Effectiveness of melatonin treatment for sleep disturbance in orthopaedic trauma patients: A prospective, randomized control trial.

OBJECTIVES: Explore sleep disturbance in postoperative orthopedic trauma patients and determine the impact of melatonin supplementation on postoperative sleep, pain, and quality of life. MATERIALS AND METHODS: In this prospective, randomized controlled trial at a Level I trauma center, 84 adult orthopedic trauma patients with operative fracture management were randomized 2-weeks postoperatively to either the melatonin or placebo group. Patients randomized to the melatonin group (42 subjects, mean age 41.8 ± 15.5 years) received 5 mg melatonin supplements. Patients in the placebo group (42 subjects, mean age 41.3 ± 14.0 years) received identical glucose tablets. Both groups were instructed to take the tablets 30 minutes before bed for 4 weeks and received sleep hygiene education and access to the Cognitive Behavioral Therapy for Insomnia (CBT-I) Coach app. MAIN OUTCOME MEASURES: Our primary outcome was sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes were pain measured by the Visual Analog Scale (VAS), quality of life measured by the 36-Item Short Form Survey (SF-36), and opioid use. RESULTS: Patients in both groups had significant sleep disturbance (PSQI ≥ 5) at 2-weeks (83%) and 6-weeks (67%) postoperatively. PSQI improved by 3.3 points (p<0.001) at follow-up, but there was no significant difference between groups (melatonin PSQI = 5.6, placebo PSQI = 6.1, P = 0.615). Compared to placebo, melatonin did not affect VAS, SF-36, or opioid use significantly. CONCLUSION: Sleep disturbance is prevalent in orthopedic trauma patients. Melatonin treatment did not significantly improve subjective sleep quality, pain, quality of life or opioid use. LEVEL OF EVIDENCE: Therapeutic Level I.

"My Surgical Success": Feasibility and Impact of a Single-Session Digital Behavioral Pain Medicine Intervention on Pain Intensity, Pain Catastrophizing, and Time to Opioid Cessation After Orthopedic Trauma Surgery-A Randomized Trial.

BACKGROUND: Behavioral pain treatments may improve postsurgical analgesia and recovery; however, effective and scalable options are not widely available. This study tested a digital perioperative behavioral medicine intervention in orthopedic trauma surgery patients for feasibility and efficacy for reducing pain intensity, pain catastrophizing, and opioid cessation up to 3 months after surgery. METHODS: A randomized controlled clinical trial was conducted at an orthopedic trauma surgery unit at a major academic hospital to compare a digital behavioral pain management intervention ("My Surgical Success" [MSS]) to a digital general health education (HE) intervention (HE; no pain management skills). The enrolled sample included 133 patients; 84 patients were randomized (MSS, n = 37; HE, n = 47) and completed study procedures. Most patients received their assigned intervention within 3 days of surgery (85%). The sample was predominantly male (61.5%), White (61.9%), and partnered (65.5%), with at least a bachelor's degree (69.0%). Outcomes were collected at 1-3 months after intervention through self-report e-surveys and electronic medical record review; an intention-to-treat analytic framework was applied. Feasibility was dually determined by the proportion of patients engaging in their assigned treatment and an application of an 80% threshold for patient-reported acceptability. We hypothesized that MSS would result in greater reductions in pain intensity and pain catastrophizing after surgery and earlier opioid cessation compared to the digital HE control group. RESULTS: The engagement rate with assigned interventions was 63% and exceeded commonly reported rates for fully automated Internet-based e-health interventions. Feasibility was demonstrated for the MSS engagers, with >80% reporting treatment acceptability. Overall, both groups improved in the postsurgical months across all study variables. A significant interaction effect was found for treatment group over time on pain intensity, such that the MSS group evidenced greater absolute reductions in pain intensity after surgery and up to 3 months later (treatment × time fixed effects; F [215] = 5.23; P = .024). No statistically significant between-group differences were observed for time to opioid cessation or for reductions in pain catastrophizing ( F [215] = 0.20; P = .653), although the study sample notably had subclinical baseline pain catastrophizing scores (M = 14.10; 95% confidence interval, 11.70-16.49). CONCLUSIONS: Study findings revealed that a fully automated behavioral pain management skills intervention (MSS) may be useful for motivated orthopedic trauma surgery patients and reduce postsurgical pain up to 3 months. MSS was not associated with reduced time to opioid cessation compared to the HE control intervention.

Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease.

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.

Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Patient-Reported Outcome Measures (PROMs): Influence of Motor Tasks and Psychosocial Factors on FAAM Scores in Foot and Ankle Trauma Patients.

Patient-reported outcome measures (PROMS) are being increasingly used as a quality of care metric. However, the validity and consistency of PROMS remain undefined. The study sought to determine whether Foot and Ankle Ability Measure (FAAM) scores improve after patients complete motor tasks evaluated on the survey and to examine the relationship between depression and self-efficacy and FAAM scores or change in scores. We conducted a prospective comparison study of adults with isolated foot, ankle, or distal tibia fractures treated operatively at level I trauma center. Twenty-seven patients completed the FAAM survey at the first clinic visit after being made weightbearing as tolerated (mean 3 months). Patients then completed 6 motor tasks queried on FAAM (standing, walking without shoes, squatting, stairs, up to toes), followed by a repeat FAAM and General Self-Efficacy scale (GSE) and Patient Health Questionnaire-2 (PHQ-2) instruments. FAAM scores before and after intervention; GSE and PHQ-2 scores compared with baseline FAAM and change in FAAM scores. Performing motor tasks significantly improved postintervention scores for squatting (P = .044) and coming up to toes (P = .012), the 2 most strenuous tasks. No difference was found for the remaining tasks. Higher depression ratings correlated with worse FAAM scores overall (P < .05). Higher self-efficacy ratings correlated with increase in FAAM Sports subscale postintervention (P = .020). FAAM scores are influenced by performing motor tasks. Self-reported depression influences baseline FAAM scores and self-efficacy may influence change in FAAM scores. Context and patient factors (modifiable and nonmodifiable) affect PROM implementation, with implications for clinical care, reimbursement models, and use of quality measure.

Inferential Learning of Serial Order of Perceptual Categories by Rhesus Monkeys (Macaca mulatta).

Category learning in animals is typically trained explicitly, in most instances by varying the exemplars of a single category in a matching-to-sample task. Here, we show that male rhesus macaques can learn categories by a transitive inference paradigm in which novel exemplars of five categories were presented throughout training. Instead of requiring decisions about a constant set of repetitively presented stimuli, we studied the macaque's ability to determine the relative order of multiple exemplars of particular stimuli that were rarely repeated. Ordinal decisions generalized both to novel stimuli and, as a consequence, to novel pairings. Thus, we showed that rhesus monkeys could learn to categorize on the basis of implied ordinal position, without prior matching-to-sample training, and that they could then make inferences about category order. Our results challenge the plausibility of association models of category learning and broaden the scope of the transitive inference paradigm.SIGNIFICANCE STATEMENT The cognitive abilities of nonhuman animals are of enduring interest to scientists and the general public because they blur the dividing line between human and nonhuman intelligence. Categorization and sequence learning are highly abstract cognitive abilities each in their own right. This study is the first to provide evidence that visual categories can be ordered serially by macaque monkeys using a behavioral paradigm that provides no explicit feedback about category or serial order. These results strongly challenge accounts of learning based on stimulus-response associations.

Case study: a case of debilitating gout in the 1st metatarsophalangeal joint.

Gout is a painful arthritic condition that affects many people worldwide. The disease has been associated with hyperuricaemia and life style risk factors such as obesity, alcohol intake, meat and seafood consumption. We present a case of a 67-year-old male with a history of gout, who attended the clinic with a painful 1st metatarsophalangeal joint, which had progressively worsened in pain, mobility and deformity in the last 20 years. Although lifestyle changes had been advised by the GP some years earlier such as a low purine based diet, management had only consisted of NSAID's, which had not significantly improved symptoms. Surgical excision of chalky white material from around the 1st metatarsophalangeal joint rendered the patient symptom free with increased mobility after 6 weeks. Histopathology confirmed the excised tissue as gouty tophus. Following this, the patient was placed on allopurinol, a xanthine oxidase inhibitor to prevent recurrent attacks. This case study highlights the importance of early recognition and prophylactic management in gout sufferers. In joints where the disease process is well-established surgical excision of the gouty tophus may help mitigate further disease progression, and restore quality of life to individuals.

UP1 extends life of primary porcine fetal fibroblasts in culture.

Genetic modification of somatic cell nuclei and subsequent nuclear transfer has opened an opportunity to create gene-targeted animals. However, somatic cells have a limited life span in culture and it is not possible to introduce precise genetic changes in both alleles in this narrow time window. To increase the life span of somatic cell in culture, both genetic and chemical approaches have been tried with varying success. Here, we report the effect of two anti-oxidants, glutathione and n-t-butyl hydroxylamine, and of the expression of UP1, a shortened derivative of heterogeneous nuclear riboprotein (hnRNP)A1, on the life extension of primary porcine fibroblasts in culture. Under our experimental conditions, the use of anti-oxidants did not result in any prolongation of the life span. In contrast, UP1 expression increased the life span significantly. While most control cells stopped growing by PDL 20, and none survived beyond PDL 35, 100% of UP1-expressing clones reached PDL50, and 40% made it to PDL65. The five UP1-expressing clones were karyotyped at PDL 50. While all of them had a range of numerical chromosomal abnormalities, two clones retained 30-40% normal cells, all the cells in other three clones had abnormal chromosome numbers. Thus, expression of UP1 may be useful in extending the life span of somatic cells in culture. This, in turn, will facilitate the process of gene targeting in this cell type.