Efficacy of Liposomal Bupivacaine and Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Periarticular Anesthetic for Patients Undergoing Knee Replacement: A Randomized Clinical Trial.

Importance: More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain. Objective: To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement. Design, Setting, and Participants: This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. Interventions: Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery. Main Outcome and Measures: The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed. Results: Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, -2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5% CI, -46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5% CI, -1.07 to -0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups. Conclusions and Relevance: This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery. Trial Registration: isrctn.com Identifier: ISRCTN54191675.

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): statistical analysis plan for a randomised controlled trial assessing the effectiveness of peri-articular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone.

BACKGROUND: Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement. METHODS/DESIGN: The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published. RESULTS: The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests. DISCUSSION: The paper provides details of the planned statistical analyses for the SPAARK trial and aims to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report. TRIAL REGISTRATION: ISRCTN54191675 . Registered on 13 November 2017.

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

PURPOSE: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. DESIGN: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. PARTICIPANTS: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. METHODS: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). MAIN OUTCOME MEASURES: Primary outcome: sensitivity of the new pathway. SECONDARY OUTCOMES: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. RESULTS: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. CONCLUSIONS: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.

Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin.

Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.

Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain.

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that modulates the reproductive physiology of birds and mammals by inhibiting gonadotropin secretion from the anterior pituitary gland. GnIH can also directly inhibit reproductive behaviors, possibly via action within the brain. Identification of the distribution of GnIH neurons and fibers may provide us with clues to how the brain controls reproductive activities of the animal. Here, we characterized the location and connectivity of GnIH neurons in the rhesus macaque (Macaca mulatta) brain. We determined the macaque GnIH precursor mRNA, and further identified a mature GnIH peptide (SGRNMEVSLVRQVLNLPQRF-NH(2)) by mass spectrometry combined with immunoaffinity purification. The majority of GnIH precursor mRNA-positive and GnIH-immunoreactive (GnIH-ir) cell bodies were localized in the intermediate periventricular nucleus (IPe) in the hypothalamus, as determined by in situ hybridization and immunocytochemistry, respectively. Abundant GnIH-ir fibers were observed in the nucleus of the stria terminalis in the telencephalon; habenular nucleus, paraventricular nucleus of the thalamus, preoptic area, paraventricular nucleus of the hypothalamus, IPe, arcuate nucleus of hypothalamus, median eminence and dorsal hypothalamic area in the diencephalon; medial region of the superior colliculus, central gray substance of the midbrain and dorsal raphe nucleus in the midbrain; and parabrachial nucleus in the pons. GnIH-ir fibers were observed in close proximity to gonadotropin-releasing hormone-I, dopamine, beta-endorphin, and gonadotropin-releasing hormone-II neurons in the preoptic area, IPe, arcuate nucleus of hypothalamus, and central gray substance of midbrain, respectively. GnIH neurons might thus regulate several neural systems in addition to pituitary gonadotropin release.

Identification of European starling GnRH-I precursor mRNA and its seasonal regulation.

Songbirds show dynamic seasonal changes in their reproductive activities during the year. Gonadotropin-releasing hormone-I (GnRH-I) is critical for the control of reproduction in vertebrates. The molecular mechanisms controlling reproduction are not well understood in songbirds, largely because the GnRH-I precursor polypeptide gene was unknown until now. Here, we report the complete sequence and seasonal regulation of GnRH-I precursor polypeptide mRNA in a songbird, European starling (Sturnus vulgaris). The translated starling GnRH-I precursor polypeptide contained an amino acid sequence that can be processed into chicken GnRH-I peptide (pEHWSYGLQPG-NH(2)). However, the overall homology of GnRH-I precursor polypeptide (including a 23 amino acid signal peptide, the decapeptide hormone and Gly-Lys-Arg cleavage site followed by 55 amino acid GnRH-associated peptide sequences) between starling and chicken was only 58%. GnRH-I mRNA and GnRH-I peptide were observed to be co-localized in the preoptic area of sexually mature birds using in situ hybridization and immunocytochemistry. GnRH-I mRNA exhibited large variance in photosensitive birds, and converged to a high level in photostimulated birds. Subsequently, GnRH-I mRNA decreased to below detectability in most of the photorefractory birds. Changes were also observed in GnRH-I peptide levels, although changes in GnRH-I peptide were not as marked. Our data indicate that GnRH-I mRNA synthesis commences but is variable in photosensitive birds, stabilizes in photostimulated birds, then ceases when birds become photorefractory. Finer-scale investigation into temporal regulation of GnRH-I precursor polypeptide mRNA will provide insight into its regulation by environmental, social and physiological cues.