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The preferred evidence of a large randomized controlled trial is difficult to adopt in scenarios, such as rare conditions or clinical subgroups with high unmet needs, and evidence from external sources, including real-world data, is being increasingly considered by decision makers. Real-world data originate from many sources, and identifying suitable real-world data that can be used to contextualize a single-arm trial, as an external control arm, has several challenges. In this viewpoint article, we provide an overview of the technical challenges raised by regulatory and health reimbursement agencies when evaluating comparative efficacy, such as identification, outcome, and time selection challenges. By breaking down these challenges, we provide practical solutions for researchers to consider through the approaches of detailed planning, collection, and record linkage to analyze external data for comparative efficacy.

Abstract Objective Between 17% and 40% of patients undergoing elective arthroplasty are preoperative opioid users. This US study analyzed patients in this population to illustrate the relationship between preoperative opioid use and adverse surgical outcomes. Design Retrospective study of administrative medical and pharmaceutical claims data. Subjects Adults (aged 18+) who received elective total knee, hip, or shoulder replacement in 2014–2015. Methods A patient was a preoperative opioid user if opioid prescription fills occurred in two periods: 1–30 and 31–90 days presurgery. Zero-truncated Poisson (incidence rate ratio [IRR]), logistic (odds ratio [OR]), Cox (hazard ratio [HR]), and quantile regressions modeled the effects of preoperative opioid use and opioid dose, adjusted for demographics, comorbidities, and utilization. Results Among 34,792 patients (38% hip, 58% knee, 4% shoulder), 6,043 (17.4%) were preoperative opioid users with a median morphine equivalent daily dose of 32 mg. Preoperative opioid users had increased length of stay (IRR = 1.03, 95% CI = 1.02 to 1.05), nonhome discharge (OR = 1.10, 95% CI = 1.00 to 1.21), and 30-day unplanned readmission (OR = 1.43, 95% CI = 1.17 to 1.74); experienced 35% higher surgical site infection (HR = 1.35, 95% CI = 1.14 to 1.59) and 44% higher surgical revision (HR = 1.44, 95% CI = 1.21 to 1.71); had a median $1,084 (95% CI = $833 to $1334) increase in medical spend during the 365 days after discharge; and had a 64% lower rate of opioid cessation (HR = 0.34, 95% CI = 0.33 to 0.35) compared with patients not filling two or more prescriptions across periods. Conclusions Preoperative opioid users had longer length of stay, increased revision rates, higher spend, and persistent opioid use, which worsened with dose. Adverse outcomes after elective joint replacement may be reduced if preoperative opioid risk is managed through increased monitoring or opioid cessation.

This study aimed to evaluate the ability of BOLD signals at high MRI field (7T) to map fine-scale single-digit activations in subdivisions (areas 3b and 1) of the human primary somatosensory cortex (SI) in individual subjects. We acquired BOLD fMRI data from cortical areas around the central suclus in six healthy human subjects while stimulating individual finger pads with 2-Hz air puffs. Discrete, single-digit responses were identified in an area along the posterior bank of the central sulcus corresponding to area 3b and in an area along the crest of the postcentral gyrus corresponding to area 1. In single subjects, activations of digits 1 to 4 in both areas 3b and 1 were organized in a somatotopic manner. The separation of digit representations was measured for adjacent digits and was approximately 1.6 times greater in area 3b than in area 1. Within individual subjects, the cortical responses to single-digit stimulations and the magnitude of the BOLD signals were reproducible across imaging runs and were comparable across subjects. Our findings demonstrate that BOLD fMRI at 7T is capable of revealing the somatotopic organization of single-digit activations with good within-subject reliability and reproducibility, and activation maps can be acquired within a reasonably short time window, which are essential characteristics for several neurological applications within patient populations. ►Single-digit somatotopic maps were identified in areas 3b and 1 of SI. ►Separation of digit representations was 1.6 times greater in area 3b than in area 1. ►Somatotopic maps acquired at 7T have high spatial and temporal reproducibility.

This study aimed to evaluate the ability of BOLD signals at high MRI field (7 T) to map fine-scale single-digit activations in subdivisions (areas 3b and 1) of the human primary somatosensory cortex (SI) in individual subjects. We acquired BOLD fMRI data from cortical areas around the central suclus in six healthy human subjects while stimulating individual finger pads with 2-Hz air puffs. Discrete, single-digit responses were identified in an area along the posterior bank of the central sulcus corresponding to area 3b and in an area along the crest of the postcentral gyrus corresponding to area 1. In single subjects, activations of digits 1 to 4 in both areas 3b and 1 were organized in a somatotopic manner. The separation of digit representations was measured for adjacent digits and was approximately 1.6 times greater in area 3b than in area 1. Within individual subjects, the cortical responses to single-digit stimulations and the magnitude of the BOLD signals were reproducible across imaging runs and were comparable across subjects. Our findings demonstrate that BOLD fMRI at 7 T is capable of revealing the somatotopic organization of single-digit activations with good within-subject reliability and reproducibility, and activation maps can be acquired within a reasonably short time window, which are essential characteristics for several neurological applications within patient populations.

Background Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity. Methods Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days. Results Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy. Conclusions Our results support the role of cytokines in the pathophysiology of CFS.

Objective: This study estimates the prevalence of pre-operative high-dose chronic opioid use and subsequent opioid tapering before knee, shoulder, and spine surgery. Methods: We conducted a retrospective review of US commercial claims between February 2014 and December 2016 from Blue Health Intelligence. Patients were included in this analysis if they had at least nine months of continuous health coverage (three months preoperative, six months postoperative) surrounding knee, shoulder, or spine surgery. Preoperative high-dose chronic opioid use was defined as a morphine equivalent daily dose (MEDD) greater than 0 mg for at least 60 of the 90 days before surgery and a MEDD greater than 50 mg at any point within 90 days before surgery, indicating candidacy for taper. Opioid tapering was determined by any reduction in MEDD in the 90 days before surgery, with an MEDD lower than the patient's 90-day median on the day before surgery. Results: The prevalence of preoperative high-dose chronic opioid use was 3% for knee surgery, 8% for spine surgery, and 3% for shoulder surgery across 103,857 members. Preoperative opioid tapering in chronic opioid users was evident in 27% of knee surgeries, 23% of shoulder surgeries, and 25% of spine surgeries. Conclusions: The prevalence of preop-erative high-dose chronic opioid use was low in this commercial population. One-fourth of high-dose chronic opioid users underwent an opioid taper before surgery. Further analysis would give insight into the impact of opioid tapering on postoperative medical utilization and outcomes.

Introduction: Preoperative opioid use has been widely reported as a significant risk factor for a variety of poor surgical outcomes. Although preoperative opioid taper is a potential intervention, its effectiveness in improving surgical outcomes remains unclear. Materials and Methods: Using Blue Health Intelligence administrative health claims data from US commercially insured members, we conducted a retrospective analysis of opioid tapering before knee arthroplasty, knee arthroscopy, shoulder arthroscopy, and anterior cervical discectomy and fusion. Between February 2014 and December 2016, 3,410 members were identified with preoperative high-dose chronic opioid use. These members were further evaluated for evidence of opioid tapering. Opioid tapering was defined as having one or more reductions in opioid dose in the 90 days before surgery and having a morphine equivalent daily dose (MEDD) on the day before surgery that was less than the 90-day preoperative MEDD median. Member opioid prescriptions and health care utilization were examined for six months following discharge. Results: Compared with other members with preoperative high-dose chronic opioid use, members who had evidence of opioid tapering before surgery were more likely to stop opioid use during their postoperative recovery. There was little evidence that opioid tapering was associated with a decrease in postoperative medical claims. Conclusions: Our initial findings suggest that preoperative opioid tapering is an effective method for reducing prolonged opioid use after surgery. Future work will correct for nonrandom exposure of opioid tapering to better understand the potential impact on postoperative health care utilization.

Abstract Objective. Prolonged exposure to opioids is known to produce neuroplastic changes in animals; however, few studies have investigated the effects of short-term prescription opioid use in humans. A previous study from our laboratory demonstrated a dosage-correlated volumetric decrease in the right amygdala of participants administered oral morphine daily for 1 month. The purpose of this current study was to replicate and extend the initial findings. Methods. Twenty-one participants with chronic low back pain were enrolled in this double-blind, placebo-controlled study. Participants were randomized to receive daily morphine (n = 11) or a matched placebo (n = 10) for 1 month. High-resolution anatomical images were acquired immediately before and after the treatment administration period. Morphological gray matter changes were investigated using tensor-based morphometry, and significant regions were subsequently tested for correlation with morphine dosage. Results. Decreased gray matter volume was observed in several reward- and pain-related regions in the morphine group, including the bilateral amygdala, left inferior orbitofrontal cortex, and bilateral pre-supplementary motor areas. Morphine administration was also associated with significant gray matter increases in cingulate regions, including the mid cingulate, dorsal anterior cingulate, and ventral posterior cingulate. Conclusions. Many of the volumetric increases and decreases overlapped spatially with the previously reported changes. Individuals taking placebo for 1 month showed neither gray matter increases nor decreases. The results corroborate previous reports that rapid alterations occur in reward-related networks following short-term prescription opioid use.

The primary somatosensory cortex (SI) plays a principal role in the processing of both somatosensory and pain information. The organization and function of this cortical region have been studied for over a century using anatomical (e.g. lesions and antero- and retrograde staining) and physiological methods (e.g. single and multiunit electrical recordings). While these invasive techniques give us insight into the architecture of the human cortex and are practical for studies in most mammalian species, they are unfeasible approaches to studying this region in most people. With the advent of ultra-high field (7 Tesla) non-invasive magnetic resonance imaging (MRI) scientists are now able to study the cortex with the resolution and precision once only available by invasive techniques. In this work we use 7 T MRI to explore how human SI responds to and processes somatosensory and noxious stimuli.

Delayed or impaired language development is a common developmental concern, yet there is little agreement about the criteria used to identify and classify language impairments in children. Children's language difficulties are at the interface between education, medicine and the allied professions, who may all adopt different approaches to conceptualising them. Our goal in this study was to use an online Delphi technique to see whether it was possible to achieve consensus among professionals on appropriate criteria for identifying children who might benefit from specialist services. We recruited a panel of 59 experts representing ten disciplines (including education, psychology, speech-language therapy/pathology, paediatrics and child psychiatry) from English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46 statements based on articles and commentaries in a special issue of a journal focusing on this topic. Panel members rated each statement for both relevance and validity on a seven-point scale, and added free text comments. These responses were synthesised by the first two authors, who then removed, combined or modified items with a view to improving consensus. The resulting set of statements was returned to the panel for a second evaluation (round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percent for 24 of 27 round 2 statements, though many respondents qualified their response with written comments. These were again synthesised by the first two authors. The resulting consensus statement is reported here, with additional summary of relevant evidence, and a concluding commentary on residual disagreements and gaps in the evidence base.