Biomarkers of Inflammation and Longitudinal Evaluation of Lung Function, Physical Activity, and Grip Strength: A Secondary Analysis in the CASCADE Study.

Rationale: Physical activity, lung function, and grip strength are associated with exacerbations, hospitalizations, and mortality in people with chronic obstructive pulmonary disease (COPD). We tested whether baseline inflammatory biomarkers were associated with longitudinal outcomes of these physiologic measurements. Methods: The COPD Activity: Serotonin Transporter, Cytokines, and Depression (CASCADE) study was a prospective observational study of individuals with COPD. Fourteen inflammatory biomarkers were measured at baseline. Participants were followed for 2 years. We analyzed associations between baseline biomarkers and FEV1, physical activity, and grip strength. We used a hierarchical hypothesis testing procedure to reduce type I error. We used Pearson correlations to test associations between baseline biomarkers and longitudinal changes in the outcomes of interest. We used Fisher's linear discriminant analysis to test if linear combinations of baseline biomarkers predict rapid FEV1 decline. Finally, we used linear mixed modeling to test associations between baseline biomarkers and outcomes of interest at baseline, year 1, and year 2; models were adjusted for age, smoking status, baseline biomarkers, and FEV1. Results: 302 participants (age 67.5 ± 8.5 years, 19.5% female, 28.5% currently smoking) were included. Baseline biomarkers were not associated with longitudinal changes in grip strength, physical activity, or rapid FEV1 decline. Higher IL-6 and CRP were associated with lower physical activity at baseline and these relationships persisted at year 1 and year 2. Conclusion: Baseline inflammatory biomarkers did not predict changes in lung function or physical activity, but higher inflammatory biomarkers were associated with persistently low levels of physical activity.

Analgesic efficacy of surgeon placed paravertebral catheters compared with thoracic epidural analgesia after Ivor Lewis esophagectomy: a retrospective non-inferiority study.

Background: The Ivor Lewis esophagectomy is an operation that involves a laparotomy and a right thoracotomy, both of which are associated with severe postoperative pain and subsequent impairment of respiratory function. Currently, the accepted "gold standard" for postoperative analgesia for laparotomies and thoracotomies is the thoracic epidural. A systematic review has shown paravertebral blocks to be equivalent to epidural analgesia for post-thoracotomy pain control and have decreased incidence of nausea and vomiting, hypotension and respiratory depression. To our knowledge, the use of the paravertebral catheter (PVC) in open Ivor Lewis esophagectomy has not been formally studied. The primary outcome is the area under the curve (AUC) pain scores in the first 48 hours after surgery. Methods: We performed a retrospective chart review of the open Ivor Lewis esophagectomy patients at our local institution, with local research ethics board (REB) approval. Results: A total of 92 patients were included in this study: 43 patients had a PVC and 49 had a thoracic epidural for postoperative pan control. Overall, the PVC group was non-inferior and statistically equivalent to the epidural group. Time to ambulation in the PVC group was non-inferior compared to epidurals. The PVC group was superior when comparing total opioid consumption. Conclusions: Our retrospective study continues to challenge the role of epidurals as the gold standard of pain control post thoracotomy and laparotomy. Further prospective studies with a larger population are needed to better compare the two modalities.

RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.

Cone-beam computed tomographic reconstructions in the evaluation of maxillary impacted canines.

Purpose: Prior to cone-beam computed tomography (CBCT), orthodontic competence included radiological interpretation. Nevertheless, maxillary impacted canines (MICs), because of their position and adjacent complex anatomy, have been challenging to interpret, particularly with regard to root resorption. Although CBCT cross-sectional reconstructions of MICs yielded clearer insights into its diagnosis and treatment planning, the value of simultaneously using 2 different cross-sectional or multiplanar reconstructions of the CBCT datasets - orthogonal and curved/panoramic multiplanar reconstructions - has hitherto not been considered. Materials and Methods: Both orthogonal and curved/panoramic multiplanar reconstruction series of 5 screenshots were each reconstructed from the 5 cm × 5 cm CBCT datasets of 15 separate MICs. Fifteen credentialled and experienced orthodontist volunteers reviewed 2 separate PowerPoints of 15 randomized series each, 1 week apart. Their review considered 6 factors that could affect treatment: the position and level of the MIC, the presence or absence of root resorption, ankylosis, cysts, and dilaceration. Results: All 15 orthodontists were statistically similar regarding overall years of experience and of CBCT use. Although either reconstruction alone allowed the orthodontists to determine whether ankylosis and, to a lesser extent, most of the other features were present or absent in the MIC, reviewing both reconstructions together was necessary to determine whether root resorption was present or absent in the adjacent tooth. Conclusion: Reviewing both orthogonal and curved/panoramic multiplanar reconstructions was necessary to evaluate the presence or absence of root resorption in the teeth adjacent to MICs and that of many other features.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Cardiovascular Autonomic Function and Incident Chronic Obstructive Pulmonary Disease Hospitalizations in Atherosclerosis Risk in Communities.

Rationale: The autonomic nervous system extensively innervates the lungs, but its role in chronic obstructive pulmonary disease (COPD) outcomes has not been well studied. Objective: We assessed relationships between cardiovascular autonomic nervous system measures (heart rate variability [HRV] and orthostatic hypotension [OH]) and incident COPD hospitalization in the multicenter ARIC (Atherosclerosis Risk In Communities) study. Methods: We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals between baseline (1987-1989) autonomic function measures (HRV measures from 2-minute electrocardiograms and OH variables) and incident COPD hospitalizations through 2019. Adjusted analyses included demographic data, smoking status, lung function, comorbidities, and physical activity. We also performed analyses stratified by baseline airflow obstruction. Results: Of the 11,625 participants, (mean age, 53.8 yr), 56.5% were female and 26.3% identified as Black. Baseline mean percentage predicted forced expiratory volume in 1 second was 94 ± 17% (standard deviation), and 2,599 participants (22.4%) had airflow obstruction. During a median follow-up time of 26.9 years, there were 2,406 incident COPD hospitalizations. Higher HRV (i.e., better autonomic function) was associated with a lower risk of incident COPD hospitalization. Markers of worse autonomic function (OH and greater orthostatic changes in systolic and diastolic blood pressure) were associated with a higher risk of incident COPD hospitalization (hazard ratio for the presence of OH, 1.5; 95% confidence interval, 1.25-1.92). In stratified analyses, results were more robust in participants without airflow obstruction at baseline. Conclusions: In this large multicenter prospective community cohort, better cardiovascular autonomic function at baseline was associated with a lower risk of subsequent hospitalization for COPD, particularly among participants without evidence of lung disease at baseline.

Analyzing the value of IONM as a complex intervention: The gap between published evidence and clinical practice.

OBJECTIVE: Intraoperative neurophysiological monitoring (IONM) was investigated as a complex intervention (CI) as defined by the United Kingdom Medical Research Council (MRC) in published studies to identify challenges and solutions in estimating IONM's effects on postoperative outcomes. METHODS: A scoping review to April 2022 of the influence of setting on what was implemented as IONM and how it influenced postoperative outcomes was performed for studies that compared IONM to no IONM cohorts. IONM complexity was assessed with the iCAT_SR tool. Causal graphs were used to represent this complexity. RESULTS: IONM implementation depended on the surgical procedure, institution and/or surgeon. "How" IONM influenced neurologic outcomes was attributed to surgeon or institutional experience with the surgical procedure, surgeon or institutional experience with IONM, co-interventions in addition to IONM, models of IONM service delivery and individual characteristics of the IONM provider. Indirect effects of IONM mediated by extent of tumor resection, surgical approach, changes in operative procedure, shorter operative time, and duration of aneurysm clipping were also described. There were no quantitative estimates of the relative contribution of these indirect effects to total IONM effects on outcomes. CONCLUSIONS: IONM is a complex intervention whose evaluation is more challenging than that of a simple intervention. Its implementation and largely indirect effects depend on specific settings that are usefully represented in causal graphs. SIGNIFICANCE: IONM evaluation as a complex intervention aided by causal graphs and multivariable analysis could provide a valuable framework for future study design and assessments of IONM effectiveness in different settings.

Contrast Enhancement in MRI Using Combined Double Action Contrast Agents and Image Post-Processing in the Breast Cancer Model.

Gd- and Fe-based contrast agents reduce T1 and T2 relaxation times, respectively, are frequently used in MRI, providing improved cancer detection. Recently, contrast agents changing both T1/T2 times, based on core/shell nanoparticles, have been introduced. Although advantages of the T1/T2 agents were shown, MR image contrast of cancerous versus normal adjacent tissue induced by these agents has not yet been analyzed in detail as authors considered changes in cancer MR signal or signal-to-noise ratio after contrast injection rather than changes in signal differences between cancer and normal adjacent tissue. Furthermore, the potential advantages of T1/T2 contrast agents using image manipulation such as subtraction or addition have not been yet discussed in detail. Therefore, we performed theoretical calculations of MR signal in a tumor model using T1-weighted, T2-weighted, and combined images for T1-, T2-, and T1/T2-targeted contrast agents. The results from the tumor model are followed by in vivo experiments using core/shell NaDyF4/NaGdF4 nanoparticles as T1/T2 non-targeted contrast agent in the animal model of triple negative breast cancer. The results show that subtraction of T2-weighted from T1-weighted MR images provides additional increase in the tumor contrast: over two-fold in the tumor model and 12% in the in vivo experiment.

Pneumoproteins and biomarkers of inflammation and coagulation do not predict rapid lung function decline in people living with HIV.

Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and HIV is an independent risk factor for the development of COPD. However, the etiology of this increased risk and means to identify persons with HIV (PWH) at highest risk for COPD have remained elusive. Biomarkers may reveal etiologic pathways and allow better COPD risk stratification. We performed a matched case:control study of PWH in the Strategic Timing of Antiretoviral Treatment (START) pulmonary substudy. Cases had rapid lung function decline (> 40 mL/year FEV1 decline) and controls had stable lung function (+ 20 to - 20 mL/year). The analysis was performed in two distinct groups: (1) those who were virally suppressed for at least 6 months and (2) those with untreated HIV (from the START deferred treatment arm). We used linear mixed effects models to test the relationship between case:control status and blood concentrations of pneumoproteins (surfactant protein-D and club cell secretory protein), and biomarkers of inflammation (IL-6 and hsCRP) and coagulation (d-dimer and fibrinogen); concentrations were measured within ± 6 months of first included spirometry. We included an interaction with treatment group (untreated HIV vs viral suppression) to test if associations varied by treatment group. This analysis included 77 matched case:control pairs in the virally suppressed batch, and 42 matched case:control pairs in the untreated HIV batch (n = 238 total) who were followed for a median of 3 years. Median (IQR) CD4 + count was lowest in the controls with untreated HIV at 674 (580, 838). We found no significant associations between case:control status and pneumoprotein or biomarker concentrations in either virally suppressed or untreated PWH. In this cohort of relatively young, recently diagnosed PWH, concentrations of pneumoproteins and biomarkers of inflammation and coagulation were not associated with subsequent rapid lung function decline.Trial registration: NCT00867048 and NCT01797367.

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia.

WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 (ClinicalTrials.gov).

Cranial Radiation Therapy as Salvage in the Treatment of Relapsed Primary CNS Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy. Standard of care is upfront high-dose methotrexate (HD-MTX) chemotherapy, while cranial radiation is more commonly used in the salvage setting. In this retrospective study, we aimed to investigate the safety and efficacy of salvage cranial radiation in PCNSL. PCNSL patients who received upfront HD-MTX chemotherapy and salvage cranial radiation after treatment failure between 1995 and 2018 were selected. Radiological response to cranial radiation was assessed as per Response Assessment in Neuro-Oncology Criteria. Twenty one patients were selected (median age 59.9 years), with median follow-up of 19.9 months. Fourteen patients (66.7%) received a boost to the gross tumour volume (GTV). Four patients (19.0%) sustained grade ≥2 treatment-related neurotoxicity post-completion of cranial radiation. Of the 19 patients who had requisite MRI with gadolinium imaging available for Response Assessment in Neuro-Oncology (RANO) criteria assessment, 47.4% achieved complete response, 47.4% achieved partial response, and 5.3% of patients exhibited stable disease. Higher dose to the whole brain (>30 Gy) was associated with higher rate of complete response (63.6%) than lower dose (≤30 Gy, 37.5%), while boost dose to the gross disease was also associated with higher rate of complete response (61.5%) compared with no boost dose (33.3%). Median overall survival was 20.0 months. PCNSL patients who relapsed following upfront chemotherapy showed a high rate of response to salvage cranial radiation, especially in those receiving greater than 30 Gy to the whole brain and boost to gross disease.

Postoperative mortality risk prediction that incorporates intraoperative vital signs: development and internal validation in a historical cohort.

PURPOSE: Accurate risk reassessment after surgery is crucial for postoperative planning for monitoring and disposition. Existing postoperative mortality risk prediction models using preoperative features do not incorporate intraoperative hemodynamic derangements that may alter risk stratification. Intraoperative vital signs may provide an objective and readily available prognostic resource. Our primary objective was to derive and internally validate a logistic regression (LR) model by adding intraoperative features to established preoperative predictors to predict 30-day postoperative mortality. METHODS: Following Research Ethics Board approval, we analyzed a historical cohort that included patients aged ≥ 45 undergoing noncardiac surgery with an overnight stay at two tertiary hospitals (2013 to 2017). Features included intraoperative vital signs (blood pressure, heart rate, end-tidal carbon dioxide partial pressure, oxygen saturation, and temperature) by threshold and duration of exposure, as well as patient, surgical, and anesthetic factors. The cohort was divided temporally 75:25 into derivation and validation sets. We constructed a multivariable LR model with 30-day all-cause mortality as the outcome and evaluated performance metrics. RESULTS: There were 30,619 patients in the cohort (mean [standard deviation] age, 66 [11] yr; 50.2% female; 2.0% mortality). In the validation set, the primary LR model showed a c-statistic of 0.893 (99% confidence interval [CI], 0.853 to 0.927), a Nagelkerke R-squared of 0.269, a scaled Brier score of 0.082, and an area under precision-recall curve of 0.158 (baseline 0.017 for an uninformative model). The addition of intraoperative vital signs to preoperative factors minimally improved discrimination and calibration. CONCLUSION: We derived and internally validated a model that incorporated vital signs to improve risk stratification after surgery. Preoperative factors were strongly predictive of mortality risk, and intraoperative predictors only minimally improved discrimination. External and prospective validations are needed. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04014010); registered on 10 July 2019.

RéSUMé: OBJECTIF: Une réévaluation précise des risques après la chirurgie est cruciale pour la planification postopératoire du monitorage et du congé. Les modèles existants de prédiction du risque de mortalité postopératoire utilisant des caractéristiques préopératoires n'intègrent pas les perturbations hémodynamiques peropératoires, lesquelles pourraient modifier la stratification du risque. Les signes vitaux peropératoires peuvent fournir une ressource pronostique objective et facilement disponible. Notre objectif principal était de dériver et de valider en interne un modèle de régression logistique (RL) en ajoutant des caractéristiques peropératoires aux prédicteurs préopératoires établis pour prédire la mortalité postopératoire à 30 jours. MéTHODE: À la suite de l'approbation du Comité d'éthique de la recherche, nous avons analysé une cohorte historique qui comprenait des patients âgés de ≥ 45 ans bénéficiant d'une chirurgie non cardiaque avec un séjour d'une nuit dans deux hôpitaux tertiaires (2013 à 2017). Les caractéristiques comprenaient les signes vitaux peropératoires (tension artérielle, fréquence cardiaque, pression télé-expiratoire en CO2, saturation en oxygène et température) par seuil et durée d'exposition, ainsi que des facteurs propres au patient, chirurgicaux et anesthésiques. La cohorte a été divisée temporellement 75:25 en ensembles de dérivation et de validation. Nous avons élaboré un modèle de RL multivariée avec la mortalité toutes causes confondues à 30 jours comme critère, et évalué les mesures de performance. RéSULTATS: Il y avait 30 619 patients dans la cohorte (âge moyen [écart type], 66 [11] ans; 50,2 % de femmes; 2,0 % de mortalité). Dans l'ensemble de validation, le modèle de RL primaire a montré une statistique c de 0,893 (intervalle de confiance [IC] à 99 %, 0,853 à 0,927), un R carré de Nagelkerke de 0,269, un score de Brier mis à l'échelle de 0,082 et une aire sous la courbe de rappel et précision de 0,158 (ligne de base 0,017 pour un modèle non informatif). L'ajout de signes vitaux peropératoires aux facteurs préopératoires a amélioré de façon minimale la discrimination et l'étalonnage. CONCLUSION: Nous avons dérivé et validé en interne un modèle qui incorporait des signes vitaux pour améliorer la stratification des risques après la chirurgie. Les facteurs préopératoires étaient fortement prédictifs du risque de mortalité, et les prédicteurs peropératoires n'ont que que très peu amélioré la discrimination. Une validation externe et prospective est nécessaire. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04014010); enregistrée le 10 juillet 2019.

Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Neurophysiology during epilepsy surgery.

Intraoperative neuromonitoring (IONM) complements modern presurgical investigations by providing information about the epileptic focus as well as real-time identification of critical functional tissue and assessment of ongoing neural integrity during resective epilepsy surgery. This chapter summarizes current IONM methods for mapping the epileptic focus and for mapping and monitoring functionally important structures with direct brain stimulation and evoked potentials. These techniques include electrocorticography, computerized high-frequency oscillation mapping, single-pulse electric stimulation, cortical and subcortical motor evoked potentials, somatosensory evoked potentials, visual evoked potentials, and cortico-cortical evoked potentials. They may help to maximize epileptic tissue resection while avoiding permanent postoperative neurologic deficits.

Monitoring scoliosis and other spinal deformity surgeries.

Surgery to correct a spinal deformity incurs a risk of injury to the spinal cord and roots. Injuries include postoperative paraplegia. Surgery for cervical myelopathy also incurs risk for postoperative motor deficits, as well as nerve injury most commonly at the C5 root. Risks can be mitigated by monitoring the nervous system during surgery. Ideally, monitoring detects an impending injury in time to intervene and correct the impairment before it becomes permanent. Monitoring includes several modalities of testing. Somatosensory evoked potentials measure axonal conduction in the spinal cord posterior columns. This can be checked almost continuously during surgery. Motor evoked potentials measure conduction along the lateral corticospinal tracts. Because motor pathway stimulation often produces a patient movement on the table, these often are tested periodically rather than continuously. Electromyography observes for spontaneous discharges accompanying injuries, and is useful to assess misplacement of pedicle screws. Literature demonstrates the usefulness of these techniques, their association with reducing motor adverse outcomes, and the relative value of the techniques. Neurophysiologic monitoring for scoliosis, kyphosis, and cervical myelopathy surgery are addressed, along with background information about those conditions.

Intraoperative evoked potential techniques.

There are many recent advances in intraoperative evoked potential techniques for mapping and monitoring neural function during surgery. In particular, somatosensory evoked potential optimization speeds surgical feedback, motor evoked potentials provide selective motor system information, and new visual evoked potential methods promise reliable visual system monitoring. This chapter reviews these advances and provides a comprehensive background for understanding their context and importance.

Opioid Prescription Following Wrist and Ankle Fracture Fixation in Scotland-Tradition Prevails.

The American 'opioid crisis' is rapidly spreading internationally. Perioperative opioid use increases the risk of long-term opioid use. We review opioid use following wrist and ankle fracture fixation across Scotland, establishing prescribing patterns and associations with patient, injury, or perioperative factors. Six Scottish orthopedic units contributed. A total of 598 patients were included. Patient demographics were similar across all sites. There was variation in anesthetic practice, length of stay, and AO fracture type (p < 0.01). For wrist fractures, 85.6% of patients received a discharge opioid prescription; 5.0% contained a strong opioid. There was no significant variation across the six units in prescribing practice. For ankle fractures, 82.7% of patients received a discharge opioid prescription; 17% contained a strong opioid. Dundee and Edinburgh used more strong opioids; Inverness and Paisley gave the least opioids overall (p < 0.01). Younger patient age, location, and length of stay were independent predictors of increased prescription on binary regression. Despite variability in perioperative practices, discharge opioid analgesic prescription remains overwhelmingly consistent. We believe that the biggest influence lies with the prescriber-institutional 'standard practice'. Education of these prescribing clinicians regarding the risk profile of opioids is key to reducing their use following surgery, thus lowering long-term opioid dependence.

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study.

PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.