Plasma metabolomics identifies key metabolites and improves prediction of diabetic retinopathy: development and validation across multi-national cohorts.

PURPOSE: To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and evaluate their utility in predicting DR development and progression. DESIGN: Multicenter, multi-ethnic cohort study. PARTICIPANTS: This study included 17,675 participants with baseline pre-diabetes/diabetes, in accordance with the 2021 American Diabetes Association guideline, and free of baseline DR from the UK Biobank (UKB); and an additional 638 diabetic participants from the Guangzhou Diabetic Eye Study (GDES) for external validation. METHODS: Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort. Model assessments included the C-statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical utility in both cohorts. MAIN OUTCOME MEASURES: DR development, progression, and retinal microvascular damage. RESULTS: Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C-statistic: 0.802, 95% CI, 0.760-0.843 vs. 0.751, 95% CI, 0.706-0.796; P = 5.56×10-4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C-statistic: 0.807, 95% CI, 0.711-0.903 vs. 0.617, 95% CI, 0.494, 0.740; P = 1.68×10-4) and progression (C-statistic: 0.797, 95% CI, 0.712-0.882 vs. 0.665, 95% CI, 0.545-0.784; P = 0.003) in the external cohort. Improvements in NRIs, IDIs, and clinical utility were also evident in both cohorts (all P <0.05). In addition, lactate and citrate were associated to microvascular damage across macular and optic disc regions (all P <0.05). CONCLUSIONS: Metabolomic profiling has proven effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology.

Daily instability in body dissatisfaction in individuals with and without eating disorders.

Body dissatisfaction (BD) includes negative thoughts and feelings about one's body shape. Although typically assessed as a trait, BD has been found to fluctuate within a day. The present study examined whether daily instability in BD differs according to trait BD, eating disorder (ED) diagnosis, and engagement in maladaptive exercise. Participants with EDs (n = 166) and controls (n = 44) completed a self-report measure of trait BD and reported BD and engagement in maladaptive exercise five times daily for 14 days as part of an ecological momentary assessment protocol. BD instability was calculated as adjusted mean squared successive difference. On average across assessments, participants with EDs reported a 16% change in their BD ratings between consecutive assessments, which was significantly higher than the 12% change in controls. Trait BD was significantly inversely associated with BD instability in individuals with EDs, but not in controls. BD instability did not differ across ED diagnoses or between days with versus without maladaptive exercise. Findings suggest that BD is a dynamic state that varies within a day, especially in participants with EDs. Further research is needed to clarify whether this heightened instability in BD is a clinically relevant factor underlying ED symptoms.

Affective processes underlying restrictive eating in atypical anorexia nervosa: Comparisons to anorexia nervosa and bulimia nervosa using ecological momentary assessment.

OBJECTIVE: Certain symptom and risk/maintenance factor similarities between individuals with atypical anorexia nervosa (AN) and 'typical' AN have been documented, but few studies have investigated how atypical AN compares to bulimia nervosa (BN). Further, the role of affective mechanisms in maintaining restrictive eating in atypical AN has not been examined. The current study investigated whether atypical AN resembles AN and/or BN on affect-related processes using questionnaires and ecological momentary assessment (EMA). METHOD: Women with atypical AN (n = 24), AN-restrictive subtype, (n = 27), AN-binge eating/purging subtype (n = 34), and BN (n = 58) completed questionnaires measuring depressive symptoms and emotion regulation difficulties. They also completed a 14-day EMA protocol during which they reported negative and positive affect and skipped meals five times/day (signal-contingent surveys) and restrictive eating after meals/snacks (event-contingent surveys). RESULTS: Diagnostic groups generally did not differ on questionnaire measures nor affective patterns surrounding restrictive eating behaviors. Momentary changes in affect did not predict or follow restriction at meals/snacks, though higher momentary negative affect ratings predicted skipped meals, and higher positive affect was reported after skipped meals. Greater average negative affect and lower average positive affect predicted both restrictive eating behaviors. DISCUSSION: Across diagnoses, reductions in food intake do not appear to be influenced by momentary changes in affect, though skipping meals may serve an emotion regulation function. Atypical AN seems to resemble AN and BN on affective processes underlying restrictive eating, raising further questions regarding the unique diagnosis of atypical AN. PUBLIC SIGNIFICANCE: Though atypical anorexia appears to strongly resemble anorexia nervosa, it is less clear how this disorder relates to bulimia nervosa. It is further unknown whether affective-related processes underlie restrictive eating in atypical anorexia nervosa, and how these processes compare to those in anorexia nervosa and bulimia nervosa. Results suggest that atypical anorexia does not differ from anorexia nervosa or bulimia nervosa on emotion-related measures, nor in affective patterns surrounding restrictive eating behaviors.

Assessing the validity of QRISK3 in predicting cardiovascular events in systemic lupus erythematosus.

OBJECTIVES: Traditional cardiovascular risk calculators such as the Framingham Risk Score (FRS) have been shown to underestimate risk in patients with SLE. The QRISK3 calculator is unique in including SLE and corticosteroid use as risk factors. This study aims to assess the validity of QRISK3 compared with other cardiovascular risk models in a cohort of patients with SLE in the USA. METHODS: We studied a prospective cohort of 366 adult patients with SLE without history of any cardiovascular event and followed them for 10 years. We compared the diagnostic performance of QRISK3 with FRS, modified FRS, Atherosclerotic Cardiovascular Disease (ASCVD), and Predictors of Risk for Elevated Flares, Damage Progression and Increased Cardiovascular Disease in Patients with SLE (PREDICTS). RESULTS: Sixty-four of the 366 patients (17.4%) experienced at least one cardiovascular event during the 10-year follow-up period. Of these patients 45% had a QRISK3 score >10%, whereas 20.5% of patients who did not have an event had a QRISK3 score >10% (p<0.001). The corresponding numbers for FRS, modified FRS, ASCVD and PREDICTS were 11.0% vs 7.2% (p=ns), 40.6% vs 28.0% (p=0.05), 12.2% vs 5.9% (p=ns), and 77% vs 32.1% (p<0.001), respectively. The areas under the receiver operating characteristic curve using QRISK3 >10% and high-risk PREDICTS were both larger than those using ASCVD >10%, FRS >10% and modified FRS >10%. CONCLUSIONS: Both QRISK3 and PREDICTS demonstrated better performance in predicting risk of cardiovascular disease in this cohort of patients with SLE compared with FRS, modified FRS and ASCVD.

Rituximab Versus Mycophenolate in the Treatment of Recalcitrant Connective Tissue Disease-Associated Interstitial Lung Disease.

OBJECTIVE: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD). METHODS: This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group). RESULTS: Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017). CONCLUSION: Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.

Intraoperative Motor Evoked Potential Improvement in Cervical Spondylotic Myelopathy: Comparison of Cortical Stimulation Parameters.

BACKGROUND AND PURPOSE: Intraoperative monitoring of the motor pathways is a routine procedure for ensuring the integrity of descending motor tracts during spinal surgery. Intraoperative motor evoked potential improvement (MEPI) may be associated with a better postsurgical outcome in cervical spondylotic myelopathy (CSM). To compare the efficacy of two cortical stimulation parameters in eliciting MEPI intraoperatively during CSM surgery. METHODS: We studied 69 patients who underwent decompression surgery for CSM over a 9-month period using either 5 (Group 1) or 9 (Group 2) stimuli. MEPI was defined as the increase in the amplitude of MEPs from baseline at the end of CSM surgery just prior to skin closure. RESULTS: An MEPI of 100% from baseline was observed in 10 patients (53%) in Group 1 and 36 patients (72%) in Group 2. Comparisons of the baseline mean MEP amplitudes of muscles bilaterally between Groups 1 and 2 did not reveal any significant differences. Supramaximal stimulation showed that a significantly higher mean intensity was required for Group 1 than for Group 2. CONCLUSIONS: MEPI is observed in a much larger proportion of cervical decompression surgery cases than previously thought. Intraoperative MEPI with longer-train cortical stimulation may reflect adequacy of decompression and provide additional guidance for the surgical procedure.

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

Enhancing collaborative pharmaceutical care for patients with chronic kidney disease: survey of community pharmacists.

BACKGROUND: The Kidney Care Clinic at Sunnybrook Health Sciences Centre provides multidisciplinary care for patients with stage 4 or 5 chronic kidney disease. These patients are at high risk of drug therapy problems. Clinic pharmacists review medications and provide recommendations at each visit, but potential gaps in care exist between clinic visits. Community pharmacists are ideally situated to identify and resolve drug therapy problems between visits. OBJECTIVES: To determine community pharmacists' confidence in managing care for patients with chronic kidney disease; to identify opportunities for improving collaboration between clinic and community pharmacists; and to determine the key clinical information that community pharmacists would use when caring for these patients. METHODS: An anonymous survey was sent by mail and electronically to community pharmacies that were providing prescription medications for clinic patients. A total of 318 surveys were sent to 96 pharmacies. Data analysis was based on descriptive statistics, including frequencies, ranges, and measures of central tendency. RESULTS: Fifty-one completed surveys were returned (response rate 16%). Thirty-five (69%) of the responding pharmacists were not aware or were unsure that a patient from the Kidney Care Clinic was a client of their pharmacy. Forty-six (90%) were confident in providing counselling about medications used to manage chronic kidney disease, and 32 (63%) indicated confidence in recommending drug dosing changes based on kidney function. Forty-five (88%) of the pharmacists indicated a willingness to play a greater role in reviewing medications for patients with chronic kidney disease, and all agreed that they would benefit from education about the complications of this disease and their management. Clinical information ranked most useful included an updated medication list with indications and details regarding recent medication changes. CONCLUSIONS: Community pharmacists indicated willingness to have greater involvement in the care of patients with chronic kidney disease. The survey results revealed a need to increase awareness of clinic patients among community providers. Participants were receptive to continuing education, and initial efforts should focus on dosing adjustments of renal drugs and the complications of chronic kidney disease. Tools for transferring clinical information must be developed.

CONTEXTE: La clinique de santé rénale du Sunnybrook Health Sciences Centre fournit des soins multidisciplinaires aux patients atteints d'une insuffisance rénale chronique de stade 4 ou 5. Ces patients sont exposés à un risque élevé de problèmes pharmacothérapeutiques. Les pharmaciens de la clinique effectuent une évaluation de la médication et formulent des recommandations à chaque visite, mais certaines lacunes potentielles dans les soins entre chaque visite à la clinique ne sont pas à exclure. Les pharmaciens communautaires sont les mieux placés pour déceler et résoudre les problèmes pharmacothérapeutiques entre les visites. OBJECTIFS: Déterminer à quel point les pharmaciens communautaires se sentent à l'aise à l'idée de prendre en charge les soins de patients atteints d'une insuffisance rénale chronique; identifier les occasions qui permettraient d'améliorer la collaboration entre les pharmaciens communautaires et ceux de la clinique; et préciser les informations cliniques clés que les pharmaciens communautaires pourraient utiliser lorsqu'ils s'occupent de ces patients. MÉTHODES: Un sondage anonyme a été envoyé par la poste et par courriel aux pharmacies communautaires qui fournissent des médicaments d'ordonnance à des patients qui fréquentent la clinique. Un total de 318 sondages ont été envoyés à 96 pharmacies. L'analyse des données reposait sur des statistiques descriptives, notamment les fréquences, les étendues et les mesures de la tendance centrale. RÉSULTATS: Cinquante et un sondages remplis ont été retournés (taux de réponse de 16 %). Trente-cinq (69 %) des pharmaciens ayant répondu au sondage ignoraient ou étaient incertains si un patient de la clinique de santé rénale était un client de leur pharmacie. Quarante-six (90 %) se sentaient à l'aise à l'idée de fournir des conseils sur les médicaments utilisés pour traiter l'insuffisance rénale chronique et 32 (63 %) ont reconnu qu'ils se sentaient à l'aise à l'idée de recommander des posologies adaptées à la fonction rénale. Quarante-cinq pharmaciens (88 %) ont manifesté leur volonté de jouer un rôle plus important dans l'évaluation de la médication des patients atteints d'une insuffisance rénale chronique et tous s'entendaient pour dire qu'ils tireraient profit d'une formation sur les complications de cette maladie et leur prise en charge. Parmi les informations cliniques jugées les plus utiles se trouvait une liste à jour des médicaments accompagnée de leurs indications et de précisions quant aux récents changements à la pharmacothérapie. CONCLUSIONS: Les pharmaciens communautaires ont manifesté leur volonté de jouer un rôle plus important dans la prise en charge des patients atteints d'une insuffisance rénale chronique. Les résultats du sondage ont mis en relief la nécessité de mieux signaler les patients de la clinique aux pharmaciens communautaires. Les participants étaient ouverts à la formation continue et les mesures en ce sens devraient d'abord être axées sur l'ajustement posologique de médicaments éliminés par voie rénale et sur les complications liées à l'insuffisance rénale chronique. De plus, des outils visant à transmettre les informations cliniques doivent être développés. [Traduction par l'éditeur].

Whole-brain mapping of direct inputs to midbrain dopamine neurons.

Recent studies indicate that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) convey distinct signals. To explore this difference, we comprehensively identified each area's monosynaptic inputs using the rabies virus. We show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas. SNc and VTA dopamine neurons receive contrasting excitatory inputs: the former from the somatosensory/motor cortex and subthalamic nucleus, which may explain their short-latency responses to salient events; and the latter from the lateral hypothalamus, which may explain their involvement in value coding. We demonstrate that neurons in the striatum that project directly to dopamine neurons form patches in both the dorsal and ventral striatum, whereas those projecting to GABAergic neurons are distributed in the matrix compartment. Neuron-type-specific connectivity lays a foundation for studying how dopamine neurons compute outputs.

Improvements in pain outcomes in a Canadian pediatric teaching hospital following implementation of a multifaceted knowledge translation initiative.

BACKGROUND: A previous audit performed at a tertiary / quaternary pediatric hospital in Toronto, Ontario, demonstrated suboptimal assessment and treatment of children's pain. Knowledge translation (KT) initiatives (education, reminders, audit and feedback) were implemented to address identified care gaps; however, the impact is unknown. OBJECTIVES: To determine the impact of KT initiatives on pain outcomes including process outcomes (eg, pain assessment and management practices) and clinical outcomes (eg, pain prevalence and intensity); and to benchmark additional pain practices, particularly opioid administration and painful procedures. METHODS: Medical records at The Hospital for Sick Children (Toronto, Ontario) were reviewed on a single day in September 2007. Pain assessment and management practices, and pain prevalence and intensity in the preceding 24 h were recorded on a standardized data collection form. Where possible, pain outcomes were compared with previous audit results. RESULTS: Records of 265 inpatients were audited. Sixty-three per cent of children underwent a documented pain assessment compared with 27% in an audit conducted previously (P<0.01). Eighty-three per cent of children with documented pain received at least one pain management intervention. Overall, 51% of children received pharmacological therapy, and 15% received either a psychological or physical pain-relieving intervention. Of those assessed, 44% experienced pain in the previous 24 h versus 66% in the previous audit (P<0.01). Fewer children experienced severe pain compared with the first audit (8.7% versus 26.1%; P<0.01). One-third of children received opioids; 19% of these had no recorded pain assessment. Among 131 children who underwent a painful procedure, 21% had a concurrent pain assessment. Painful procedures were accompanied by a pain-relieving intervention in 12.5% of cases. CONCLUSIONS: Following KT initiatives, significant improvements in pain processes (pain assessment documentation and pain management interventions) and clinical outcomes (pain prevalence, pain intensity) were observed. Further improvements are recommended, specifically with respect to procedural pain practices and opioid utilization patterns.

Multimodal intraoperative neuromonitoring in corrective surgery for adolescent idiopathic scoliosis: Evaluation of 354 consecutive cases.

BACKGROUND: Multimodal intraoperative neuromonitoring is recommended during corrective spinal surgery, and has been widely used in surgery for spinal deformity with successful outcomes. Despite successful outcomes of corrective surgery due to increased safety of the patients with the usage of spinal cord monitoring in many large spine centers, this modality has not yet achieved widespread popularity. We report the analysis of prospectively collected intraoperative neurophysiological monitoring data of 354 consecutive patients undergoing corrective surgery for adolescent idiopathic scoliosis (AIS) to establish the efficacy of multimodal neuromonitoring and to evaluate comparative sensitivity and specificity. MATERIALS AND METHODS: The study group consisted of 354 (female = 309; male = 45) patients undergoing spinal deformity corrective surgery between 2004 and 2008. Patients were monitored using electrophysiological methods including somatosensory-evoked potentials and motor-evoked potentials simultaneously. RESULTS: Mean age of patients was 13.6 years (+/-2.3 years). The operative procedures involved were instrumented fusion of the thoracic/lumbar/both curves, Baseline somatosensory-evoked potentials (SSEP) and neurogenic motor-evoked potentials (NMEP) were recorded successfully in all cases. Thirteen cases expressed significant alert to prompt reversal of intervention. All these 13 cases with significant alert had detectable NMEP alerts, whereas significant SSEP alert was detected in 8 cases. Two patients awoke with new neurological deficit (0.56%) and had significant intraoperative SSEP + NMEP alerts. There were no false positives with SSEP (high specificity) but 5 patients with false negatives with SSEP (38%) reduced its sensitivity. There was no false negative with NMEP but 2 of 13 cases were false positive with NMEP (15%). The specificity of SSEP (100%) is higher than NMEP (96%); however, the sensitivity of NMEP (100%) is far better than SSEP (51%). Due to these results, the overall sensitivity, specificity and positive predictive value of combined multimodality neuromonitoring in this adult deformity series was 100, 98.5 and 85%, respectively. CONCLUSION: Neurogenic motor-evoked potential (NMEP) monitoring appears to be superior to conventional SSEP monitoring for identifying evolving spinal cord injury. Used in conjunction, the sensitivity and specificity of combined neuromonitoring may reach up to 100%. Multimodality monitoring with SSEP + NMEP should be the standard of care.