Where Are All the Pediatricians?

This Viewpoint highlights the current decline in US medical graduates choosing pediatrics as a specialty; discusses some reasons for, and the long-term ramifications of, this decline; and suggests measures that could be taken to reverse the decline and ensure that children receive excellent care.

Characterization of Quantitative Trait Loci for Leaf Rust Resistance from CI 13227 in Three Winter Wheat Populations.

Leaf rust is a widespread foliar wheat disease causing substantial yield losses worldwide. Slow-rusting is "adult plant" resistance that significantly slows epidemic development and thereby reduces yield loss. Wheat accession CI 13227 was previously characterized as having slow-rusting resistance. To validate the quantitative trait loci (QTL) and develop diagnostic markers for slow rusting resistance in CI 13227, a new population of recombinant inbred lines (RILs) of CI 13227 × Everest was evaluated for latent period (LP), final severity (FS), area under disease progress curve (AUDPC), and infection type (IT) in greenhouses and genotyped using genotyping-by-sequencing (GBS). Four QTL were identified on chromosome arms 2BL, 2DS, 3BS, and 7BL, explaining 6.82 to 28.45% of the phenotypic variance for these traits. Seven kompetitive allele specific polymorphism (KASP) markers previously reported to be linked to the QTL in two other CI 13227 populations were validated. In addition, the previously reported QLr.hwwg-7AL was remapped to 2BL (renamed QLr.hwwg-2BL) after adding new markers in this study. Phenotypic data showed that the RILs harboring two or three of the QTL had a significantly longer LP. QLr.hwwg-2DS on 2DS showed a major effect on all rust resistance traits and was finely mapped to a 2.7 Mb interval by two newly developed flanking markers from exome capture. Three disease-resistance genes and two transporter genes were identified as the putative candidates for QLr.hwwg-2DS. The validated QTL can be used as slow rusting resistance resources and the markers developed in this study will be useful for marker-assisted selection.

Academic performance of students in an accelerated medical pathway.

Accelerated medical school curricula, such as three-year programs, have gained attention in recent years but studies evaluating their impact are still scarce. This study examines the Fully Integrated Readiness for Service Training (FIRST) program, a three-year accelerated pathway, to assess its impact on students' academic performance preparedness for residency. In this observational study, we compared the academic outcomes of FIRST program students to traditional four-year curriculum students from 2018 to 2023. We analyzed multiple metrics, including exam performance (United States Medical Licensing Examination Step scores, shelf exam scores, and pre-clinical course scores) and clinical performance scores during the application and individualization phases. Analysis of Variance was used to examine the effect of accelerated pathway program experience relative to traditional 4-year medical school curriculum on the learning outcomes. FIRST program students were on average 1.5 years younger upon graduation than their traditional peers. While FIRST program students scored slightly lower on Step 2 Clinical Knowledge (CK), they exhibited no significant differences in other exam scores or clinical performance relative to the traditional students. Notably, FIRST students achieved equivalent clinical performance ratings during critical clerkships and rotations. Our findings suggest that a three-year medical school curriculum can effectively prepare students for residency and produce graduates with comparable medical knowledge and clinical skills, offering potential benefits in terms of financial relief and personal well-being for medical students.

A Longitudinal Pediatric Primary Care Residency Tailored to Meet Workforce Need: A 10-Year Evaluation.

Background We started a primary care residency program intended to prepare graduates for primary care and increase entry into primary care, using time-limited funds from the Health Resources and Services Administration (HRSA). Objective To compare the graduates of the primary care residency program to their categorical peers, and whether they remained in the state, began primary care careers, and whether they identified as underrepresented in medicine. Methods This is a retrospective study of a cohort of 39 residents who graduated from the University of North Carolina primary care residency program from 2014-2023. In 2016, HRSA grant funding expired and the program continued with ongoing financial support from the 2 institutions. Graduate demographics and career choices were compared to categorical residents (159 total) for graduate years 2014 to 2023. Results The primary care pediatrics residency has graduated 39 residents to date. Job placement data was obtained for all 39 graduates. Graduates of the program have 5.5-fold greater odds (95% CI, 2.5-12.5) of working in primary care roles following graduation than peer categorical residents. Most graduates (33 of 39, 85%) have taken jobs in general pediatrics (including primary care, urgent care, adolescent medicine, or hospital medicine). The program has recruited a large proportion of its residents (12 of 39, 31%) from groups historically underrepresented in medicine. Conclusions We developed an innovative primary care pediatric residency in collaboration with a community partner, spurred by HRSA funds, that has trained a diverse group of new primary care pediatricians.

Multimodal processing of noisy cues in bumblebees.

Multimodal cues can improve behavioral responses by enhancing the detection and localization of sensory cues and reducing response times. Across species, studies have shown that multisensory integration of visual and olfactory cues can improve response accuracy. However, in real-world settings, sensory cues are often noisy; visual and olfactory cues can be deteriorated, masked, or mixed, making the target cue less clear to the receiver. In this study, we use an associative learning paradigm (Free Moving Proboscis Extension Reflex, FMPER) to show that having multimodal cues may improve the accuracy of bees' responses to noisy cues. Adding a noisy visual cue improves the accuracy of response to a noisy olfactory cue, despite neither the clear nor noisy visual cue being sufficient when paired with a novel olfactory cue. This may provide insight into the neural mechanisms underlying multimodal processing and the effects of environmental change on pollination services.

Association Between In-Training Exam Scores and Clinical Exposure During the COVID-19 Pandemic.

BACKGROUND: We sought to evaluate changes in In-Training Examination (ITE) scores and associations with clinical work during the COVID-19 pandemic. We hypothesized that residents saw a decrease in clinical encounters during the pandemic and that this would be associated with smaller gains in ITE scores. METHODS: We compared ITE score changes with data on patient notes for three classes of pediatric residents at four residency programs: one not exposed to the pandemic during their intern year who entered residency in 2018, one partially exposed to COVID-19 in March of their intern year (2019-2020), and one that was fully exposed to the pandemic, starting residency in June of 2020. RESULTS: ITE scores on average improved from the PGY1 to PGY2 year in the "no covid" and "partial COVID" cohorts. The "full COVID" cohort had little to no improvement, on average. The total number of patient encounters was not associated with a change in ITE scores from PGY1 to PGY2. There was a small but statistically significant association between change in ITE score and number of inpatient H+P notes. CONCLUSIONS: A drop in ITE scores occurred in pediatric residents who entered residency during the COVID-19 pandemic. This change was largely unrelated to clinical encounter number changes.

Missing the mark? Exploratory analysis of the 10-year-old cutoff as an independent marker of high-risk disease in pediatric B-ALL.

This single-center, retrospective study evaluated age as a risk factor for relapsed/refractory disease and/or death in 153 children with B-cell acute lymphoblastic leukemia. The study sample included children near the 10-year age cutoff for high-risk disease (6.0-13.9 years at diagnosis) and without other high-risk features (high white cell count, unfavorable cytogenetics). Children 10.0-13.9 years treated per high-risk protocols did not have inferior outcomes compared with children aged 6.0-9.9 years initiating treatment per standard-risk protocols. The study indicates that, in the era of cytogenetics, an age threshold of 10 years might not be an independent prognostic marker. Multicenter analyses are needed.

Early Peanut Introduction in Infants: Improving Guideline Adherence With EMR Standardization.

OBJECTIVES: Peanut allergy in children is a population health problem. Evidence suggests early peanut introduction (EPI) for infants can reduce the development of peanut allergy. Primary care settings have not widely adopted guidelines recommending EPI. Peanut allergy prevention depends on primary care providers incorporating EPI guidelines into well-child check (WCC) encounters. We aimed to improve guideline adherence in a primary care setting by implementing a bundle of clinical decision support (CDS) tools. METHODS: Using quality improvement methodology, the team developed a standardized work protocol and CDS tools within an electronic medical record (EMR) at 4, 6, and 9-month WCC encounters. The team executed changes and modifications through plan-do-study-act cycles and analyzed results with statistical process control charts. RESULTS: We collected data from 445 WCC encounters from baseline through sustainability. EMR documentation of EPI guidance at 4, 6, and 9-month WCCs shifted from 13.9% to 83.5% over 12 months. Provider adoption of smart lists and templates increased from 2% to 73%, the distribution of home peanut introduction handouts increased from 5.2% to 54.1%, and caregiver-reported peanut ingestion increased from 0% to 34.6%. Diphtheria-tetanus-acellular pertussis vaccination rates remained at 100% for 6-month visits, and patient in-room time remained at 65 minutes. CONCLUSIONS: Quality improvement methodology improved documentation of EPI guidance and increased reported peanut ingestion at routine WCC encounters without impacting other measures. Broader use of bundled CDS tools and EMR standardization could further improve guideline adherence and increase early peanut introduction to prevent peanut allergy in infants.

Skim exome capture genotyping in wheat.

Next-generation sequencing (NGS) technology advancements continue to reduce the cost of high-throughput genome-wide genotyping for breeding and genetics research. Skim sequencing, which surveys the entire genome at low coverage, has become feasible for quantitative trait locus (QTL) mapping and genomic selection in various crops. However, the genome complexity of allopolyploid crops such as wheat (Triticum aestivum L.) still poses a significant challenge for genome-wide genotyping. Targeted sequencing of the protein-coding regions (i.e., exome) reduces sequencing costs compared to whole genome re-sequencing and can be used for marker discovery and genotyping. We developed a method called skim exome capture (SEC) that combines the strengths of these existing technologies and produces targeted genotyping data while decreasing the cost on a per-sample basis compared to traditional exome capture. Specifically, we fragmented genomic DNA using a tagmentation approach, then enriched those fragments for the low-copy genic portion of the genome using commercial wheat exome baits and multiplexed the sequencing at different levels to achieve desired coverage. We demonstrated that for a library of 48 samples, ∼7-8× target coverage was sufficient for high-quality variant detection. For higher multiplexing levels of 528 and 1056 samples per library, we achieved an average coverage of 0.76× and 0.32×, respectively. Combining these lower coverage SEC sequencing data with genotype imputation using a customized wheat practical haplotype graph database that we developed, we identified hundreds of thousands of high-quality genic variants across the genome. The SEC method can be used for high-resolution QTL mapping, genome-wide association studies, genomic selection, and other downstream applications.

Quantitative trait loci for rolled leaf in a wheat EMS mutant from Jagger.

KEY MESSAGE: Two QTLs with major effects on rolled leaf trait were consistently detected on chromosomes 1A (QRl.hwwg-1AS) and 5A (QRl.hwwg-5AL) in the field experiments. Rolled leaf (RL) is a morphological strategy to protect plants from dehydration under stressed field conditions. Identification of quantitative trait loci (QTLs) underlining RL is essential to breed drought-tolerant wheat cultivars. A mapping population of 154 recombinant inbred lines was developed from the cross between JagMut1095, a mutant of Jagger, and Jagger to identify quantitative trait loci (QTLs) for the RL trait. A linkage map of 3106 cM was constructed with 1003 unique SNPs from 21 wheat chromosomes. Two consistent QTLs were identified for RL on chromosomes 1A (QRl.hwwg-1AS) and 5A (QRl.hwwg-5AL) in all field experiments. QRl.hwwg-1AS explained 24-56% of the phenotypic variation and QRl.hwwg-5AL explained up to 20% of the phenotypic variation. The combined percent phenotypic variation associated with the two QTLs was up to 61%. Analyses of phenotypic and genotypic data of recombinants generated from heterogeneous inbred families of JagMut1095 × Jagger delimited QRl.hwwg-1AS to a 6.04 Mb physical interval. This work lays solid foundation for further fine mapping and map-based cloning of QRl.hwwg-1AS.

Improving Prescribing for Otitis Media in a Pediatric Emergency Unit: A Quality Improvement Initiative.

Acute otitis media (AOM) is a commonly overtreated pediatric diagnosis. The American Academy of Pediatrics (AAP) recommends shorter antibiotic courses and wait-and-see prescriptions (WSPs) for healthy children with mild-to-moderate AOM. Still, clinicians do not consistently prescribe these in pediatric emergency units (EUs). Methods: We performed a quality improvement project to improve antibiotic prescribing in a tertiary pediatric EU over 16 months, focusing on shorter prescription durations and WSPs. We assessed AOM management via chart review, then implemented interventions, including clinician education, a guideline card, visual reminders, and updated emails. In addition, we contacted a percentage of families after their visit to assess their child's outcome and parental satisfaction. Results: Our baseline data showed that only 39% of patients prescribed antibiotics were prescribed an appropriate duration based on age and estimated AOM severity, and only 3% were prescribed WSPs. Via 2 plan-do-study-act (PDSA) cycles, we increased the percentage of patients who received appropriate antibiotics to an average of 67%, sustained for >6 months. Follow-up phone calls suggested no difference in satisfaction or need for nonroutine follow-up care based on prescription length. We did not see a substantial increase in WSPs. Conclusions: AOM management in our children's hospital's EU was often inconsistent with AAP guidelines. Two PDSA cycles improved the rate of appropriate duration antibiotics, and follow-up phone calls suggested no difference in satisfaction or need for nonroutine follow-up care based on prescription length. The next steps involve developing an order set and implementing individualized feedback.

If it ain't broke, don't fix it: evaluating the effect of increased recombination on response to selection for wheat breeding.

Meiotic recombination is a source of allelic diversity, but the low frequency and biased distribution of crossovers that occur during meiosis limits the genetic variation available to plant breeders. Simulation studies previously identified that increased recombination frequency can retain more genetic variation and drive greater genetic gains than wildtype recombination. Our study was motivated by the need to define desirable recombination intervals in regions of the genome with fewer crossovers. We hypothesized that deleterious variants, which can negatively impact phenotypes and occur at higher frequencies in low recombining regions where they are linked in repulsion with favorable loci, may offer a signal for positioning shifts of recombination distributions. Genomic selection breeding simulation models based on empirical wheat data were developed to evaluate increased recombination frequency and changing recombination distribution on response to selection. Comparing high and low values for a range of simulation parameters identified that few combinations retained greater genetic variation and fewer still achieved higher genetic gain than wildtype. More recombination was associated with loss of genomic prediction accuracy, which outweighed the benefits of disrupting repulsion linkages. Irrespective of recombination frequency or distribution and deleterious variant annotation, enhanced response to selection under increased recombination required polygenic trait architecture, high heritability, an initial scenario of more repulsion than coupling linkages, and greater than 6 cycles of genomic selection. Altogether, the outcomes of this research discourage a controlled recombination approach to genomic selection in wheat as a more efficient path to retaining genetic variation and increasing genetic gains compared with existing breeding methods.

Population genomics of Puccinia graminis f.sp. tritici highlights the role of admixture in the origin of virulent wheat rust races.

Puccinia graminis f.sp. tritici (Pgt) causes stem rust disease in wheat that can result in severe yield losses. The factors driving the evolution of its virulence and adaptation remain poorly characterized. We utilize long-read sequencing to develop a haplotype-resolved genome assembly of a U.S. isolate of Pgt. Using Pgt haplotypes as a reference, we characterize the structural variants (SVs) and single nucleotide polymorphisms in a diverse panel of isolates. SVs impact the repertoire of predicted effectors, secreted proteins involved in host-pathogen interaction, and show evidence of purifying selection. By analyzing global and local genomic ancestry we demonstrate that the origin of 8 out of 12 Pgt clades is linked with either somatic hybridization or sexual recombination between the diverged donor populations. Our study shows that SVs and admixture events appear to play an important role in broadening Pgt virulence and the origin of highly virulent races, creating a resource for studying the evolution of Pgt virulence and preventing future epidemic outbreaks.

Genomic variants affecting homoeologous gene expression dosage contribute to agronomic trait variation in allopolyploid wheat.

Allopolyploidy greatly expands the range of possible regulatory interactions among functionally redundant homoeologous genes. However, connection between the emerging regulatory complexity and expression and phenotypic diversity in polyploid crops remains elusive. Here, we use diverse wheat accessions to map expression quantitative trait loci (eQTL) and evaluate their effects on the population-scale variation in homoeolog expression dosage. The relative contribution of cis- and trans-eQTL to homoeolog expression variation is strongly affected by both selection and demographic events. Though trans-acting effects play major role in expression regulation, the expression dosage of homoeologs is largely influenced by cis-acting variants, which appear to be subjected to selection. The frequency and expression of homoeologous gene alleles showing strong expression dosage bias are predictive of variation in yield-related traits, and have likely been impacted by breeding for increased productivity. Our study highlights the importance of genomic variants affecting homoeolog expression dosage in shaping agronomic phenotypes and points at their potential utility for improving yield in polyploid crops.

Development of the Wheat Practical Haplotype Graph database as a resource for genotyping data storage and genotype imputation.

To improve the efficiency of high-density genotype data storage and imputation in bread wheat (Triticum aestivum L.), we applied the Practical Haplotype Graph (PHG) tool. The Wheat PHG database was built using whole-exome capture sequencing data from a diverse set of 65 wheat accessions. Population haplotypes were inferred for the reference genome intervals defined by the boundaries of the high-quality gene models. Missing genotypes in the inference panels, composed of wheat cultivars or recombinant inbred lines genotyped by exome capture, genotyping-by-sequencing (GBS), or whole-genome skim-seq sequencing approaches, were imputed using the Wheat PHG database. Though imputation accuracy varied depending on the method of sequencing and coverage depth, we found 92% imputation accuracy with 0.01× sequence coverage, which was slightly lower than the accuracy obtained using the 0.5× sequence coverage (96.6%). Compared to Beagle, on average, PHG imputation was ∼3.5% (P-value < 2 × 10-14) more accurate, and showed 27% higher accuracy at imputing a rare haplotype introgressed from a wild relative into wheat. We found reduced accuracy of imputation with independent 2× GBS data (88.6%), which increases to 89.2% with the inclusion of parental haplotypes in the database. The accuracy reduction with GBS is likely associated with the small overlap between GBS markers and the exome capture dataset, which was used for constructing PHG. The highest imputation accuracy was obtained with exome capture for the wheat D genome, which also showed the highest levels of linkage disequilibrium and proportion of identity-by-descent regions among accessions in the PHG database. We demonstrate that genetic mapping based on genotypes imputed using PHG identifies SNPs with a broader range of effect sizes that together explain a higher proportion of genetic variance for heading date and meiotic crossover rate compared to previous studies.

The Haplotype-Based Analysis of Aegilops tauschii Introgression Into Hard Red Winter Wheat and Its Impact on Productivity Traits.

The introgression from wild relatives have a great potential to broaden the availability of beneficial allelic diversity for crop improvement in breeding programs. Here, we assessed the impact of the introgression from 21 diverse accessions of Aegilops tauschii, the diploid ancestor of the wheat D genome, into 6 hard red winter wheat cultivars on yield and yield component traits. We used 5.2 million imputed D genome SNPs identified by the whole-genome sequencing of parental lines and the sequence-based genotyping of introgression population, including 351 BC1F3:5 lines. Phenotyping data collected from the irrigated and non-irrigated field trials revealed that up to 23% of the introgression lines (ILs) produce more grain than the parents and check cultivars. Based on 16 yield stability statistics, the yield of 12 ILs (3.4%) was stable across treatments, years, and locations; 5 of these lines were also high yielding lines, producing 9.8% more grain than the average yield of check cultivars. The most significant SNP- and haplotype-trait associations were identified on chromosome arms 2DS and 6DL for the spikelet number per spike (SNS), on chromosome arms 2DS, 3DS, 5DS, and 7DS for grain length (GL) and on chromosome arms 1DL, 2DS, 6DL, and 7DS for grain width (GW). The introgression of haplotypes from A. tauschii parents was associated with an increase in SNS, which was positively correlated with a heading date (HD), whereas the haplotypes from hexaploid wheat parents were associated with an increase in GW. We show that the haplotypes on 2DS associated with an increase in the spikelet number and HD are linked with multiple introgressed alleles of Ppd-D1 identified by the whole-genome sequencing of A. tauschii parents. Meanwhile, some introgressed haplotypes exhibited significant pleiotropic effects with the direction of effects on the yield component traits being largely consistent with the previously reported trade-offs, there were haplotype combinations associated with the positive trends in yield. The characterized repertoire of the introgressed haplotypes derived from A. tauschii accessions with the combined positive effects on yield and yield component traits in elite germplasm provides a valuable source of alleles for improving the productivity of winter wheat by optimizing the contribution of component traits to yield.

Takeoff diversity in Diptera.

The order Diptera (true flies) are named for their two wings because their hindwings have evolved into specialized mechanosensory organs called halteres. Flies use halteres to detect body rotations and maintain stability during flight and other behaviours. The most recently diverged dipteran monophyletic subsection, the Calyptratae, is highly successful, accounting for approximately 12% of dipteran diversity, and includes common families like house flies. These flies move their halteres independently from their wings and oscillate their halteres during walking. Here, we demonstrate that this subsection of flies uses their halteres to stabilize their bodies during takeoff, whereas non-Calyptratae flies do not. We find that flies of the Calyptratae are able to take off more rapidly than non-Calyptratae flies without sacrificing stability. Haltere removal decreased both velocity and stability in the takeoffs of Calyptratae, but not other flies. The loss of takeoff velocity following haltere removal in Calyptratae (but not other flies) is a direct result of a decrease in leg extension speed. A closely related non-Calyptratae species (D. melanogaster) also has a rapid takeoff, but takeoff duration and stability are unaffected by haltere removal. Haltere use thus allows for greater speed and stability during fast escapes, but only in the Calyptratae clade.