Medical delivery without representation?: Examining disability representation within the healthcare community.

 Individuals with disabilities comprise approximately 13% of the overall population. This editorial explores recent events that may involve ableism. The recent COVID pandemic created a rapid need and pressure to develop ventilator allotment policies. Many concluded several state policies were discriminatory in nature toward persons with disabilities (PWD). Lack of disability representation in medical fields may contribute to such discrimination within state and hospital medical policies. The underrepresented numbers of PWD in medical fields are explored. We conclude that improved education for all medical providers is needed. Possible strategies for improving healthcare representation and delivery within the United States are discussed.

Deep brain stimulation in a pediatric dystonia patient with cochlear implants and mitochondrial disorder: novel application of a frameless stereotactic system and navigating the anesthesia choice and neurosurgical complexities. Illustrative case.

BACKGROUND: This report presents a case of medically refractory dystonia in a pediatric patient successfully treated with bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) while under general anesthesia by using microelectrode recordings (MERs) with intraoperative computed tomography (CT). OBSERVATIONS: The patient was an 18-year-old female with primary dystonia secondary to mitochondrial Leigh syndrome. Her past medical history was significant for complex partial epilepsy and hearing loss treated with cochlear implants. Her cochlear implants precluded anatomical targeting via magnetic resonance imaging. Additionally, the patient could not tolerate awake surgery with MER. The decision was made to proceed with bilateral STN DBS with intraoperative CT with the patient under general anesthesia. The patient's cochlear implants made standard frame placement difficult, so navigation was performed with the Nexframe system. Recordings were obtained with the patient under general anesthesia with ketamine, dexmedetomidine, and remifentanil. At the 3- and 6-month follow-ups, the patient demonstrated marked improvement in dystonia without neurological complications. LESSONS: This is the first case of dystonia secondary to Leigh syndrome treated with DBS. Additionally, the authors describe the novel use of the Nexframe for DBS lead placement in a pediatric patient. This demonstrates that STN DBS with the use of MER and intraoperative CT can be a safe and effective method of treating dystonia in certain pediatric patients.

A risk-stratified approach toward safely resuming OnabotulinumtoxinA injections based on dosing and ambulatory status in pediatric patients with cerebral palsy during the Coronavirus pandemic of 2019 (COVID-19).

PURPOSE: After the onset of the Coronavirus pandemic of 2019-2020 (COVID-19), physicians who inject OnabotulinumtoxinA (BoNT-A) were left with determining risks and benefits in pediatric patients with cerebral palsy. Many of these patients have pre-existing conditions that make them more prone to COVID-19 symptoms, and this susceptibility potentially increases after BoNT-A injections. METHODS: A retrospective chart review of 500 patients identified 256 pediatric patients with cerebral palsy who received an intramuscular BoNT-A injection to determine relative doses used for each Gross Motor Functional Classification Score (GMFCS). Data regarding age, weight, GMFCS, BoNT-A total body dosage, and inpatient hospitalizations for 6 months post-injection were collected. Differences between GMFCS levels were analyzed using one-way analysis of variance testing. Inpatient hospitalizations were recorded and assessed using relative risk to determine the population risk of hospitalization in the setting of initiating injections during the COVID-19 pandemic. RESULTS: Based on GMFCS level, patients who were GMFCS I or II received fewer units of BoNT-A medication per kilogram of body weight compared to GMFCS III-V (p< 0.0005, F= 25.38). There was no statistically significant difference in frequency or time to hospitalization when comparing patients receiving BoNT-A compared to a control group. CONCLUSIONS: Resumption of BoNT-A injections during the time of COVID-19 requires a systematic approach based on risks and potential benefits. Data from this analysis does not show increased risk for patients who received injections historically; however, recommendations for resumption of injections has not previously been proposed in the setting of a pandemic. In this manuscript, a tiered approach to considerations for injections was proposed. Botulinum toxin type A injections have a history of improving spasticity in the pediatric patient with cerebral palsy. Ensuring appropriate selection of patients for injection with BoNT-A during this pandemic is increasingly important.

Ecological distributions, phenological isolation, and genetic structure in sympatric and parapatric populations of the Larrea tridentata polyploid complex.

PREMISE OF THE STUDY: Polyploidy is widely recognized as a mechanism of diversification. Contributions of polyploidy to specific pre- and postzygotic barriers-and classifications of polyploid speciation as "ecological" vs. "non-ecological"-are more contentious. Evaluation of these issues requires comprehensive studies that test ecological characteristics of cytotypes as well as the coincidence of genetic structure with cytotype distributions. METHODS: We investigated a classical example of autopolyploid speciation, Larrea tridentata, at multiple areas of cytotype co-occurrence. Habitat and phenological differences were compared between diploid, tetraploid, and hexaploid populations on the basis of edaphic, community composition, and flowering time surveys. Frequency of hybridization between diploids and tetraploids was investigated using a diploid-specific chloroplast DNA (cpDNA) marker; genetic structure for all cytotypes was assessed using amplified fragment length polymorphisms (AFLPs). KEY RESULTS: Across contact zones, we found cytotypes in habitats distinguished by soil and vegetation. We observed modest differences in timing and production of flowers, indicating a degree of assortative mating that was asymmetric between cytotypes. Nonetheless, cpDNA analyses in diploid-tetraploid contact zones suggested that ∼5% of tetraploid plants had hybrid origins involving unilateral sexual polyploidization. Genetic structure of AFLPs largely coincided with cytotype distributions in diploid-tetraploid contact zones. In contrast, there was little structure in areas of contact between tetraploids and hexaploids, suggesting intercytotype gene flow or recurrent hexaploid formation. CONCLUSIONS: Diploid, tetraploid, and hexaploid cytotypes of L. tridentata are segregated by environmental distributions and flowering phenology in contact zones, with diploid and tetraploid populations having corresponding differences in genetic structure.

Back to the future with phenotypic screening.

There are no disease-modifying drugs for any old age associated neurodegenerative disease or stroke. This is at least in part due to the failure of drug developers to recognize that the vast majority of neurodegenerative diseases arise from a confluence of multiple toxic insults that accumulate during normal aging and interact with genetic and environmental risk factors. Thus, it is unlikely that the current single target approach based upon rare dominant mutations or even a few preselected targets is going to yield useful drugs for these conditions. Therefore, the identification of drug candidates for neurodegeneration should be based upon their efficacy in phenotypic screening assays that reflect the biology of the aging brain, not a single, preselected target. It is argued here that this approach to drug discovery is the most likely to produce safe and effective drugs for neurodegenerative diseases.

Ecological studies of polyploidy in the 100 years following its discovery.

Polyploidy is a mutation with profound phenotypic consequences and thus hypothesized to have transformative effects in plant ecology. This is most often considered in the context of geographical and environmental distributions-as achieved from divergence of physiological and life-history traits-but may also include species interactions and biological invasion. This paper presents a historical overview of hypotheses and empirical data regarding the ecology of polyploids. Early researchers of polyploidy (1910 s-1930 s) were geneticists by training but nonetheless savvy to its phenotypic effects, and speculated on the importance of genome duplication to adaptation and crop improvement. Cytogenetic studies in the 1930 s-1950 s indicated that polyploids are larger (sturdier foliage, thicker stems and taller stature) than diploids while cytogeographic surveys suggested that polyploids and diploids have allopatric or parapatric distributions. Although autopolyploidy was initially regarded as common, influential writings by North American botanists in the 1940 s and 1950 s argued for the principle role of allopolyploidy; according to this view, genome duplication was significant for providing a broader canvas for hybridization rather than for its phenotypic effects per se. The emphasis on allopolyploidy had a chilling effect on nascent ecological work, in part due to taxonomic challenges posed by interspecific hybridization. Nonetheless, biosystematic efforts over the next few decades (1950s-1970s) laid the foundation for ecological research by documenting cytotype distributions and identifying phenotypic correlates of polyploidy. Rigorous investigation of polyploid ecology was achieved in the 1980s and 1990 s by population biologists who leveraged flow cytometry for comparative work in autopolyploid complexes. These efforts revealed multi-faceted ecological and phenotypic differences, some of which may be direct consequences of genome duplication. Several classical hypotheses about the ecology of polyploids remain untested, however, and allopolyploidy--regarded by most botanists as the primary mode of genome duplication--is largely unstudied in an ecological context.

Emergent decarboxylase activity and attenuation of α/ß-hydrolase activity during the evolution of methylketone biosynthesis in tomato.

Specialized methylketone-containing metabolites accumulate in certain plants, in particular wild tomatoes in which they serve as toxic compounds against chewing insects. In Solanum habrochaites f. glabratum, methylketone biosynthesis occurs in the plastids of glandular trichomes and begins with intermediates of de novo fatty acid synthesis. These fatty-acyl intermediates are converted via sequential reactions catalyzed by Methylketone Synthase2 (MKS2) and MKS1 to produce the n-1 methylketone. We report crystal structures of S. habrochaites MKS1, an atypical member of the α/ß-hydrolase superfamily. Sequence comparisons revealed the MKS1 catalytic triad, Ala-His-Asn, as divergent to the traditional α/ß-hydrolase triad, Ser-His-Asp. Determination of the MKS1 structure points to a novel enzymatic mechanism dependent upon residues Thr-18 and His-243, confirmed by biochemical assays. Structural analysis further reveals a tunnel leading from the active site consisting mostly of hydrophobic residues, an environment well suited for fatty-acyl chain binding. We confirmed the importance of this substrate binding mode by substituting several amino acids leading to an alteration in the acyl-chain length preference of MKS1. Furthermore, we employ structure-guided mutagenesis and functional assays to demonstrate that MKS1, unlike enzymes from this hydrolase superfamily, is not an efficient hydrolase but instead catalyzes the decarboxylation of 3-keto acids.

Polyploidy and ecological adaptation in wild yarrow.

Chromosome evolution in flowering plants is often punctuated by polyploidy, genome duplication events that fundamentally alter DNA content, chromosome number, and gene dosage. Polyploidy confers postzygotic reproductive isolation and is thought to drive ecological divergence and range expansion. The adaptive value of polyploidy, however, remains uncertain; ecologists have traditionally relied on observational methods that cannot distinguish effects of polyploidy per se from genic differences that accumulate after genome duplication. Here I use an experimental approach to test how polyploidy mediates ecological divergence in Achillea borealis (Asteraceae), a widespread tetraploid plant with localized hexaploid populations. In coastal California, tetraploids and hexaploids occupy mesic grassland and xeric dune habitats, respectively. Using field transplant experiments with wild-collected plants, I show that hexaploids have a fivefold fitness advantage over tetraploids in dune habitats. Parallel experiments with neohexaploids--first-generation mutants screened from a tetraploid genetic background--reveal that a 70% fitness advantage is achieved via genome duplication per se. These results suggest that genome duplication transforms features of A. borealis in a manner that confers adaptation to a novel environment.

Rapid adaptive divergence in new world achillea, an autopolyploid complex of ecological races.

Adaptive evolution is often associated with speciation. In plants, however, ecotypic differentiation is common within widespread species, suggesting that climatic and edaphic specialization can outpace cladogenesis and the evolution of postzygotic reproductive isolation. We used cpDNA sequence (5 noncoding regions, 3.5 kb) and amplified fragment length polymorphisms (AFLPs: 4 primer pairs, 1,013 loci) to evaluate the history of ecological differentiation in the North American Achillea millefolium, an autopolyploid complex of "ecological races" exhibiting morphological, physiological, and life-history adaptations to diverse environments. Phylogenetic analyses reveal North American A. millefolium to be a monophyletic group distinct from its European and Asian relatives. Based on patterns of sequence divergence, as well as fossil and paleoecological data, colonization of North America appears to have occurred via the Bering Land Bridge during the Pleistocene (1.8 MYA to 11,500 years ago). Population genetic analyses indicate negligible structure within North American A. millefolium associated with varietal identity, geographic distribution, or ploidy level. North American populations, moreover, exhibit the signature of demographic expansion. These results affirm the "ecotype" concept of the North American Achillea advocated by classical research and demonstrate the rapid rate of ecological differentiation that sometimes occurs in plants.

Components of reproductive isolation between the monkeyflowers Mimulus lewisii and M. cardinalis (Phrymaceae).

Evolutionists have long recognized the role of reproductive isolation in speciation, but the relative contributions of different reproductive barriers are poorly understood. We examined the nature of isolation between Mimulus lewisii and M. cardinalis, sister species of monkeyflowers. Studied reproductive barriers include: ecogeographic isolation; pollinator isolation (pollinator fidelity in a natural mixed population); pollen competition (seed set and hybrid production from experimental interspecific, intraspecific, and mixed pollinations in the greenhouse); and relative hybrid fitness (germination, survivorship, percent flowering, biomass, pollen viability, and seed mass in the greenhouse). Additionally, the rate of hybridization in nature was estimated from seed collections in a sympatric population. We found substantial reproductive barriers at multiple stages in the life history of M. lewisii and M. cardinalis. Using range maps constructed from herbarium collections, we estimated that the different ecogeographic distributions of the species result in 58.7% reproductive isolation. Mimulus lewisii and M. cardinalis are visited by different pollinators, and in a region of sympatry 97.6% of pollinator foraging bouts were specific to one species or the other. In the greenhouse, interspecific pollinations generated nearly 50% fewer seeds than intraspecific controls. Mixed pollinations of M. cardinalis flowers yielded >75% parentals even when only one-quarter of the pollen treatment consisted of M. cardinalis pollen. In contrast, both species had similar siring success on M. lewisii flowers. The observed 99.915% occurrence of parental M. lewisii and M. cardinalis in seeds collected from a sympatric population is nearly identical to that expected, based upon our field observations of pollinator behavior and our laboratory experiments of pollen competition. F1 hybrids exhibited reduced germination rates, high survivorship and reproduction, and low pollen and ovule fertility. In aggregate, the studied reproductive barriers prevent, on average, 99.87% of gene flow, with most reproductive isolation occurring prior to hybrid formation. Our results suggest that ecological factors resulting from adaptive divergence are the primary isolating barriers in this system. Additional studies of taxa at varying degrees of evolutionary divergence are needed to identify the relative importance of pre- and postzygotic isolating mechanisms in speciation.