The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

The integrated on-chip isolation and detection of circulating tumour cells.

Circulating tumour cells (CTCs) are cancer cells shed from a primary tumour which intravasate into the blood stream and have the potential to extravasate into distant tissues, seeding metastatic lesions. As such, they can offer important insight into cancer progression with their presence generally associated with a poor prognosis. The detection and enumeration of CTCs is, therefore, critical to guiding clinical decisions during treatment and providing information on disease state. CTC isolation has been investigated using a plethora of methodologies, of which immunomagnetic capture and microfluidic size-based filtration are the most impactful to date. However, the isolation and detection of CTCs from whole blood comes with many technical barriers, such as those presented by the phenotypic heterogeneity of cell surface markers, with morphological similarity to healthy blood cells, and their low relative abundance (∼1 CTC/1 billion blood cells). At present, the majority of reported methods dissociate CTC isolation from detection, a workflow which undoubtedly contributes to loss from an already sparse population. This review focuses on developments wherein isolation and detection have been integrated into a single-step, microfluidic configuration, reducing CTC loss, increasing throughput, and enabling an on-chip CTC analysis with minimal operator intervention. Particular attention is given to immune-affinity, microfluidic CTC isolation, coupled to optical, physical, and electrochemical CTC detection (quantitative or otherwise).

Antigen-Mimic Nanoparticles in Ultrasensitive on-Chip Integrated Anti-p53 Antibody Quantification.

As a tumor-suppressing protein, p53 plays a crucial role in preventing cancer development. Its utility as an early cancer detection tool is significant, potentially enabling clinicians to forestall disease advancement and improve patient prognosis. In response to the pathological overexpression of this antigen in tumors, the prevalence of anti-p53 antibodies increases in serum, in a manner quantitatively indicative of cancer progression. This spike can be detected through techniques, such as Western blotting, immunohistochemistry, and immunoprecipitation. In this study, we present an electrochemical approach that supports ultrasensitive and highly selective anti-p53 autoantibody quantification without the use of an immuno-modified electrode. We specifically employ antigen-mimicking and antibody-capturing peptide-coated magnetic nanoparticles, along with an AC magnetic field-promoted sample mixing, prior to the presentation of Fab-captured targets to simple lectin-modified sensors. The subfemtomolar assays are highly selective and support quantification from serum-spiked samples within minutes.

Solvent effects in anion recognition.

Anion recognition is pertinent to a range of environmental, medicinal and industrial applications. Recent progress in the field has relied on advances in synthetic host design to afford a broad range of potent recognition motifs and novel supramolecular structures capable of effective binding both in solution and at derived molecular films. However, performance in aqueous media remains a critical challenge. Understanding the effects of bulk and local solvent on anion recognition by host scaffolds is imperative if effective and selective detection in real-world media is to be viable. This Review seeks to provide a framework within which these effects can be considered both experimentally and theoretically. We highlight proposed models for solvation effects on anion binding and discuss approaches to retain strong anion binding in highly competitive (polar) solvents. The synthetic design principles for exploiting the aforementioned solvent effects are explored.

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction: A pooled analysis of DAPA-HF and DELIVER data.

AIM: To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. CONCLUSIONS: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.

Validation of a Model Estimating the Budget Impact of Video Capsule Endoscopy for Surveillance of Crohn's Disease in an Italian Center.

Background: Crohn's disease is a chronic ailment affecting the gastrointestinal tract. Mucosal healing, a marker of reduced disease activity, is currently assessed in the colonic sections using ileocolonoscopy and magnetic resonance enteroscopy. Video capsule endoscopy (VCE) offers visualization of the entire GI mucosae. Objective: To validate a Crohn's disease model estimating the budget impact of VCE compared with the standard of care (SOC) in Italy. Methods: A patient-level, discrete-event simulation was developed to estimate the budget impact of VCE compared with SOC for Crohn's disease surveillance over 5 years in the Italian setting. Input data were sourced from a physician-initiated study from Sant'Orsola-Malpighi Hospital in Bologna, Italy, and the literature. The care pathway followed hospital clinical practice. Comparators were the current SOC (ileocolonoscopy, with or without magnetic resonance enteroscopy) and VCE. Sensitivity analysis was performed using 500-patient bootstraps. A comparative analysis regarding clinical outcomes (biologics use, surgical interventions, symptom remission) was performed to explore the validity of the model compared with real-world data. Cumulative event incidences were compared annually and semi-annually. Bayesian statistical analysis further validated the model. Results: Implementing VCE yielded an estimated €67 savings per patient per year, with savings in over 55% of patients, compared with SOC. While annual costs are higher up to the second year, VCE becomes cost saving from the third year onward. The real-world validation analysis proved a good agreement between the model and real-world patient records. The highest agreement was found for biologics, where Bayesian analysis estimated an 80.4% probability (95% CI: 72.2%-87.5%) that a decision maker would accept the result as an actual reflection of real-world data. Even where trend data diverged (eg, for surgery [43.1% likelihood of acceptance, 95% CI: 33.7%-52.8%]), the cumulative surgery count over 5 years was within the margin of error of the real-world data. Conclusions: Implementing VCE in the surveillance of patients with Crohn's disease and small bowel involvement may be cost saving in Italy. The congruence between model predictions and real-world patient records supports using this discrete-event simulation to inform healthcare decisions.

Dapagliflozin in chronic kidney disease: cost-effectiveness beyond the DAPA-CKD trial.

Background: The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial enrolled patients with estimated glomerular filtration rate 25-75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio >200 mg/g. The Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial enrolled patients with type 2 diabetes, a higher range of kidney function and no albuminuria criterion. The study objective was to estimate the cost-effectiveness of dapagliflozin in a broad chronic kidney disease population based on these two trials in the UK, Spain, Italy and Japan. Methods: We adapted a published Markov model based on the DAPA-CKD trial but to a broader population, irrespective of urine albumin-to-creatinine ratio, using patient-level data from the DAPA-CKD and DECLARE-TIMI 58 trials. We sourced cost and utility inputs from literature and the DAPA-CKD trial. The analysis considered healthcare system perspectives over a lifetime horizon. Results: Treatment with dapagliflozin was predicted to attenuate disease progression and extend projected life expectancy by 0.64 years (12.5 versus 11.9 years, undiscounted) in the UK, with similar estimates in other settings. Clinical benefits translated to mean quality-adjusted life year (QALY; discounted) gains between 0.45 and 0.68 years across countries. Incremental cost-effectiveness ratios in the UK, Spain, Italy and Japan ($10 676/QALY, $14 479/QALY, $7771/QALY and $13 723/QALY, respectively) were cost-effective at country-specific willingness-to-pay thresholds. Subgroup analyses suggest dapagliflozin is cost-effective irrespective of urinary albumin-to-creatine ratio and type 2 diabetes status. Conclusion: Treatment with dapagliflozin may be cost-effective for patients across a wider spectrum of estimated glomerular filtration rates and albuminuria than previously demonstrated, with or without type 2 diabetes, in the UK, Spanish, Italian and Japanese healthcare systems.

Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease.

IMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, and PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.

Anion Sensing through Redox-Modulated Fluorescent Halogen Bonding and Hydrogen Bonding Hosts.

Anion sensing via either optical or electrochemical readouts has separately received enormous attention, however, a judicious combination of the advantages of both modalities remains unexplored. Toward this goal, we herein disclose a series of novel, redox-active, fluorescent, halogen bonding (XB) and hydrogen bonding (HB) BODIPY-based anion sensors, wherein the introduction of a ferrocene motif induces remarkable changes in the fluorescence response. Extensive fluorescence anion titration, lifetime and electrochemical studies reveal anion binding-induced emission modulation through intramolecular photoinduced electron transfer (PET), the magnitude of which is dependent on the nature of both the XB/HB donor and anion. Impressively, the XB sensor outperformed its HB congener in terms of anion binding strength and fluorescence switching magnitude, displaying significant fluorescence turn-OFF upon anion binding. In contrast, redox-inactive control receptors display a turn-ON response, highlighting the pronounced impact of the introduction of the redox-active ferrocene on the optical sensing performance. Additionally, the redox-active ferrocene motif also serves as an electrochemical reporter group, enabling voltammetric anion sensing in competitive solvents. The combined advantages of both sensing modalities were further exploited in a novel, proof-of-principle, fluorescence spectroelectrochemical anion sensing approach, enabling simultaneous and sensitive read out of optical and electrochemical responses in multiple oxidation states and at very low receptor concentration.

Cohesion Assessment Team: A Multidisciplinary Unit Assessment Grounded in Army Doctrine.

INTRODUCTION: The Cohesion Assessment Team (CAT) provides battalion and brigade command teams with actionable insight into the climate of their unit and the presence of certain harmful behaviors. This assessment, initiated by the Vice Chief of Staff of the Army and initially managed by the Headquarters Department of the Army's People First Task Force, employs a framework from the Center for Army Professional Leadership to structure data and findings. MATERIALS AND METHODS: This manuscript describes how to conduct a CAT assessment. To start, two battalions within the same brigade are selected or volunteer for observation based on various metrics. Data are collected from multiple sources including (1) army metrics, such as promotion rates and Uniformed Code of Military Justice actions, (2) subject matter expert in-person observations and interactions, (3) discussions with battalion and brigade staff, (4) survey data from approximately 90% of the soldiers in participating units, and (5) targeted interviews, focus groups, and listening sessions. Onsite data are collected and synthesized with the survey results within a week. Results are presented to battalion and brigade command teams. Briefs highlight key elements of the unit climate that should be maintained or improved. In addition, summarized results are presented to progressively higher echelons of leadership, culminating with the Vice Chief of Staff of the Army for consideration of army-wide changes. RESULTS AND CONCLUSIONS: The CAT focuses on providing leaders at brigade and below with relevant and actionable information to help inform their internal decision-making to improve their unit's climate. This capability is distinct in many ways, including its non-attributional systems focus and its methodical approach to quickly collecting and triangulating multiple data points. Additionally, the CAT helps leaders identify areas under their control that will impact unit climate, similar to the feedback that training events provide on unit readiness. Army leadership deemed the CAT pilot a success, and responsibility for future CATs was transferred to the Training and Doctrine Command (TRADOC) in October 2022.

Growing Healthy Hearts: a single-arm feasibility study of a digitally delivered gardening, cooking, and nutrition intervention for adults with risk factors for cardiovascular disease.

BACKGROUND: Food gardening may positively influence cardiovascular disease (CVD) risk-related behaviors. However, the vast majority of existing gardening interventions have used an in-person delivery model which has limitations for scalability. It is not known whether a digitally delivered gardening intervention would be feasible or acceptable to participants. The purpose of this pilot study was to assess the feasibility of a digitally delivered gardening intervention in three domains: participant acceptability, demand, and practicality. METHODS: A single-arm, pre-post-study design was used. Participants (n = 30) were aged 20 + with no plans to garden in the coming season and had at least 1 CVD risk factor. The intervention included ten 1-h video-conferencing sessions, written materials, and access to a study website. Content focused on gardening skills, cooking skills, and the Dietary Approaches to Stop Hypertension (DASH) diet. Feasibility outcomes included acceptability (post-program ratings), demand (session attendance rate), and practicality (ability to start a garden and grow F&V). The study was considered feasible if the following criteria were met: ≥ 70% rated the intervention as good or excellent, overall session attendance rate was ≥ 70%, and > 70% were able to start a garden and grow F&V. We also assessed pre-post-program changes in behavioral mediators (gardening confidence, gardening enjoyment, cooking confidence, and nutrition knowledge). Descriptive statistics were calculated. Pre-post differences were evaluated with means and 95% confidence intervals (95% CI). Effect sizes were calculated (Cohen's d). RESULTS: All feasibility criteria were met. A total of 93.3% of participants rated the intervention as good or excellent, 96% started a garden and grew F&V, and the overall session attendance rate was 81%. The largest mean pre-post changes were in gardening confidence (pre 7.1 [95% CI: 6.4, 7.9], post 9.0 [95% CI: 8.6, 9.5], Cohen's d = 1.15), gardening enjoyment (pre: 6.3 [95% CI: 5.9, 6.7], post: 7.5 [95% CI: 7.1, 7.9], Cohen's d = 1.69), and cooking self-efficacy (pre: 4.7 [95% CI: 4.3, 5.1], post: 7.7 [95% CI: 7.3, 8.0], Cohen's d = 3.0). CONCLUSION: A digitally delivered gardening intervention was feasible, acceptable to participants, and they had meaningful changes in behavioral mediators. The next step is to evaluate the impact of the intervention in a future randomized controlled trial.

Comparison of methods for correcting QT interval in athletes and young people: A systematic review.

Screening elite athletes for conditions associated with sudden cardiac death is recommended by numerous international guidelines. Current athlete electrocardiogram interpretation criteria recommend the Bazett formula (QTcB) for correcting QT interval. However, other formulae may perform better at lower and higher heart rates (HR). This review aimed to examine the literature on various QT correction methods in athletes and young people aged 14-35 years and determine the most accurate method of calculating QTc in this population. A systematic review of MEDLINE, EMBASE, Scopus, and SportDiscus was performed. Papers comparing at least two different methods of QT interval correction in athletes or young people were included. Quality and risk of bias were assessed using a standardized tool. The search strategy identified 545 papers, of which 10 met the criteria and were included. Nine of these studies concluded that QTcB was least reliable for removing the effect of HR and was inaccurate at both high (>90 beats per min [BPM]) and low (<60 BPM) HRs. No studies supported the use of QTcB in athletes and young people. Alternative QT correction algorithms such as Fridericia (QTcF) produce more accurate correction of QT interval at HRs seen in athletes and young people. QTcB is less accurate at lower and higher HRs. QTcF has been shown to be more accurate in these HR ranges and may be preferred to QTcB for QTc calculation in athletes and young people. However, accurate QTc reference values for discrete HRs using alternative algorithms are not well established and require further research.

Phosphinecarboxamide based InZnP QDs - an air tolerant route to luminescent III-V semiconductors.

We describe a new synthetic methodology for the preparation of high quality, emission tuneable InP-based quantum dots (QDs) using a solid, air- and moisture-tolerant primary phosphine as a group-V precursor. This presents a significantly simpler synthetic pathway compared to the state-of-the-art precursors currently employed in phosphide quantum dot synthesis which are volatile, dangerous and air-sensitive, e.g. P(Si(CH3)3)3.

The cost-effectiveness of dapagliflozin in heart failure with preserved or mildly reduced ejection fraction: A European health-economic analysis of the DELIVER trial.

AIMS: To determine the cost-effectiveness of dapagliflozin, added to usual care, in patients with heart failure (HF) with mildly reduced or preserved ejection fraction for the UK, German and Spanish payers using detailed patient-level data from the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial. METHODS AND RESULTS: A lifetime Markov state-transition cohort model was developed. Quartiles of the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) defined health states and monthly transition count data informed transition probabilities. Multivariable generalized estimating equations captured the incidence of HF hospitalizations and urgent HF visits, while cardiovascular deaths and all-cause mortality were estimated using adjusted parametric survival models. Health state costs were assigned to KCCQ-TSS quartiles (2021 British pound [GBP]/Euro) and patient-reported outcomes were sourced from DELIVER. Future values of costs and effects were discounted according to country-specific rates. In the UK, dapagliflozin treatment was predicted to increase quality-adjusted life years (QALYs) and life-years by 0.231 and 0.354, respectively, and extend the time spent in the best quartile of KCCQ-TSS by 4.2 months. Comparable outcomes were projected for Germany and Spain. The incremental cost-effectiveness ratios were £7761, €9540 and €5343/QALY in the UK, Germany and Spain, respectively. According to regional willingness-to-pay thresholds, 91%, 89% and 92% of simulations in the UK, Germany and Spain, respectively, were cost-effective following probabilistic sensitivity analyses. CONCLUSION: Dapagliflozin, added to usual care, is very likely cost-effective for HF with mildly reduced or preserved ejection fraction in several European countries.

Characterization of miR-335-5p and miR-335-3p in human osteoarthritic tissues.

OBJECTIVE: We aimed to characterize the expression patterns, gene targets, and functional effects of miR-335-5p and miR-335-3p among seven primary human knee and hip osteoarthritic tissue types. METHODS: We collected synovial fluid, subchondral bone, articular cartilage, synovium, meniscus/labrum, infrapatellar/acetabular fat, anterior cruciate ligament/ligamentum teres, and vastus medialis oblique/quadratus femoris muscle (n = 7-20) from surgical patients with early- or late-stage osteoarthritis (OA) and quantified miR-335-5p and miR-335-3p expression by real-time PCR. Predicted gene targets were measured in knee OA infrapatellar fat following miRNA inhibitor transfection (n = 3), and prioritized gene targets were validated following miRNA inhibitor and mimic transfection (n = 6). Following pathway analyses, we performed Oil-Red-O staining to assess changes in total lipid content in infrapatellar fat. RESULTS: Showing a 227-fold increase in knee OA infrapatellar fat (the highest expressing tissue) versus meniscus (the lowest expressing tissue), miR-335-5p was more abundant than miR-335-3p (92-fold increase). MiR-335-5p showed higher expression across knee tissues versus hip tissues, and in late-stage versus early-stage knee OA fat. Exploring candidate genes, VCAM1 and MMP13 were identified as putative direct targets of miR-335-5p and miR-335-3p, respectively, showing downregulation with miRNA mimic transfection. Exploring candidate pathways, predicted miR-335-5p gene targets were enriched in a canonical adipogenesis network (p = 2.1e - 5). Modulation of miR-335-5p in late-stage knee OA fat showed an inverse relationship to total lipid content. CONCLUSION: Our data suggest both miR-335-5p and miR-335-3p regulate gene targets in late-stage knee OA infrapatellar fat, though miR-335-5p appears to be more prominent, with tissue-, joint-, and stage-specific effects.

Impact of Alignment and Alignment Correction on Outcomes Following Robotic Medial Unicompartmental Knee Arthroplasty.

BACKGROUND: The purpose of this study was to retrospectively examine the relationship between preoperative and postoperative alignment in robotic unicompartmental knee arthroplasty (UKA) and postoperative patient-reported outcome measures. METHODS: A retrospective review of 374 patients who underwent robotic-assisted UKA was conducted. Patient demographics, history, and preoperative and postoperative Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores were obtained via chart review. Average follow-up period was 2.4 years (range: 0.4 to 4.5 years) to chart review and 9.5 months (range: 6 to 48 months) to latest KOOS-JR. Preoperative and postoperative robotically-measured knee alignment was obtained from operative reports. Incidence of conversion to total knee arthroplasty (TKA) was determined by review of a health information exchange tool. RESULTS: Multivariate regressions showed no statistically significant relationship between preoperative alignment, postoperative alignment, or degrees of alignment correction and change in KOOS-JR score or achievement of KOOS-JR minimal clinically important difference (MCID) (P > .05). Patients who had >8 degrees of postoperative varus alignment had on average a 20% lower achievement of KOOS-JR MCID compared to patients who had <8 degrees of postoperative varus alignment; however, this difference was not statistically significant (P > .05). There were 3 patients who required conversion to TKA in the follow-up period, with no significant relationship to alignment variables (P > .05). CONCLUSION: There was no significant difference in KOOS-JR change for those patients who had a larger or smaller degree of deformity correction, and correction did not predict MCID achievement.

Alternating Magnetic Field-Promoted Nanoparticle Mixing: The On-Chip Immunocapture of Serum Neuronal Exosomes for Parkinson's Disease Diagnostics.

The analysis of cargo proteins in exosome subpopulations has considerable value in diagnostics but a translatable impact has been limited by lengthy or complex exosome extraction protocols. We describe herein a scalable, fast, and low-cost exosome extraction using an alternating (AC) magnetic field to support the dynamic mixing of antibody-coated magnetic beads (MBs) with serum samples within 3D-printed microfluidic chips. Zwitterionic polymer-coated MBs are, specifically, magnetically agitated and support ultraclean exosome capture efficiencies >70% from <50 µL of neat serum in 30 min. Applied herein to the immunocapture of neuronal exosomes using anti-L1CAM antibodies, prior to the array-based assaying of α-synuclein (α-syn) content by a standard duplex electrochemical sandwich ELISA, sub pg/mL detection was possible with an excellent coefficient of variation and a sample-to-answer time of ∼75 min. The high performance and semiautomation of this approach hold promise in underpinning low-cost Parkinson's disease diagnostics and is of value in exosomal biomarker analyses more generally.

The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Intravenous dexamethasone has been shown to reduce pain in total joint arthroplasty. This double-blind, randomized, placebo-controlled trial investigated the postoperative effects and safety of oral dexamethasone as a potential augment to multimodal pain management in outpatient knee arthroplasty. METHODS: The authors prospectively randomized 109 consecutive patients undergoing primary total knee arthroplasty. Patients assigned to Group A (57 patients) received 4 mg of dexamethasone by mouth twice per day starting postoperative day (POD) 1 for 4 days and those assigned to Group B received placebo capsules. All healthcare professionals and patients were blinded to group allocation. The primary outcome was defined as postoperative pain scores. Secondary outcomes included 90-day postoperative complications, nausea and vomiting, daily opioid usage, assistance for ambulation, difficulty sleeping, and early patient reported outcomes. Demographics were similar between groups. RESULTS: The patients who received dexamethasone had a statistically significant decrease in VAS scores when averaging POD 1 to 4 (P = .01). The average VAS scores among individual days were significantly lower with dexamethasone on POD 2, 3, and 4. While taking dexamethasone, morning and mid-day VAS scores were significantly lower. There was no difference between the groups with opioid use, nausea or vomiting, 90-day complications, ability to walk with/without assistance, difficulty sleeping, and early patient reported outcomes. CONCLUSION: This double-blind, randomized, placebo-controlled trial demonstrated that oral dexamethasone following primary total knee arthroplasty can reduce postoperative pain. This may be a beneficial option in ambulatory surgery where intravenous limitations exist, but larger series are needed to further evaluate the safety profile in this population.

Ultrahigh magnetic resonance contrast switching with water gated polymer-silica nanoparticles.

Very high T1 magnetic resonance imaging (MRI) switches can be obtained with pH-responsive polymer-coated paramagnetic mesoporous silica nanoparticles (MSNs), as the local environment traverses the pKa of the polymer coat (Δr1 ∼ 50 mM-1 s-1 at 1.5 T and Δr1 ∼ 22 mM-1 s-1 at 3 T). We assign these characteristics to a strong peripheral hydration capping at the mesopores, impacting channel-confined water mobility such that outer sphere contributions to contrast are greatly enhanced.