The Association of Preoperative Opioid Use with Post-Discharge Outcomes: A Cohort Study of the Michigan Surgical Quality Collaborative.

OBJECTIVE: To examine the association of prescription opioid fills over the year prior to surgery with postoperative outcomes. BACKGROUND: Nearly one third of patients report opioid use in the year preceding surgery, yet an understanding of how opioid exposure influences patient-reported outcomes after surgery remains incomplete. Therefore, this study was designed to test the hypothesis that preoperative opioid exposure may impede recovery in the postoperative period. METHODS: This retrospective cohort study used a statewide clinical registry from 70 hospitals linked to opioid fulfillment data from the state's prescription drug monitoring program to categorize patients' preoperative opioid exposure as none (naïve), minimal, intermittent, or chronic. Outcomes were patient-reported pain intensity (primary), as well as 30-day clinical and patient-reported outcomes (secondary). RESULTS: Compared to opioid-naïve patients, opioid exposure was associated with higher reported pain scores at 30 days after surgery. Predicted probabilities was higher among the opioid exposed versus naive group for reporting moderate pain (43.5% [95% CI 42.6 - 44.4%] vs 39.3% [95% CI 38.5 - 40.1%]) and severe pain (13.% [95% CI 12.5 - 14.0%] vs 10.0% [95% CI 9.5 - 10.5%]), and increasing probability was associated increased opioid exposure for both outcomes. Clinical outcomes (incidence of ED visits, readmissions, and reoperation within 30-days) and patient-reported outcomes (reported satisfaction, regret, and quality of life) were also worse with increasing preoperative opioid exposure for most outcomes. CONCLUSIONS: This study is the first to examine the effect of presurgical opioid exposure on both clinical and non-clinical outcomes in a broad cohort of patients, and shows that exposure is associated with worse postsurgical outcomes. A key question to be addressed is whether and to what extent opioid tapering before surgery mitigates these risks after surgery.

Impact of a dedicated cardiac protocol on diagnosis of infective endocarditis in patients undergoing [18F]-FDG-thoracic digital-PET/CT - Effects of expertise level.

BACKGROUND: This study aimed to assess the impact of dedicated cardiac protocol (DCP) on diagnostic accuracy of state-of-the-art digital [18F]-FDG-PET/CT in infective endocarditis (IE) and the intra-individual comparison of the performance with that of conventional whole-body approach (WBA) and to analyze the effects of the expertise level of the investigators. METHODS: 44 patients suspected for IE underwent digital-FDG-PET/CT after overnight fasting. Each three consultants and trainees reread PET images blinded to the examination approach and clinical information. Visual and semiquantitative analyses were performed. RESULTS: Digital-FDG-PET/CT with DCP revealed sensitivity, specificity, and accuracy of 89%, 93%, and 91% for native valve endocarditis (NVE) and 93%, 86%, and 91% for prosthetic valve endocarditis. Compared to WBA, substantial improvement of the diagnostic performance for NVE in DCP was evident, especially in trainees, but not as high compared to consultants. Digital-FDG-PET/CT enabled 79.5% reclassification of modified-Duke-Clinical-Criteria (mDC) with 34.1% upgrading and 45.4% downgrading. CONCLUSIONS: This study provides new data using state-of-the-art digital-FDG-PET/CT with DCP improving the diagnostic accuracy in challenging cases of possible IE, particularly in NVE, provided that the investigators involved have the necessary expertise. These findings may have a significant impact on IE-related morbidity, mortality, and patient's management and might be meaningful for updates on the prevailing opinion regarding the value of FDG PET/CT in NVE.

The Effect of Artificial Intelligence on Patient-Physician Trust: Cross-Sectional Vignette Study.

BACKGROUND: Clinical decision support systems (CDSSs) based on routine care data, using artificial intelligence (AI), are increasingly being developed. Previous studies focused largely on the technical aspects of using AI, but the acceptability of these technologies by patients remains unclear. OBJECTIVE: We aimed to investigate whether patient-physician trust is affected when medical decision-making is supported by a CDSS. METHODS: We conducted a vignette study among the patient panel (N=860) of the University Medical Center Utrecht, the Netherlands. Patients were randomly assigned into 4 groups-either the intervention or control groups of the high-risk or low-risk cases. In both the high-risk and low-risk case groups, a physician made a treatment decision with (intervention groups) or without (control groups) the support of a CDSS. Using a questionnaire with a 7-point Likert scale, with 1 indicating "strongly disagree" and 7 indicating "strongly agree," we collected data on patient-physician trust in 3 dimensions: competence, integrity, and benevolence. We assessed differences in patient-physician trust between the control and intervention groups per case using Mann-Whitney U tests and potential effect modification by the participant's sex, age, education level, general trust in health care, and general trust in technology using multivariate analyses of (co)variance. RESULTS: In total, 398 patients participated. In the high-risk case, median perceived competence and integrity were lower in the intervention group compared to the control group but not statistically significant (5.8 vs 5.6; P=.16 and 6.3 vs 6.0; P=.06, respectively). However, the effect of a CDSS application on the perceived competence of the physician depended on the participant's sex (P=.03). Although no between-group differences were found in men, in women, the perception of the physician's competence and integrity was significantly lower in the intervention compared to the control group (P=.009 and P=.01, respectively). In the low-risk case, no differences in trust between the groups were found. However, increased trust in technology positively influenced the perceived benevolence and integrity in the low-risk case (P=.009 and P=.04, respectively). CONCLUSIONS: We found that, in general, patient-physician trust was high. However, our findings indicate a potentially negative effect of AI applications on the patient-physician relationship, especially among women and in high-risk situations. Trust in technology, in general, might increase the likelihood of embracing the use of CDSSs by treating professionals.

Neighborhood socioeconomic disadvantages influence outcomes following rotator cuff repair in the non-Medicaid population.

BACKGROUND: Prior investigations have utilized various surrogate markers of socioeconomic status to assess how health care disparities impact outcomes after rotator cuff repair (RCR). When taken as individual markers, these factors have inconsistent associations. Medicaid insurance status is an accessible marker that has recently been correlated with less optimal outcomes after RCR. Socioeconomic disparities exist within the non-Medicaid population as well and are arguably more difficult to characterize. The Area Deprivation Index (ADI) uses seventeen socioeconomic variables to establish a spectrum of neighborhood health care disparity. The purpose of this study was to determine the influence of neighborhood socioeconomic disadvantages, quantified by ADI, on 2-year patient reported outcome scores following RCR in the non-Medicaid population. METHODS: A retrospective review of patients who underwent RCR from 2015 to 2020 was performed. All procedures were performed by a group of 7 surgeons at a large academic center. Patient demographics and comorbidities were collected from charts. Rotator cuff tear size was assessed from arthroscopic pictures. ADI scores were calculated based on patients' home addresses using the Neighborhood Atlas tool. The primary outcome measure was American Shoulder and Elbow Surgeons (ASES) score with a minimum follow-up of 2 years. A linear regression analysis with covariate control for age and patient comorbidities was performed. RESULTS: There were 287 patients with a mean age of 60.11 years. The linear regression model between ADI and 2-year ASES score was significant (P = .02). When controlling for both age and patient comorbidities, every 0.9-point reduction in ADI resulted in a 1-point increase in the ASES score (P = .03). Patients with an ADI of 8, 9, or 10 had lower mean 2-year ASES scores than those with an ADI of 1 (87.08 vs. 93.19, P = .04), but both groups had similar change from preoperative ASES score (40.17 vs. 32.88, P = .12). The change in ASES score at 2-years in our study surpassed all established minimal clinically important difference values irrespective of ADI. CONCLUSION: Patients with greater levels of disparity in their home neighborhoods have worse final ASES scores at 2 years, but patients significantly improve from their preoperative state regardless of social disadvantages. This is the first study to the authors' knowledge that examines ADI and outcomes following RCR. Providers should be aware that patients with higher ADI scores may have inferior preoperative shoulder function. The results of this study support the utilization of primary RCR in applicable tears regardless of socioeconomic status.

Measure what matters: Single Assessment Numeric Evaluation (SANE) score as the critical measure for shoulder outcomes.

BACKGROUND: Implementation of a system anchored in patient outcomes is challenged to gain widespread adoption required to demonstrate the value of care provided for shoulder conditions. This is in large part because of the administrative burden created by current tools and clinical implementation barriers that limit practical use and therefore leave most clinicians, administrators, payers, and patients without a measure of what matters most: Are patients improving? Thus, we must ask ourselves, How do we accurately and efficiently measure and report quality of care in a simple, reliable, and easily communicated manner? We propose that the Single Assessment Numeric Evaluation (SANE) score is the best solution to measure patient improvement and can be used universally for all shoulder conditions. The measure is simple, valid, reliable, and sensitive to change and has the lowest implementation barrier compared with all other outcome measures. METHODS: We synthesized the available literature (11 studies) that demonstrates strong psychometrics comparable to legacy measures across >4000 patients with a wide range of shoulder conditions. RESULTS: SANE scores range from 40% to 60% at baseline for most patients before treatment and range from 75% to 85% at 1 year after therapy depending on the condition, similar to legacy scores such as the American Shoulder and Elbow Surgeons score. Additionally, the SANE score shows similar baseline and post-care measures across conditions that can be used to guide clinical care. This finding shows that the observed baseline and improvement scores can provide valuable patient assessment and can be used in aggregate for quality improvement and other value-based purposes. CONCLUSION: We strongly recommend the SANE score as the primary patient outcome measure for patients with all shoulder conditions, given the value of measuring every patient's progress and growing pressure to quantify patient outcomes.

Judicious use of corticosteroid injections prior to shoulder arthroplasty does not compromise outcomes at a minimum of 2 years following surgery.

BACKGROUND: The use of total shoulder arthroplasty is continuing to rise with its expanding indications. For patients with chronic conditions, such as glenohumeral arthritis and rotator cuff arthropathy, nonoperative treatment is typically done prior to arthroplasty and often includes corticosteroid injections (CSIs). Recent studies in the shoulder arthroplasty literature as well as applied from the hip and knee literature have focused on the risk of periprosthetic infection. Literature is lacking as to whether the judicious use of corticosteroids in the year prior to arthroplasty influences patient-reported outcomes (PROs). The purpose of this study was to determine if preoperative CSIs prior to shoulder arthroplasty affected 2-year PROs. METHODS: Retrospective review of anatomic and reverse total shoulder arthroplasty (RSA) patients (n = 230) was performed at a single institution including multiple surgeons. Patients were included if they had preoperative and a minimum of 2-year postoperative PROs, including: American Shoulder and Elbow Surgeons (ASES), visual analog scale, Single Assessment Numeric Evaluation, Veteran's RAND 12 Physical Component Score, and Veteran's RAND 12 Mental Component Score. Patients were included in the injection group if they had received an injection, either glenohumeral or subacromial, within 12 months prior to arthroplasty (inject = 134). Subgroup analysis included anatomic (total shoulder arthroplasty [TSA] = 92) and RSA (RSA = 138) as well as those with no injection within 12 months prior to surgery. An analysis of variance was used to compare outcomes between patients who received an injection and those who did not prior to TSA and RSA. RESULTS: There were 230 patients included with 134 patients in the injection group and 96 in the no injection group. Patients who received an injection in the year prior to arthroplasty displayed a significantly higher ASES (82 [16.23 standard deviation] vs. 76 [19.43 standard deviation], P < .01) and Single Assessment Numeric Evaluation (70 [24.49 standard deviation] vs. 63 [29.22 standard deviation], P < .01) scores vs. those who had not received injection. There was no difference when comparing preoperative injection vs. no injection in patients undergoing TSA. Those patients undergoing RSA displayed significantly higher ASES scores (P < .01). There were no significant differences in visual analog scale, Veteran's RAND 12 Physical Component Score, and Veteran's RAND 12 Mental Component Score among any analysis (P > .05), and the minimal clinically important difference in ASES was not different between groups (P.09). CONCLUSION: CSIs within 12 months prior to anatomic and RSA do not compromise PROs during a minimum of 2-year follow-up. Although more complications occurred in the injection group, it did not reach statistical significance and warrants further study in a larger population.

No clinical difference in outcomes between inlay and onlay arthroscopic biceps tenodesis techniques during rotator cuff repair.

BACKGROUND: Both inlay and onlay arthroscopic biceps tenodesis (ABT) are common procedures performed during rotator cuff repair. The inlay method involves creating a bone socket in the bicipital groove to secure the long head of the biceps tendon using an interference screw. The onlay method utilizes a suture anchor to secure the long head of the biceps tendon on the surface of the bicipital groove. Little is known on the long-term differences in patient-reported outcomes between these 2 techniques. The primary purpose of this study was to compare patient-reported outcomes of inlay vs. onlay ABT with a minimum follow-up of 2 years. Secondary aims were to evaluate the impact of rotator cuff tear size on outcomes and compare rates of complications between the 2 techniques. METHODS: A retrospective chart review was performed to identify patients who had an ABT during a full-thickness rotator cuff repair. Any symptom specific to the biceps were noted, including pain and cramping, Popeye deformity, or revision surgery. Complication rates were compared between groups. The visual analog scale pain score, American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation, and Veteran's RAND-12 score (VR-12) scores were compared at 2 years. The impact of rotator cuff tear size was analyzed by categorizing into small/medium or large/massive based on operative reports and arthroscopic images. RESULTS: There were 165 patients identified (106 in the inlay group and 59 in the onlay group). No revision surgeries were performed secondary to the biceps tendon in either group. Eleven patients (10%) in the inlay group complained of biceps pain or cramping compared to 2 patients (3%) in the onlay group (P = .11). One Popeye deformity was noted in each group (P = .67). No significant differences were found between groups for visual analog scale (P = .41), ASES functional (P = .61), ASES index (P = .91), Single Assessment Numeric Evaluation (P = .09), VR-12 Physical Component Score (P = .77), or VR-12 Mental Component Score (P = .09). Rotator cuff tear size within the groups also did not demonstrate statistical significance. CONCLUSION: No clinical differences or complications were found at minimum 2-year follow-up between inlay and onlay ABT in patients undergoing rotator cuff repair when controlling for tear size. The clinical relevance suggests either technique is effective and can be based on surgeon preference.

Time to Reflect on Return to Sport Timing Following ACL Reconstruction.

The time of return to sport following anterior cruciate ligament (ACL) reconstruction is a commonly discussed topic within clinical settings and the sports medicine literature. Emerging science has demonstrated protective effects of delaying the time of sport clearance on athlete reinjury. Though a single time cutoff is unlikely to be applicable for all athletes, large inconsistencies in the time of return to sport clearance are present in both the literature and within prescribed clinical protocols. A multitude of patient factors, such as perceived function, objective function, confidence, post-operative goals, among others, are vital for how athletes are progressed and released for sport participation. This Current Opinion article is constructed to discuss the time to return to sport after ACL reconstruction-factors that may influence timing decisions, how time is assessed within the scientific literature-and to promote discussion on this common topic within the sports medicine and athletic communities. The aim of the article is not to establish defined clinical time cutoffs for this population.

Cardiac PET/MRI: Recent Developments and Future Aspects.

Positron emission tomography/magnetic resonance (PET/MRI) hybrid imaging is now available for over a decade and although the quantity of installed systems is rather low, the number of emerging applications for cardiovascular diseases is still growing. PET/MRI provides integrated images of high quality anatomical and functional assessment obtained by MRI with the possibilities of PET for quantification of molecular parameters such as metabolism, inflammation, and perfusion. In recent years, sequential co-registration of myocardial tissue characterization with its molecular data had become an increasingly helpful tool in clinical practice and an integrated device simplifies this task. This review summarizes recent developments and future possibilities in the use of the PET/MRI in the diagnosis and treatment of cardiovascular disorders.

Quantitative NMR Spectrometry of Phenylpropanoids, including Isoeugenol in Herbs, Spices, and Essential Oils.

Isoeugenol (2-methoxy-4-(1-propenyl)phenol) has been recently classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC). This study conducted an analysis of isoeugenol in common herbs and spices, including basil, cinnamon, ginger, and nutmeg, using 1H nuclear magnetic resonance (NMR) spectrometry. Additionally, over 1300 coffee samples were analysed by 1H-NMR for isoeugenol, but it was not detected in any of the analysed samples. Various essential oils, including nutmeg, basil, clove, sweet flag, and ylang-ylang oils, were examined for isoeugenol content. Out of the twelve nutmeg oils tested, four contained isoeugenol, with concentrations ranging from 3.68 ± 0.09 g/kg to 11.2 ± 0.10 g/kg. However, isoeugenol was not detected in the essential oils of calamus, basil, ylang-ylang, and clove using NMR spectrometry. These findings warrant critical evaluation of the previous literature, given reports of high isoeugenol levels in some of these matrices. A toxicological assessment has determined that there is no risk to human health by exposure to isoeugenol via nutmeg essential oils.

Exploring the associations between skeletal muscle echogenicity and physical function in aging adults: A systematic review with meta-analyses.

BACKGROUND: Assessment and quantification of skeletal muscle within the aging population is vital for diagnosis, treatment, and injury/disease prevention. The clinical availability of assessing muscle quality through diagnostic ultrasound presents an opportunity to be utilized as a screening tool for function-limiting diseases. However, relationships between muscle echogenicity and clinical functional assessments require authoritative analysis. Thus, we aimed to (a) synthesize the literature to assess the relationships between skeletal muscle echogenicity and physical function in older adults (≥60 years), (b) perform pooled analyses of relationships between skeletal muscle echogenicity and physical function, and (c) perform sub-analyses to determine between-muscle relationships. METHODS: CINAHL, Embase, MEDLINE, PubMed, and Web of Science databases were systematically searched to identify articles relating skeletal muscle echogenicity to physical function in older adults. Risk-of-bias assessments were conducted along with funnel plot examination. Meta-analyses with and without sub-analyses for individual muscles were performed utilizing Fisher's Z transformation for the most common measures of physical function. Fisher's Z was back-transformed to Pearson's r for interpretation. RESULTS: Fifty-one articles (n = 5095, female = ∼2759, male = ∼2301, 72.5 ± 5.8 years, mean ± SD (1 study did not provide sex descriptors)) were extracted for review, with previously unpublished data obtained from the authors of 13 studies. The rectus femoris (n = 34) and isometric knee extension strength (n = 22) were the most accessed muscle and physical qualities, respectively. The relationship between quadriceps echogenicity and knee extensor strength was moderate (n = 2924, r = -0.36 (95% confidence interval: -0.38 to -0.32), p < 0.001), with all other meta-analyses (grip strength, walking speed, sit-to-stand, timed up-and-go) resulting in slightly weaker correlations (r:  -0.34 to -0.23, all p < 0.001). Sub-analyses determined minimal differences in predictive ability between muscle groups, although combining muscles (e.g., rectus femoris + vastus lateralis) often resulted in stronger correlations with maximal strength. CONCLUSION: While correlations are modest, the affordable, portable, and noninvasive ultrasonic assessment of muscle quality is a consistent predictor of physical function in older adults. Minimal between-muscle differences suggest that echogenicity estimates of muscle quality are systemic. Therefore, practitioners may be able to scan a single muscle to estimate full-body skeletal muscle quality/composition, while researchers should consider combining multiple muscles to strengthen the model.

A Clinical Role of PET-MRI in Prostate Cancer?

PET/MRI is a relevant application field for prostate cancer management, offering advantages in early diagnosis, staging, and therapy planning. Despite drawbacks such as higher costs, longer acquisition time, and the need for skilled personnel, the technical integration of PET and MRI provides valuable information for detecting primary tumors, identifying metastases, and characterizing the disease, leading to more accurate staging and personalized treatment strategies. However, PET/MRI adoption has been slow, but ongoing technological advancements and AI integration might overcome challenges and improve clinical utility. As precision medicine gains importance in oncology, PET/MRI's multiparametric data can tailor treatment plans to individual patients, providing a comprehensive assessment of tumor biology and aggressiveness for more effective therapeutic strategies.

Simultaneous 18-FDG PET and MR imaging in lower extremity arterial disease.

Background: Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is a novel hybrid imaging method integrating the advances of morphological tissue characterization of MRI with the pathophysiological insights of PET applications. Aim: This study evaluated the use of simultaneous 18-FDG PET/MR imaging for characterizing atherosclerotic lesions in lower extremity arterial disease (LEAD). Methods: Eight patients with symptomatic stenoses of the superficial femoral artery (SFA) under simultaneous acquisition of 18-FDG PET and contrast-enhanced MRI using an integrated whole-body PET/MRI scanner. Invasive plaque characterization of the SFA was performed by intravascular imaging using optical coherence tomography. Histological analysis of plaque specimens was performed after directional atherectomy. Results: MRI showed contrast enhancement at the site of arterial stenosis, as assessed on T2-w and T1-w images, compared to a control area of the contralateral SFA (0.38 ± 0.15 cm vs. 0.23 ± 0.11 cm; 1.77 ± 0.19 vs. 1.57 ± 0.15; p-value <0.05). On PET imaging, uptake of 18F-FDG (target-to-background ratio TBR > 1) at the level of symptomatic stenosis was observed in all but one patient. Contrast medium-induced MR signal enhancement was detected in all plaques, whereas FDG uptake in PET imaging was increased in lesions with active fibroatheroma and reduced in fibrocalcified lesions. Conclusion: In this multimodal imaging study, we report the feasibility and challenges of simultaneous PET/MR imaging of LEAD, which might offer new perspectives for risk estimation.

Untwining the intertwined: a comprehensive review on differentiating pathologies of the shoulder and spine.

Background: The anatomic interplay and overlap between the cervical spine and the shoulder constitutes a challenge for shoulder and spine surgeons, as symptoms of spine and shoulder pathologies are often similar and may lead to entity misdiagnosis. Methods: PubMed, Cochrane, and Google Scholar (page 1-20) searches were updated to October 2023 in search of the qualified papers. Boolean Operators were used with a combination of the keywords "spine" OR "neck" And "Shoulder". Furthermore, reference lists from papers were also searched to find literature. Results: It is of pivotal importance to conduct comprehensive preoperative clinical investigation to appropriately evaluate and assess the source of the pathology and the leading causes behind it. Certain markers can help guide surgeons towards etiologies, and these include areas of pain and physical exam findings with the arm squeeze test having the highest sensitivity and specificity for diagnosing cervical radiculopathy. As for the shoulder, despite its low sensitivity, the Yergason test had the highest specificity for diagnosing subacromial impingement. Local anesthetic injection can help as well in the diagnostic approach. Moreover, the interplay between these anatomic locations is not solely related to preoperative diagnosis. Studies have shown that previous surgery for cervical spine pathology may negatively affect the outcomes of shoulder procedures like arthroplasties. Conclusion: Shoulder and spine surgeons should be wary and vigilant of accurately diagnosing the etiology of the presenting symptoms to ensure proper management and optimize prognosis.

Corticosteroid injection prior to surgery had no effect on 2-year outcomes following arthroscopic rotator cuff repair.

Background: Corticosteroid injections (CSIs) can be an effective nonsurgical treatment for patients with rotator cuff tears. Recent large database studies have raised concern that CSI may result in a higher reoperation rate, increased infection risk, and worse outcome after arthroscopic rotator cuff repair (ARCR). The purpose of this study was to evaluate the reoperation rate, incidence of postoperative infection, and two-year outcomes of patients undergoing ARCR with and without the use of preoperative CSI. Methods: An institutional database generated from fellowship-trained orthopedic sports surgeons was retrospectively queried for patients who underwent ARCR with a minimum of two-year follow-up. Inclusion criteria consisted of 1) primary full-thickness rotator cuff tear and 2) preoperative and minimum two-year patient-reported outcome measures (PROMs). Of the 219 patients identified, 134 patients had preoperative subacromial CSI administered within one year of ARCR. Reoperation rate, number of injections, Visual Analog Scale, American Shoulder and Elbow Surgeons Score, Single Assessment Numeric Evaluation, and Veterans Rand 12-Item Health Survey Physical Component Score/Mental Component Score were compared between groups at six months, one year, and two years. Chi-square and t-tests were used to compare baseline differences, postoperative infections, and reoperations. A repeated measures Analyses of Covariance was used to measure differences between PROMs at each time point. Simple Analyses of Covariance were used for the two-year sub-analyses for patients receiving CSI within 90 days of surgery and if multiple preoperative CSI had been given (α ≤ 0.05). Results: There were no significant demographic differences between groups (P > .05). Preoperative use of subacromial CSI within one year prior to ARCR did not increase reoperation rate (P = .85) or impact PROMs at any timepoint. There were two reoperations during the study period in the CSI group (2 lysis of adhesions). No infections occurred in either cohort. No differences were found if injections were performed within 90 days of surgery or if more than one CSI was administered within the year prior to surgery (P > .05). Conclusion: Our results show that preoperative CSI prior to primary ARCR did not increase risk of reoperation, infection, or influence PROMs with a minimum follow-up of 2 years.

Creating a more strategic small molecule biophysical hit characterization workflow.

To confirm target engagement of hits from our high-throughput screening efforts, we ran biophysical assays on several hundreds of hits from 15 different high-throughput screening campaigns. Analyzing the biophysical assay results from these screening campaigns led us to conclude that we could be more strategic in our biophysical analysis of hits by first confirming activity in a thermal shift assay (TSA) and then confirming activity in either a surface plasmon resonance (SPR) assay or a temperature-related intensity change (TRIC) assay. To understand how this new workflow shapes the quality of the final hits, we compared TSA/SPR or TSA/TRIC confirmed and unconfirmed hits to one another using four measures of compound quality: quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility. In general, we found that the biophysically confirmed hits performed better in the compound quality metrics than the unconfirmed hits, demonstrating that our workflow not only confirmed target engagement of the hits but also enriched for higher quality hits.

An in silico modeling approach to understanding the dynamics of the post-burn immune response.

Introduction: Burns are characterized by a massive and prolonged acute inflammation, which persists for up to months after the initial trauma. Due to the complexity of the inflammatory process, Predicting the dynamics of wound healing process can be challenging for burn injuries. The aim of this study was to develop simulation models for the post-burn immune response based on (pre)clinical data. Methods: The simulation domain was separated into blood and tissue compartments. Each of these compartments contained solutes and cell agents. Solutes comprise pro-inflammatory cytokines, anti-inflammatory cytokines and inflammation triggering factors. The solutes diffuse around the domain based on their concentration profiles. The cells include mast cells, neutrophils, and macrophages, and were modeled as independent agents. The cells are motile and exhibit chemotaxis based on concentrations gradients of the solutes. In addition, the cells secrete various solutes that in turn alter the dynamics and responses of the burn wound system. Results: We developed an Glazier-Graner-Hogeweg method-based model (GGH) to capture the complexities associated with the dynamics of inflammation after burn injuries, including changes in cell counts and cytokine levels. Through simulations from day 0 - 4 post-burn, we successfully identified key factors influencing the acute inflammatory response, i.e., the initial number of endothelial cells, the chemotaxis threshold, and the level of chemoattractants. Conclusion: Our findings highlight the pivotal role of the initial endothelial cell count as a key parameter for intensity of inflammation and progression of acute inflammation, 0 - 4 days post-burn.

Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial.

BACKGROUND: Efforts to identify therapies to treat hospitalised patients with COVID-19 are being continued. Alkaline phosphatase (AP) dephosphorylates pro-inflammatory adenosine triphosphate (ATP) into anti-inflammatory adenosine. METHODS: In a randomised controlled trial, we investigated the safety and efficacy of AP in patients with SARS-CoV-2 infection admitted to the ICU. AP or a placebo was administered for four days following admission to the ICU. The primary outcome was the duration of mechanical ventilation. Mortality in 28 days, acute kidney injury, need for reintubation, safety, and inflammatory markers relevant to the described high cytokine release associated with SARS-CoV-2 infection were the secondary outcomes. RESULTS: Between December 2020 and March 2022, 97 patients (of the intended 132) were included, of which 51 were randomised to AP. The trial was terminated prematurely based on meeting the threshold for futility. Compared to the placebo, AP did not affect the duration of mechanical ventilation (9.0 days vs. 9.3 days, p = 1.0). No safety issues were observed. After 28 days, mortality was 9 (18%) in the AP group versus 6 (13%) in the placebo group (p = 0.531). Additionally, no statistically significant differences between the AP and the placebo were observed for the other secondary outcomes. CONCLUSIONS: Alkaline phosphatase (AP) therapy in COVID-19 ICU patients showed no significant benefits in this trial.

Single cell transcriptomics reveals early photoreceptor states, cell-specific transcript isoforms, and cancer-predisposing features.

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin. Here, we used deep full-length single-cell RNA-sequencing to distinguish post-mitotic cone and rod developmental states and cone-specific features that contribute to retinoblastomagenesis. The analyses revealed early post-mitotic cone- and rod-directed populations characterized by higher THRB or NRL regulon activities, an immature photoreceptor precursor population with concurrent cone and rod gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Unexpectedly, both L/M cone and rod precursors co-expressed NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL isoforms and prematurely terminated THRB transcripts. Early L/M cone precursors exhibited successive expression of lncRNAs along with MYCN, which composed the seventh most L/M-cone-specific regulon, and SYK, which contributed to the early cone precursors' proliferative response to RB1 loss. These findings reveal previously unrecognized photoreceptor precursor states and a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation.