A Modified Delphi Consensus Approach to Define Entrustable Professional Activities for Neurocritical Care Advanced Practice Providers.

OBJECTIVES: To define consensus entrustable professional activities (EPAs) for neurocritical care (NCC) advanced practice providers (APPs), establish validity evidence for the EPAs, and evaluate factors that inform entrustment expectations of NCC APP supervisors. DESIGN: A three-round modified Delphi consensus process followed by application of the EQual rubric and assessment of generalizability by clinicians not affiliated with academic medical centers. SETTING: Electronic surveys. SUBJECTS: NCC APPs ( n = 18) and physicians ( n = 12) in the United States with experience in education scholarship or APP program leadership. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The steering committee generated an initial list of 61 possible EPAs. The panel proposed 30 additional EPAs. A total of 47 unique nested EPAs were retained by consensus opinion. The steering committee defined six core EPAs addressing medical knowledge, procedural competencies, and communication proficiency which encompassed the nested EPAs. All core EPAs were retained and subsequently met the previously described cut score for quality and structure using the EQual rubric. Most clinicians who were not affiliated with academic medical centers rated each of the six core EPAs as very important or mandatory. Entrustment expectations did not vary by prespecified groups. CONCLUSIONS: Expert consensus was used to create EPAs for NCC APPs that reached a predefined quality standard and were important to most clinicians in different practice settings. We did not identify variables that significantly predicted entrustment expectations. These EPAs may aid in curricular design for an EPA-based assessment of new NCC APPs and may inform the development of EPAs for APPs in other critical care subspecialties.

Influence of reconsolidation in maintenance of cocaine-associated contextual memories formed during adolescence or adulthood.

Adolescents are at increased risk to develop substance use disorders and suffer from relapse throughout life. Targeted weakening of drug-associated memories has been shown to reduce relapse-like behavior in adult rats, however this process has been understudied in adolescents. We aimed to examine whether adolescent-formed, cocaine-associated memories could be manipulated via reconsolidation mechanisms. To accomplish this objective, we used an abbreviated operant cocaine self-administration paradigm (ABRV Coc-SA). Adult and adolescent rats received jugular catheterization surgery followed by ABRV Coc-SA in a distinct context for 2 h, 2×/day over 5 days. Extinction training (EXT) occurred in a second context for 2 h, 2×/day over 4 days. To retrieve cocaine-context memories, rats were exposed to the cocaine-paired context for 15 min, followed by subcutaneous injection of vehicle or the protein synthesis inhibitor cycloheximide (2.5 mg/kg). Two additional EXT sessions were conducted before a 2 h reinstatement test in the cocaine-paired context to assess cocaine-seeking behavior. We find that both adult and adolescent cocaine-exposed rats show similar levels of cocaine-seeking behavior regardless of post-reactivation treatment. Our results suggest that systemic treatment with the protein synthesis inhibitor cycloheximide does not impair reconsolidation of cocaine-context memories and subsequent relapse during adulthood or adolescence.

Soft Tissue Pathology.

A wide spectrum of pathologies can lead to soft tissue abnormalities within the ankle joint. Many of these disorders can develop into irreversible joint degeneration if left untreated. Arthroscopy is frequently used to treat these soft tissue conditions such as instability, synovitis, impingement, arthrofibrosis, and other inflammatory disorders in the rearfoot and ankle. In general, the etiology of these ankle soft tissue disorders can be classified as traumatic, inflammatory, and congenital/neoplastic. Overall, the goal of diagnosing and treating soft tissue pathologies of the ankle is to restore anatomic and physiologic motion, reduce pain, optimize functional return to activity, and decrease the chance of recurrence while minimizing complications.

Context-drug-associations and reinstatement of drug-seeking behavior in male rats: Adolescent and adult time-dependent effects.

RATIONALE: Drug use during adolescence results in a life-long risk to develop substance-use disorders. Adolescent rats are sensitive to different drug-associated cues, compared to adults; however, the contribution of adolescent-formed context-drug-associations to elicit relapse-like behavior is underexplored. OBJECTIVES: The present study compared the effect of adolescent vs adult-formed context-drug associations to elicit time-dependent increases in cocaine-seeking behavior. This objective was accomplished using an abbreviated (ABRV) operant cocaine self-administration (Coc-SA), Extinction (EXT) paradigm, with cocaine-seeking tests occurring 1 day after training (T1, early relapse) or following 15 days of abstinence (T15, late relapse). METHODS: Adolescent and adult rats received ABRV Coc-SA in a distinct context (2 hr, 2x/day over 5 days) then EXT in a second context (2 hr, 2x/day over 4 days). Adolescent or adult cocaine-exposed rats were then tested (2 hr, non-rewarded) in either the previous EXT or Coc-paired contexts during early or late relapse. RESULTS & CONCLUSIONS: As previously reported, both adolescent and adult cocaine-exposed rats displayed similar magnitudes of cocaine intake and lever presses during Coc-SA, EXT, and early relapse. Independent analysis of adolescent and adult groups revealed differences in lever responding, specifically rats with cocaine exposure during adolescence showed time-dependent increases in lever responding during late relapse. These data suggest that cocaine-context associations formed during adolescence can elicit craving during adulthood and that these age-specific differences in contextual sensitivity may not be immediately observed at early relapse periods.

Identifying the Potential Role of Regional Bone Mineral Density on the Degree of Malleolar Involvement in Acute Ankle Fractures.

Ankle fractures are a common traumatic lower extremity injury and are generally classified and characterized by the rotational mechanism of injury. At each malleolus (i.e., posterior, medial, and lateral) a fracture can occur or a ligamentous injury may be sustained. The purpose of this retrospective study was to determine if bone mineral density is a contributing factor on the number of fractured malleoli versus soft tissue injury in adult ankle fractures. Data was obtained from a registry of ankle fractures that were operatively treated by the foot and ankle team throughout our institutional facilities, from July 2017 to August 2019, and in which a preoperative computerized tomography scan was performed. Regional bone mineral density (BMD) was measured by calculating the average Hounsfield Unit (HU) on axial computerized tomography images of the distal fibula and tibia. The average HU was then compared to the number of fractured malleoli. One hundred eight patients met the study criteria. We identified statistically significant relationships between decreased BMD with increasing age (p < .01) and the male gender (p < .01). After adjusting for the covariates age and gender, no statistically significant relationship was identified between BMD and the number of malleoli involved in a given ankle fracture (p = .11). These findings suggest that while more investigation is required for ankle fracture patterns and BMD evaluation, increased age and biologic female gender is significantly related to decreased BMD as identified via HU.

Cocaine reward and reinstatement in adolescent versus adult rodents.

Adolescence is a critical juncture when initiation of drug use intersects with profound developmental changes in the brain. Adolescent drug use increases the risk to develop substance use disorders (SUDs) later in life, but the mechanisms that confer this vulnerability are not understood. SUDs are defined by cycles of use, abstinence, and relapse. Intense craving during drug-free periods is often triggered by cues and environmental contexts associated with previous use. In contrast to our understanding of stimuli that elicit craving and relapse in adults, the behavioral processes that occur during periods of abstinence and relapse in adolescents are poorly understood. The current mini-review will summarize findings from preclinical rodent studies that used cocaine conditioned place preference and operant cocaine self-administration to examine subsequent effects on reward, relapse and incubation of craving.

Vitamin D status in chimpanzees in human care: a Europe wide study.

While vitamin D deficiency is a public health concern in humans, comparatively little is known about vitamin D levels in non-human primates. Vitamin D plays a crucial role in overall health and its deficiency is associated with a range of disorders, including cardiovascular disease, which is a leading cause of death in great apes. Serum samples (n = 245) from chimpanzees (Pan troglodytes) housed at 32 European zoos were measured for 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and total 25-hydroxyvitamin D (25-OHD) using liquid chromatography and tandem mass spectrometry. Of these samples, 33.1% indicated inadequate vitamin D status, using the human reference interval (25-OHD < 50 nmol/L). The season of the year, health status of the animal, and the provision of daily outdoor access had a significant effect on vitamin D status. This is the first large-scale study on vitamin D status of non-human great apes in human care. Inadequate 25-OHD serum concentrations are widespread in the chimpanzee population in Europe and could be a risk factor for the development of idiopathic myocardial fibrosis, a major cause of mortality in this species, as well as other diseases. A review of husbandry and nutrition practices is recommended to ensure optimal vitamin D supply for these endangered animals.

Effects of Patient-Specific Instrumentation and Ancillary Surgery Performed in Conjunction With Total Ankle Implant Arthroplasty: Postoperative Radiographic Findings.

Accuracy and reproducibility when performing total ankle implant arthroplasty (TAA) are essential for longevity of the implant, maintaining relative stability of the joint, and theoretically reducing the formation of adjacent joint arthritis in the subtalar and knee joints. Studies have helped to illustrate the accuracy of implantation when using patient-specific instrumentation in both knee and ankle implant arthroplasty. Despite the findings of these studies, few have gone on to evaluate the effects of ancillary procedures on TAA; particularly their effects on postoperative implant congruity when performed simultaneously with joint replacement surgery. In this study, preoperative plans on implant alignment based on patient-specific computed tomography images were compared with the alignment observed on immediate postoperative radiographs. Additionally, postoperative joint congruity was measured, and operative reports were assessed to determine if concomitant procedures performed with total ankle replacement had a significant effect on overall alignment. In our population, 46/47 implants were within 1.5° of their anticipated placement in the coronal plane, and 100% were within 2° of anticipated placement in the sagittal plane. Using a spearman's rank-order correlation, our data failed to show any significant relationship between conducting additional procedures in conjunction with TAA (rho = 0.178; p value = .232) and postoperative congruency of the implant. These findings help support the accuracy of ankle implantation using patient-specific instrumentation, while also supporting the appropriate use of indicated procedures in conjunction with total ankle replacement to help obtain a congruent joint postoperatively.

Percutaneous trigeminal tractotomy for trigeminal neuralgia: Postoperative MRI findings.

BACKGROUND AND PURPOSE: Percutaneous trigeminal tractotomy is an ablative procedure that can be used to treat trigeminal neuralgia in patients who have failed prior pharmacologic and surgical treatments. Using perioperative computed tomography (CT) guidance, ablation of the descending spinal trigeminal nucleus and trigeminal tract can be performed precisely to mitigate damage to surrounding structures. These patients are subsequently followed with postoperative imaging and clinical visits to assess long-term pain relief. METHODS: In this report, we present a series of four patients with trigeminal neuralgia who were had refractory disease after prior medical and surgical interventions. These patients underwent CT-guided percutaneous trigeminal tractotomy for pain relief. The patients underwent postoperative MRI and were followed for up to 6 months for long-term clinical outcomes. RESULTS: For intraoperative CT, we find that preprocedure lumbar contrast injection enables better visualization of the cord during placement of the ablation probe. On postoperative imaging, we find that all four patients have hyperintense lesions on T2-weighted MRI that correspond with the location of the trigeminal nucleus and tract. Three patients had short-term pain relief, one of which continued to have long-term relief. CONCLUSION: Intraoperative CT and postoperative MRI serve as useful modalities for confirming localization, evaluating complications, and can be used as a metric for quality control.

COVID-19 Pandemic-Associated Changes in the Acuity of Brain MRI Findings: A Secondary Analysis of Reports Using Natural Language Processing.

RATIONALE AND OBJECTIVES: We aimed to assess early COVID-19 pandemic-associated changes in brain MRI examination frequency and acuity of imaging findings acuity. METHODS: Using a natural language processing model, we retrospectively categorized reported findings of 12,346 brain MRI examinations performed during 6-month pre-pandemic and early pandemic time periods across a large metropolitan health system into 3 acuity levels: (1) normal or near normal; (2) incidental or chronic findings not requiring a management change; and (3) new or progressive findings requiring a management change. Brain MRI frequency and imaging finding acuity level were compared over time. RESULTS: Between March and August of 2019 (pre-pandemic) and 2020 (early pandemic), our health system brain MRI examination volumes decreased 17.0% (6745 vs 5601). Comparing calendar-matched 6-month periods, the proportion of higher acuity findings increased significantly (P< 0.001) from pre-pandemic (22.5%, 43.6% and 34.0% in acuity level 1, 2, and 3, respectively) to early pandemic periods (19.1%, 40.9%, and 40.1%). During the second 3 months of the early pandemic period, as MRI volumes recovered to near baseline, the proportion of higher acuity findings remained high (42.6% vs 34.1%) compared with a similar pre-pandemic period. In a multivariable analysis, Black (B coefficient, 0.16) and underinsured population (B coefficient, 0.33) presented with higher acuity findings (P< 0.05). CONCLUSIONS: As the volume of brain MRI examinations decreased during the early COVID-19 pandemic, the relative proportion of examinations with higher acuity findings increased significantly. Pandemic-related changes in patient outcomes related to reduced imaging access merits further attention.

Incidence of Talar Osteochondral Lesions After Acute Ankle Fracture: A Retrospective Analysis.

Recent literature suggests the majority of osteochondral lesions occur in the ankle joint. Previous studies have suggested that varying incidences of talar osteochondral lesions (OCLT) are associated with ankle fractures. The primary aim of our study was to investigate the incidence of osteochondral lesions associated with acute ankle fractures as observed on computed tomographic (CT) imaging. We also compared the rates of talar osteochondral lesions in patients who had ankle fractures with dislocation and closed manual reduction (CMR) prior to open reduction with internal fixation, to those who did not suffer from ankle joint dislocation. Additionally, a correlation between the location of talar dome lesions with type of ankle fracture as classified by Lauge-Hansen was investigated. Preoperative CT imaging was retrospectively reviewed in 108 patients with acute ankle fractures. A CT-modified version of Berndt Hardy's classification of osteochondral lesions, as previously described by Loomer et al, was used for diagnosis of lesions in our study. The incidence of lesions was calculated across all subjects, and retrospective comparison was performed in those who did and did not undergo closed manual reduction. Supplementary data on location of lesion and its association with ankle fracture type was also recorded. We found an overall incidence of 50.9% OCLT in patients with acute ankle fractures. This number did not significantly differ from those who underwent closed manual reduction (49%). Although a majority of lesions did occur posteriorly, we saw no statistically significant information was seen between either type of fractures or OCLT locations. Careful consideration and thorough evaluation of preoperative CT imaging should be assessed by the performing surgeon, as this could guide both diagnostic and therapeutic treatments for patients with possible osteochondral lesions of the talus undergoing surgical repair of a fractured ankle.

Revision of the Malaligned Ankle Arthrodesis.

A malaligned ankle arthrodesis is a painful and complicated pathology. Deformities may be present in the frontal, sagittal, or transverse plane or a combination of planes. Thorough preoperative evaluation of the deformity and the patient as a whole is crucial to successful revision. Surgical site for revision should be based on center of rotation of angulation, when possible. Revision commonly is performed through opening wedge osteotomy. Closing wedge and focal dome osteotomies, however, are excellent options. Revision also may be performed through external fixation or total ankle replacement. Although the literature is not rich with data, the options discussed provide favorable results.

Revision Surgery for the Achilles Tendon.

Treatment of Achilles tendon ruptures may be surgical or nonsurgical depending on health, history, age, acuity, and severity of the injury. With chronic or revisional injuries, the best method often requires an open repair with reconstructive soft tissue procedures. Revision surgery can be challenging because of the complexity involving tendinous deficits with nonviable and friable tissue. Surgical treatment is based on tendon approximation, size of the defect, tendon integrity, and functional demands. The goal is to restore anatomic and physiologic tension, provide adequate strength for proper ambulation, optimize functional return to activity, decrease pain, and decrease complications.

Current Concepts Regarding Total Ankle Replacement as a Viable Treatment Option for Advanced Ankle Arthritis: What You Need to Know.

Much of the current literature suggests that total ankle replacement (TAR) is no longer an inferior or fringe treatment for advanced ankle arthritis compared with ankle fusion, but rather a viable option for recalcitrant arthritic ankle pathology in the correct patient population. In this article, current concepts associated with successful outcomes for TAR are discussed with an emphasis on ankle joint anatomy and biomechanics, preoperative planning and patient selection, understanding pathomechanics and soft tissue balancing, as well as the surgeon's learning curve.

Rewriting yeast central carbon metabolism for industrial isoprenoid production.

A bio-based economy has the potential to provide sustainable substitutes for petroleum-based products and new chemical building blocks for advanced materials. We previously engineered Saccharomyces cerevisiae for industrial production of the isoprenoid artemisinic acid for use in antimalarial treatments. Adapting these strains for biosynthesis of other isoprenoids such as ß-farnesene (C15H24), a plant sesquiterpene with versatile industrial applications, is straightforward. However, S. cerevisiae uses a chemically inefficient pathway for isoprenoid biosynthesis, resulting in yield and productivity limitations incompatible with commodity-scale production. Here we use four non-native metabolic reactions to rewire central carbon metabolism in S. cerevisiae, enabling biosynthesis of cytosolic acetyl coenzyme A (acetyl-CoA, the two-carbon isoprenoid precursor) with a reduced ATP requirement, reduced loss of carbon to CO2-emitting reactions, and improved pathway redox balance. We show that strains with rewired central metabolism can devote an identical quantity of sugar to farnesene production as control strains, yet produce 25% more farnesene with that sugar while requiring 75% less oxygen. These changes lower feedstock costs and dramatically increase productivity in industrial fermentations which are by necessity oxygen-constrained. Despite altering key regulatory nodes, engineered strains grow robustly under taxing industrial conditions, maintaining stable yield for two weeks in broth that reaches >15% farnesene by volume. This illustrates that rewiring yeast central metabolism is a viable strategy for cost-effective, large-scale production of acetyl-CoA-derived molecules.

Soft Tissue Impingement of the Ankle: Pathophysiology, Evaluation, and Arthroscopic Treatment.

Soft tissue impingement (STI) syndrome is one of 3 causes of a larger all-encompassing joint impingement pathologic condition, which also includes bone and neuropathic entrapment. Altered joint biomechanics and friction of joint tissues combine to cause chronic pain and often functional instability. Although the most common form of STI to the ankle is anterolateral in location, posterior and anteromedial impingement is also discussed in this article. Furthermore, a discussion of biomechanical deficiencies and how they may effect location and cause of STI of the ankle is explored along with pathophysiology, clinical and diagnostic evaluation, current treatments, and long-term outcomes.

Small Joint Arthroscopy in the Foot.

Arthroscopy has advanced in the foot and ankle realm, leading to new innovative techniques designed toward treatment of small joint abnormality. A range of abnormalities that are currently widespread for arthroscopic treatment in larger joints continues to be translated to congruent modalities in the small joints. Small joint arthroscopy offers relief from foot ailments with a noninvasive element afforded by arthroscopy. Early studies have found comparable results from arthroscopic soft tissue procedures as well as arthrodesis of the small joints when compared with the standard open approach.

Genotype Specification Language.

We describe here the Genotype Specification Language (GSL), a language that facilitates the rapid design of large and complex DNA constructs used to engineer genomes. The GSL compiler implements a high-level language based on traditional genetic notation, as well as a set of low-level DNA manipulation primitives. The language allows facile incorporation of parts from a library of cloned DNA constructs and from the "natural" library of parts in fully sequenced and annotated genomes. GSL was designed to engage genetic engineers in their native language while providing a framework for higher level abstract tooling. To this end we define four language levels, Level 0 (literal DNA sequence) through Level 3, with increasing abstraction of part selection and construction paths. GSL targets an intermediate language based on DNA slices that translates efficiently into a wide range of final output formats, such as FASTA and GenBank, and includes formats that specify instructions and materials such as oligonucleotide primers to allow the physical construction of the GSL designs by individual strain engineers or an automated DNA assembly core facility.