with sets of the highest ranked gaps. Of 23 invited participants, 14 completed all 5 rounds. In Rounds 1 and 2, participants submitted 65 clinical and 58 operational gaps, and thematic analysis identified 23 unique clinical gaps and 28 unique operational gaps. The final prioritized list of clinical EBG gaps was: 1) airway management in adult and pediatric patients, 2) care of the pediatric patient, and 3) management of prehospital behavioral health emergencies, with 79% of participants agreeing. The final prioritized list of operational EBG gaps was: 1) define and measure the impact of EMS care on patient outcomes, 2) practitioner wellness, and 3) practitioner safety in the out-of-hospital environment, with 86% of participants agreeing. This modified Delphi study identifies gaps in prehospital EBGs that, if prioritized for development and research funding, would be expected to have the greatest impact on prehospital clinical care and operations.
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http://dx.doi.org/10.1080/10903127.2021.1894276DOI Listing
March 2021

Multiseriate cortical sclerenchyma enhance root penetration in compacted soils.

Proc Natl Acad Sci U S A 2021 02;118(6)

Department of Plant Science, Pennsylvania State University, University Park, PA 16802;

Mechanical impedance limits soil exploration and resource capture by plant roots. We examine the role of root anatomy in regulating plant adaptation to mechanical impedance and identify a root anatomical phene in maize () and wheat () associated with penetration of hard soil: Multiseriate cortical sclerenchyma (MCS). We characterize this trait and evaluate the utility of MCS for root penetration in compacted soils. Roots with MCS had a greater cell wall-to-lumen ratio and a distinct UV emission spectrum in outer cortical cells. Genome-wide association mapping revealed that MCS is heritable and genetically controlled. We identified a candidate gene associated with MCS. Across all root classes and nodal positions, maize genotypes with MCS had 13% greater root lignin concentration compared to genotypes without MCS. Genotypes without MCS formed MCS upon exogenous ethylene exposure. Genotypes with MCS had greater lignin concentration and bending strength at the root tip. In controlled environments, MCS in maize and wheat was associated improved root tensile strength and increased penetration ability in compacted soils. Maize genotypes with MCS had root systems with 22% greater depth and 49% greater shoot biomass in compacted soils in the field compared to lines without MCS. Of the lines we assessed, MCS was present in 30 to 50% of modern maize, wheat, and barley cultivars but was absent in teosinte and wild and landrace accessions of wheat and barley. MCS merits investigation as a trait for improving plant performance in maize, wheat, and other grasses under edaphic stress.
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http://dx.doi.org/10.1073/pnas.2012087118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017984PMC
February 2021

Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy.

J Med Chem 2021 02 28;64(3):1346-1361. Epub 2021 Jan 28.

Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, 1700 Third Avenue, Huntington, West Virginia 25755, United States.

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the -acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01679DOI Listing
February 2021

Patients' Experiences of Interprofessional Collaborative Practice in Primary Care: A Scoping Review of the Literature.

J Patient Exp 2020 Dec 27;7(6):1466-1475. Epub 2020 May 27.

Department of Public Health, The University of Tennessee Knoxville, TN, USA.

Interprofessional collaboration (IPC) has been shown to improve patient safety and quality of care. Particularly, IPC assists health care providers to manage complex and chronic diseases. To this end, primary care centers around the world have begun practicing IPC; however, little is known about the patient's experience of IPC in primary care (IPC-pc). The goals of this scoping review were to identify the studies exploring patients' perspectives on IPC-pc and to reveal gaps in the literature for future research in order to inform policy and practice. A key word search strategy was conducted using PubMed to identify studies published from 1997 to 2017 on IPC-pc that included data collected from patients or their caregivers about patient experience or satisfaction. Seven studies met the inclusion criteria for the scoping review, and these studies were evaluated by interprofessional intervention, collaboration, and outcomes.
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http://dx.doi.org/10.1177/2374373520925725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786771PMC
December 2020

Plant roots sense soil compaction through restricted ethylene diffusion.

Science 2021 01;371(6526):276-280

School of Biosciences, University of Nottingham, Sutton Bonington LE12 5RD, UK.

Soil compaction represents a major challenge for modern agriculture. Compaction is intuitively thought to reduce root growth by limiting the ability of roots to penetrate harder soils. We report that root growth in compacted soil is instead actively suppressed by the volatile hormone ethylene. We found that mutant and rice roots that were insensitive to ethylene penetrated compacted soil more effectively than did wild-type roots. Our results indicate that soil compaction lowers gas diffusion through a reduction in air-filled pores, thereby causing ethylene to accumulate in root tissues and trigger hormone responses that restrict growth. We propose that ethylene acts as an early warning signal for roots to avoid compacted soils, which would be relevant to research into the breeding of crops resilient to soil compaction.
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http://dx.doi.org/10.1126/science.abf3013DOI Listing
January 2021

Frequency and Risk Factors of Acute Kidney Injury During Diabetic Ketoacidosis in Children and Association With Neurocognitive Outcomes.

JAMA Netw Open 2020 12 1;3(12):e2025481. Epub 2020 Dec 1.

Department of Pediatrics, University of California, Davis School of Medicine, Sacramento.

Importance: Acute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear.

Objective: To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA.

Design, Setting, And Participants: This cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and venous pH less than 7.25 or serum bicarbonate level less than 15 mEq/L.

Exposures: DKA requiring intravenous insulin therapy.

Main Outcomes And Measures: AKI occurrence and stage were assessed using serum creatinine measurements using Kidney Disease: Improving Global Outcomes criteria. DKA episodes with and without AKI were compared using univariable and multivariable methods, exploring associated factors.

Results: Among 1359 DKA episodes (mean [SD] patient age, 11.6 [4.1] years; 727 [53.5%] girls; 651 patients [47.9%] with new-onset diabetes), AKI occurred in 584 episodes (43%; 95% CI, 40%-46%). A total of 252 AKI events (43%; 95% CI, 39%-47%) were stage 2 or 3. Multivariable analyses identified older age (adjusted odds ratio [AOR] per 1 year, 1.05; 95% CI, 1.00-1.09; P = .03), higher initial serum urea nitrogen (AOR per 1 mg/dL increase, 1.14; 95% CI, 1.11-1.18; P < .001), higher heart rate (AOR for 1-SD increase in z-score, 1.20; 95% CI, 1.09-1.32; P < .001), higher glucose-corrected sodium (AOR per 1 mEq/L increase, 1.03; 95% CI, 1.00-1.06; P = .001) and glucose concentrations (AOR per 100 mg/dL increase, 1.19; 95% CI, 1.07-1.32; P = .001), and lower pH (AOR per 0.1 increase, 0.63; 95% CI, 0.51-0.78; P < .001) as variables associated with AKI. Children with AKI, compared with those without, had lower scores on tests of short-term memory during DKA (mean [SD] digit span recall: 6.8 [2.4] vs 7.6 [2.2]; P = .02) and lower mean (SD) IQ scores 3 to 6 months after recovery from DKA (100.0 [12.2] vs 103.5 [13.2]; P = .005). Differences persisted after adjusting for DKA severity and demographic factors, including socioeconomic status.

Conclusions And Relevance: These findings suggest that AKI may occur more frequently in children with greater acidosis and circulatory volume depletion during DKA and may be part of a pattern of multiple organ injury involving the kidneys and brain.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.25481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718599PMC
December 2020

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.

Genet Med 2021 03 5;23(3):543-554. Epub 2020 Nov 5.

Department of Medical Genetics, Lyon University Hospital, Lyon, France.

Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.

Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.

Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.

Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
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http://dx.doi.org/10.1038/s41436-020-01011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935717PMC
March 2021

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

Clin Genet 2021 02 23;99(2):259-268. Epub 2020 Nov 23.

Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.
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http://dx.doi.org/10.1111/cge.13874DOI Listing
February 2021

Continuous function of 80 primary renal allografts for 30-47 years with maintenance prednisone and azathioprine/mycophenolate mofetil therapy: A clinical mosaic of long-term successes.

Clin Transplant 2021 01 27;35(1):e14131. Epub 2020 Nov 27.

Department of Nephrology & Hypertension, Cleveland Clinic, Cleveland, OH, USA.

Eighty primary renal allograft recipients, 61 living-related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30-47 years. They were treated with three different early immunosuppression programs (1963-1970: thymectomy, splenectomy, high oral prednisone; 1971-1979: divided-dose intravenous methylprednisolone; and 1980-1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long-term treatment often included the anti-platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40-year success. At 35 years, death-censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan-Meier estimate). Biopsy-documented early acute cellular and highly probable antibody-mediated rejections were reversed with divided-dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non-plasma-cell malignancies was identified. Twenty-seven azathioprine-treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a "low immunosuppression state of allograft acceptance (LISAA)". The lifetime achievements of these patients following a single renal allograft and low-dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic.
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http://dx.doi.org/10.1111/ctr.14131DOI Listing
January 2021

COVID-19 Result Follow-Up Process in the Pediatric Emergency Department Setting.

Disaster Med Public Health Prep 2020 Oct 22:1-5. Epub 2020 Oct 22.

Children's National Medical Center, Washington, DC, USA.

The novel coronavirus disease 2019 (COVID-19) pandemic upended the world. As emergency departments and hospitals across the nation and world braced themselves for the surge of this new disease, the emergency department (ED) at Children's National Hospital (CNH) quickly created a process to address surges in patient visits and follow-ups for coronavirus testing. Within 2 wk of the first reported pediatric patient diagnosed with COVID-19 in the Washington, DC, metropolitan area, CNH ED implemented a new comprehensive follow-up process. This article describes the novel process that ensured timely notification of testing results, enabled patients to speak remotely with ED providers, increased patient and staff safety by reducing unnecessary exposures, and suggested a good patient experience. With over 1900 patients discharged pending their COVID-19 results, the program is successful. We anticipate expansion into antibody testing and notification as the pandemic progresses.
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http://dx.doi.org/10.1017/dmp.2020.403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884666PMC
October 2020

Genetic control of root anatomical plasticity in maize.

Plant Genome 2020 03 25;13(1):e20003. Epub 2020 Mar 25.

Dep. of Plant Science, Pennsylvania State Univ., University Park, PA, 16802, USA.

Root anatomical phenes have important roles in soil resource capture and plant performance; however, their phenotypic plasticity and genetic architecture is poorly understood. We hypothesized that (a) the responses of root anatomical phenes to water deficit (stress plasticity) and different environmental conditions (environmental plasticity) are genetically controlled and (b) stress and environmental plasticity are associated with different genetic loci than those controlling the expression of phenes under water-stress and well-watered conditions. Root anatomy was phenotyped in a large maize (Zea mays L.) association panel in the field with and without water deficit stress in Arizona and without water deficit stress in South Africa. Anatomical phenes displayed stress and environmental plasticity; many phenotypic responses to water deficit were adaptive, and the magnitude of response varied by genotype. We identified 57 candidate genes associated with stress and environmental plasticity and 64 candidate genes associated with phenes under well-watered and water-stress conditions in Arizona and under well-watered conditions in South Africa. Four candidate genes co-localized between plasticity groups or for phenes expressed under each condition. The genetic architecture of phenotypic plasticity is highly quantitative, and many distinct genes control plasticity in response to water deficit and different environments, which poses a challenge for breeding programs.
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http://dx.doi.org/10.1002/tpg2.20003DOI Listing
March 2020
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