Distributable, metabolic PET reporting of tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

Selection and horizontal gene transfer underlie microdiversity-level heterogeneity in resistance gene fate during wastewater treatment.

Activated sludge is the centerpiece of biological wastewater treatment, as it facilitates removal of sewage-associated pollutants, fecal bacteria, and pathogens from wastewater through semi-controlled microbial ecology. It has been hypothesized that horizontal gene transfer facilitates the spread of antibiotic resistance genes within the wastewater treatment plant, in part because of the presence of residual antibiotics in sewage. However, there has been surprisingly little evidence to suggest that sewage-associated antibiotics select for resistance at wastewater treatment plants via horizontal gene transfer or otherwise. We addressed the role of sewage-associated antibiotics in promoting antibiotic resistance using lab-scale sequencing batch reactors fed field-collected wastewater, metagenomic sequencing, and our recently developed bioinformatic tool Kairos. Here, we found confirmatory evidence that fluctuating levels of antibiotics in sewage are associated with horizontal gene transfer of antibiotic resistance genes, microbial ecology, and microdiversity-level differences in resistance gene fate in activated sludge.

Direct radical functionalization of native sugars.

Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity1,2. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies3 to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transformation of native sugars to complex saccharides remains a notable challenge. Here we describe a photoinduced approach to achieve site- and stereoselective chemical glycosylation from widely available native sugar building blocks, which through homolytic (one-electron) chemistry bypasses unnecessary hydroxyl group masking and manipulation. This process is reminiscent of nature in its regiocontrolled generation of a transient glycosyl donor, followed by radical-based cross-coupling with electrophiles on activation with light. Through selective anomeric functionalization of mono- and oligosaccharides, this protecting-group-free 'cap and glycosylate' approach offers straightforward access to a wide array of metabolically robust glycosyl compounds. Owing to its biocompatibility, the method was extended to the direct post-translational glycosylation of proteins.

A one health approach for monitoring antimicrobial resistance: developing a national freshwater pilot effort.

Antimicrobial resistance (AMR) is a world-wide public health threat that is projected to lead to 10 million annual deaths globally by 2050. The AMR public health issue has led to the development of action plans to combat AMR, including improved antimicrobial stewardship, development of new antimicrobials, and advanced monitoring. The National Antimicrobial Resistance Monitoring System (NARMS) led by the United States (U.S) Food and Drug Administration along with the U.S. Centers for Disease Control and U.S. Department of Agriculture has monitored antimicrobial resistant bacteria in retail meats, humans, and food animals since the mid 1990's. NARMS is currently exploring an integrated One Health monitoring model recognizing that human, animal, plant, and environmental systems are linked to public health. Since 2020, the U.S. Environmental Protection Agency has led an interagency NARMS environmental working group (EWG) to implement a surface water AMR monitoring program (SWAM) at watershed and national scales. The NARMS EWG divided the development of the environmental monitoring effort into five areas: (i) defining objectives and questions, (ii) designing study/sampling design, (iii) selecting AMR indicators, (iv) establishing analytical methods, and (v) developing data management/analytics/metadata plans. For each of these areas, the consensus among the scientific community and literature was reviewed and carefully considered prior to the development of this environmental monitoring program. The data produced from the SWAM effort will help develop robust surface water monitoring programs with the goal of assessing public health risks associated with AMR pathogens in surface water (e.g., recreational water exposures), provide a comprehensive picture of how resistant strains are related spatially and temporally within a watershed, and help assess how anthropogenic drivers and intervention strategies impact the transmission of AMR within human, animal, and environmental systems.

What comes next in glycobiology.

Glycans, with their variable compositions and highly dynamic conformations, vastly expand the heterogeneity of whatever factor or cell they are attached to. These properties make them crucial contributors to biological function and organismal health and also very difficult to study. That may be changing as we look to the future of glycobiology.

Using implementation science to decrease variation and high opioid administration in a surgical ICU.

BACKGROUND: High doses and prolonged duration of opioids are associated with tolerance, dependence, and increased mortality. Unfortunately, despite recent efforts to curb outpatient opioid prescribing because of the ongoing epidemic, utilization remains high in the intensive care setting, with intubated patients commonly receiving infusions with a potency much higher than doses required to achieve pain control. We attempted to use implementation science techniques to monitor and reduce excessive opioid prescribing in ventilated patients in our Surgical ICU. METHODS: We conducted a prospective study investigating opioid administration in a closed SICU at an academic medical center over 18 months. Commonly accepted conversions were used to aggregate daily patient opioid use. Patients with a history of chronic opioid use and those being treated with an ICP monitor/drain, neuromuscular blocker, or ECMO were excluded. If the patient spent a portion of a day on a ventilator, that day's total was included in the "vent group." MMEs per patient were collected for each patient and assigned to the on-call intensivist. Intensivists were blinded to the data for the first seven months. They were then provided with academic detailing followed by audit & feedback over the subsequent 11 months, demonstrating how opioid utilization during their time in the SICU compared to the unit average and a blinded list of the other attendings. Student's T-tests were performed to compare opioid utilization before and after initiation of academic detailing and audit & feedback. RESULTS: Opioid utilization in patients on a ventilator decreased by 20.1% during the feedback period, including less variation among all intensivists and a 30.9% reduction by the highest prescribers. CONCLUSION: Implementation science approaches can effectively reduce variation in opioid prescribing, especially for high outliers in a SICU. These interventions may reduce the risks associated with prolonged use of high-dose opioids. LEVEL OF EVIDENCE: Prospective pre-post-intervention, Level II.

Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis.

PURPOSE: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. METHODS: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. RESULTS: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. CONCLUSIONS: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.

Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions.

Dependence of the Metal-Insulator-Semiconductor Schottky Barrier Height on Insulator Composition.

The effects of different high-κ tunnel oxides on the metal-insulator-semiconductor Schottky barrier height (ΦB) were systematically investigated. While these high-κ interlayers have been previously observed to affect ΦB, there has never been a clear consensus as to why this ΦB modulation occurs. Changes in ΦB were measured when adding 0.5 nm of seven different high-κ oxides to n-Si/Ni contacts with a thin native silicon oxide also present. Depending on the high-κ oxide composition and ΦB measurement technique, increases in ΦB up to 0.4 eV and decreases up to 0.2 eV with a high-κ introduction were measured. The results were compared to several different hypotheses regarding the effects of tunnel oxides on ΦB. The experimental data correlated most closely with the model of a dipole formed at the SiOx/high-κ interface due to the difference in the oxygen areal density between the two oxides. Knowledge of this relationship will aid in the design of Schottky and ohmic contacts by providing criteria to predict the effects of different oxide stacks on ΦB.

Enhancing User Performance by Adaptively Changing Haptic Feedback Cues in a Fitts's Law Task.

Enhancing human user performance in some complex task is an important research question in many domains from skilled manufacturing to rehabilitation and surgical training. Many examples in the literature explore the effects of both haptic assistance or guidance to complete a task, as well as haptic hindrance to temporarily increase task difficulty for the ultimate goal of faster learning. Studies also suggest adaptively changing guidance based on expertise may be most effective. However, to our knowledge, there has not yet been a conclusive study evaluating these enhancement modes in a systematic experiment. In this article, we evaluate learning outcomes for 24 human subjects in a randomized control trial performing a Fitt's law reaching task under various haptic feedback conditions including: no haptics, assistive haptics, resistive haptics, and adaptively changing haptics tied to current performance measures. Subjects each performed 400 trials total and this paper reports results for 40 pre-test and 40 post-test trials. While most conditions did show improvements in performance, we found statistically significant results indicating that our adaptive haptic feedback condition leads to faster and more effective learning as evidenced by metrics of movement time, overshoot, performance index, and speed when compared to the other groups.

Late-Stage Functionalization of Living Organisms: Rethinking Selectivity in Biology.

With unlimited selectivity, full post-translational chemical control of biology would circumvent the dogma of genetic control. The resulting direct manipulation of organisms would enable atomic-level precision in "editing" of function. We argue that a key aspect that is still missing in our ability to do this (at least with a high degree of control) is the selectivity of a given chemical reaction in a living organism. In this Review, we systematize existing illustrative examples of chemical selectivity, as well as identify needed chemical selectivities set in a hierarchy of anatomical complexity: organismo- (selectivity for a given organism over another), tissuo- (selectivity for a given tissue type in a living organism), cellulo- (selectivity for a given cell type in an organism or tissue), and organelloselectivity (selectivity for a given organelle or discrete body within a cell). Finally, we analyze more traditional concepts such as regio-, chemo-, and stereoselective reactions where additionally appropriate. This survey of late-stage biomolecule methods emphasizes, where possible, functional consequences (i.e., biological function). In this way, we explore a concept of late-stage functionalization of living organisms (where "late" is taken to mean at a given state of an organism in time) in which programmed and selective chemical reactions take place in life. By building on precisely analyzed notions (e.g., mechanism and selectivity) we believe that the logic of chemical methodology might ultimately be applied to increasingly complex molecular constructs in biology. This could allow principles developed at the simple, small-molecule level to progress hierarchically even to manipulation of physiology.

The Minimum Protein Staple? - Towards 'bio'-Baldwin's rules via inter-phosphosite linking in the MEK1 activation loop.

In small molecule organic chemistry, the heuristic insight into ring-forming processes that was enabled by Baldwin's rules some 50 years ago proved a step-change in the role of mechanistically guided synthesis. It created a lens upon and marker of fundamental stereoelectronic and conformation-guided chemical processes. However, despite the widespread role of stereoelectronics and conformational control in Biology, no equivalent coherent exploitation of trapped, ring-forming processes yet exists in biomolecules. In the development of a minimal ring-closing process in intact proteins that might prove suitable in a coherent rule-set, we have tested endo-trig ring-closing conjugate thioether lanthionine (Lan) -CH2-S-CH2- formation as a limiting cyclization. Spontaneous Lan formation in proteins is rare if not non-existent and when found in natural product cyclic peptides it requires the mediation of corresponding biosynthetic enzymes as well as productive reactive conformations to guide it. Here, we show that within a conformationally flexible and functionally important protein loop - the MAPK kinase phosphorylation-targeted activation loop - Lan ring-closing is possible. Ring-closing proves to be critically dependent on the location of a trig electrophilic site in just one of two regioisomeric potential precursors to allow phosphosite-to-phosphosite 'stapling'. This first example of spontaneous protein thioether ring-closing/'stapling' and its accessibility from just one precursor (despite the potential for both to form an identical 'staple') now reveals the potential for Lan formation not only as an accessible form of minimal stapling in proteins but also as an exquisitely sensitive probe of associated protein geometries. We suggest that the use of this (as well as the development of other such, intramolecular protein traps that are dependent on inherent protein-controlled reactivity rather than forced crosslinking) may allow the broader trapping and mapping of relevant, even minor, protein states. In this way, protein ring formation may enable a form of extended 'bio-Baldwin's rules' that help to delineate relevant protein conformational space.

Progressive Reduction in Preventable Mortality in a State Trauma System Using Continuous Preventable Mortality Review to Drive Provider Education: Results of Analyzing 1,979 Trauma Deaths from 2015 to 2022.

BACKGROUND: The state legislature codified and funded the Arkansas Trauma System (ATS) in 2009. Quarterly preventable mortality reviews (PMRs) by the ATS began in 2015 and were used to guide state-wide targeted education to reduce preventable or potentially preventable (P/PP) deaths. We present the results of this PMR-education initiative from 2015 to 2022. STUDY DESIGN: The ATS uses a statistical sampling model of the Arkansas Trauma Registry to select ~40% of the deaths for quarterly review, reflecting the overall the Arkansas Trauma Registry mortality population. A multispecialty PMR committee reviews the medical records from prehospital care to death, and hospital and regional advisory council reviews for each death. The PMR committee assigns opportunities for improvement (OFIs), cause(s) of death, and the likelihood of preventability for each case. Education to improve trauma care includes annual state-wide trauma meetings, novel classes targeted at level III/IV trauma center hospital providers, trauma evidence-based guidelines, and PMR "pearls." RESULTS: We reviewed 1,979 deaths with 211 (10.6%) deaths judged to be P/PP deaths. There was a progressive decrease in P/PP deaths and OFIs for P/PP deaths. Five OFI types targeted by education accounted for 72% of the 24 possible OFI types in the P/PP cases, and 94% of the "contributory OFIs." Reductions in "delay in treatment" resulted in the most rapid decrease in P/PP deaths. CONCLUSIONS: Using ongoing PMR studies to target provider education led to a reduction in P/PP deaths and OFIs for P/PP deaths. Focusing on education designed to improve preventable mortality can result in a substantial decrease in P/PP deaths by 43% (14% to 8%) for trauma systems.

Impact of Pendent Ammonium Groups on Solubility and Cycling Charge Carrier Performance in Nonaqueous Redox Flow Batteries.

The synthesis, characterization, electrochemical performance, and theoretical modeling of two base-metal charge carrier complexes incorporating a pendent quaternary ammonium group, [Ni(bppn-Me3)][BF4], 3', and [Fe(PyTRENMe)][OTf]3, 4', are described. Both complexes were produced in high yield and fully characterized using NMR, IR, and UV-vis spectroscopies as well as elemental analysis and single-crystal X-ray crystallography. The solubility of 3' in acetonitrile showed a 283% improvement over its neutral precursor, whereas the solubility of complex 4' was effectively unchanged. Cyclic voltammetry indicates an ∼0.1 V positive shift for all waves, with some changes in reversibility depending on the wave. Bulk electrochemical cycling demonstrates that both 3' and 4' can utilize the second more negative wave to a degree, whereas 4' ceases to have a reversible positive wave. Flow cell testing of 3' and 4' with Fc as the posolyte reveals little improvement to the cycling performance of 3' compared with its parent complex, whereas 4' exhibits reductions in capacity decay when cycling either negative wave. Postcycling CVs indicate that crossover is the likely source of capacity loss in complexes 3, 3', and 4' because there is little change in the CV trace. Density functional theory calculations indicate that the ammonium group lowers the HOMO energy in 3' and 4', which may impart stability to cycling negative waves while making positive waves less accessible. Overall, the incorporation of a positively charged species can improve solubility, stored electron density, and capacity decay depending on the complex, features critical to high energy density redox flow battery performance.

Toxic Epidermal Necrolysis after COVID-19 mRNA-1237 Vaccination.

This letter illustrates a case of toxic epidermal necrolysis (TEN) after COVID-19 mRNA-1273 vaccination, which corresponds with the existing published data and contributes detailed knowledge of TEN reaction after vaccination. Interestingly, the reaction started at the site of vaccination and the patient went on to tolerate a major excipient of the vaccine suggesting the reaction may be associated with the mRNA itself or is triggered by the immunostimulatory action of the vaccine.

Let the Program Evaluation Committee SOAR: Applying the Strengths, Opportunities, Aspirations, and Results (SOAR) Framework for Program Evaluation.

OBJECTIVE: Annual program evaluations are important activities of all graduate medical education programs. Although the Accreditation Council for Graduate Medical Education provides general guidelines, there is substantial scope for educational innovation. Strengths, opportunities, aspirations, and results (SOAR) is a strengths-based framework for strategic planning. Because SOAR emphasizes positivity and engagement, it is an appealing framework for evaluating graduate medical education programs. Our objective was to demonstrate the feasibility and acceptability of SOAR in a program evaluation committee of a fellowship program to generate strategic initiatives. METHODS: The authors used the four steps of SOAR within the program evaluation committee in 2022. Interviewers collected positive stories to understand program strengths. Then, rapid ideation was used to translate strengths into opportunities. These opportunities were condensed and refined for fellows to assess how well they align with aspirations. The ones that aligned best with aspirations were prioritized for implementation. Results were monitored through a scorecard based on specific, measurable, achievable, relevant, and time-bound (SMART) goals every month. RESULTS: Of 15 divisional members, 11 participated (73.3%). Five major strengths were identified: supportive environment, variety of cases, scheduling flexibility, integration with larger networks, and multidisciplinary collaboration. These 5 yielded 15 opportunities, which were refined and condensed to 9. Four were selected for implementation: scholarly works accountability group, hybrid-flex curriculum, fellowship weekly huddles, and structured electives. Scorecards have shown successful implementation during a 4-month period. CONCLUSIONS: SOAR is an innovative and feasible approach to program evaluation that uses trainee engagement to translate and synergize existing program strengths into actionable program improvement.

ARGem: a new metagenomics pipeline for antibiotic resistance genes: metadata, analysis, and visualization.

Antibiotic resistance is of crucial interest to both human and animal medicine. It has been recognized that increased environmental monitoring of antibiotic resistance is needed. Metagenomic DNA sequencing is becoming an attractive method to profile antibiotic resistance genes (ARGs), including a special focus on pathogens. A number of computational pipelines are available and under development to support environmental ARG monitoring; the pipeline we present here is promising for general adoption for the purpose of harmonized global monitoring. Specifically, ARGem is a user-friendly pipeline that provides full-service analysis, from the initial DNA short reads to the final visualization of results. The capture of extensive metadata is also facilitated to support comparability across projects and broader monitoring goals. The ARGem pipeline offers efficient analysis of a modest number of samples along with affordable computational components, though the throughput could be increased through cloud resources, based on the user's configuration. The pipeline components were carefully assessed and selected to satisfy tradeoffs, balancing efficiency and flexibility. It was essential to provide a step to perform short read assembly in a reasonable time frame to ensure accurate annotation of identified ARGs. Comprehensive ARG and mobile genetic element databases are included in ARGem for annotation support. ARGem further includes an expandable set of analysis tools that include statistical and network analysis and supports various useful visualization techniques, including Cytoscape visualization of co-occurrence and correlation networks. The performance and flexibility of the ARGem pipeline is demonstrated with analysis of aquatic metagenomes. The pipeline is freely available at https://github.com/xlxlxlx/ARGem.

Decreasing Post-Operative Narcotic Usage Following Total Knee Arthroplasty Requires More than Simple Education: A Blinded Randomized Controlled Trial.

The purpose of this study was to understand if including a patient opioid education document would decrease opioid consumption following TKA. Patients were balanced between the control and intervention group based on age, sex, and date of surgery. At 5 weeks following surgery, there were significantly fewer patients driving in the education cohort as compared to the control cohort. There was not a significant difference in mean 2-week post-operative VAS pain score, mean 5 weeks post-operative VAS pain score, mean number of dispensed pills. Reducing post-operative narcotic usage likely requires a more comprehensive strategy.

Reimagining the Rheumatology Fellowship Interview: Using Participatory Design-Thinking Process to Create a More Applicant-Centered Experience.

OBJECTIVE: Design thinking is a creative problem-solving process used to better understand users' needs and experiences so that a product or service can be improved. Its emphasis on empathy, iterative prototyping, and participatory collaboration make it an ideal methodology for innovation in medical education. We apply this framework to the virtual rheumatology fellowship interview process so that interviews can become more applicant centered. METHODS: This educational quality improvement project uses a design-thinking framework to identify opportunities and challenges for rheumatology fellowship applicants. The investigators use the 5-step process (Empathize, Define, Ideate, Prototype, Test) and incorporate rapid qualitative analysis of semistructured interviews to innovate the interview experience. The iterative and collaborative nature of this process has empowered participants to codesign an applicant-centered interview experience. RESULTS: Interviews with fellowship applicants (n = 9), fellow physicians (n = 4), and faculty members (n = 3) identified three major dynamics of the interview process: (1) Is it a safe environment to ask questions? (2) How do I exchange information effectively? and (3) How do I fit all these data into the bigger picture? Creative brainstorming techniques at a series of three workshops yielded four prototypes emphasizing customization, hybridization, facilitation, and preparation. A finalized applicant-centered interview template was devised in preparation for the 2023-2024 application season. CONCLUSION: Design thinking has yielded insights into three important dynamics that drive applicant experiences. These insights allow for a redesign of processes so that virtual interviews can be more applicant centered. This framework allows for further iterations and modifications as the needs of applicants and programs evolve over time.

A UK Single-Center, Retrospective, Noninterventional Study of Clinical Outcomes and Costs of Two BotulinumtoxinA Treatments for Limb Spasticity.

Service model changes at the North Staffordshire Rehabilitation Centre (UK) included switching spasticity treatment from onabotulinumtoxinA (onaBoNT-A) to abobotulinumtoxinA (aboBoNT-A). This noninterventional, retrospective, longitudinal study (NCT04396704) describes the clinical and economic outcomes in toxin-naive adults with spasticity who received onaBoNT-A (Cohort 1; 2015-2017) or aboBoNT-A (Cohort 2; 2017-2019). Outcomes included Goal Attainment Scale T (GAS-T) score, treatment satisfaction, quality of life (QoL; EQ-5D visual analog scale [VAS] score), and treatment costs. Adverse events were recorded for Cohort 2. Cohort 1 included 60 patients (mean [standard deviation] dose, 206.0 [98.8] U); Cohort 2 included 54 patients (753.7 [457.3] U). Mean (95% confidence interval) GAS-T scores for Cohorts 1 and 2 were 43.1 (39.3-46.9) and 47.8 (43.7-51.9) at Week 6, and 43.2 and 44.3 at Week 12, respectively. In both cohorts most patients were satisfied with treatment. At Week 12, QoL had not changed in Cohort 1 but had improved in Cohort 2 (EQ-5D VAS, -5). Mean estimated per-patient costs (in 2021) for Cohorts 1 and 2 were £315.56 and £249.25, respectively, at Week 6, and £343.20 and £273.21, respectively, at Week 12. Fifteen non-treatment-related serious adverse events and two deaths were recorded. These data may warrant a larger prospective study powered to compare outcomes of aboBoNT-A and onaBoNT-A.