Towards a Physiology-Based Measure of Pain: Patterns of Human Brain Activity Distinguish Painful from Non-Painful Thermal Stimulation

Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p<0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Primary squamous cell of the thyroid–an abbreviated clinical presentation

Article deposited according to publisher policies: http://www.biomedcentral.com/about/copyright [July 16, 2014].YesFunding provided by the Open Access Authors Fund

The Otolaryngology boot camp: a scoping review evaluating commonalities and appraisal for curriculum design and delivery

Abstract Objective Surgical boot camps are becoming increasingly popular in Otolaryngology–Head and Neck Surgery (OHNS) residency programs. Despite pioneering virtual reality and simulation-based surgical education, these boot camps have lacked critical appraisal. The objective of this article was to examine the adoption and utility of surgical boot camps in OHNS residency training programs around the world. Data Sources Ovid Medline and PubMed databases were systematically searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews. Additionally, a grey literature search was performed. Review Methods Inclusion criteria were peer-reviewed publications and grey literature sources that reported on OHNS boot camps for the novice learner. The search was restricted to human studies published in English. Studies were excluded if they were not examining junior trainees. Results A total of 551 articles were identified. Following removal of duplicates, screening, and full text review, 16 articles were included for analysis. Seven major boot camps were identified across various academic sites in the world. Most boot camps were one-day intensive camps incorporating a mixture of didactic, skill specific, and simulation sessions using an array of task trainers and high-fidelity simulators focusing on OHNS emergencies. Studies measuring trainee outcomes demonstrated improvement in trainee confidence, immediate knowledge, and skill acquisition. Conclusion Surgical boot camps appear to be an effective tool for short term knowledge and skill acquisition. Further studies should examine retention of skill and maintenance of confidence over longer intervals, as little is known about these lasting effects

Assessing the role of virtual reality training in Canadian Otolaryngology–Head & Neck Residency Programs: a national survey of program directors and residents

Abstract Background Given mounting pressure of work hour restrictions, resource constraints, and variability of clinical exposure, Otolaryngology–Head & Neck Surgery (OHNS) residency training has shifted away from the apprenticeship model to embrace the Royal College of Physicians and Surgeons of Canada’s “Competence by Design” initiative. As a result, appraising both current and potential educational adjuncts has become increasingly important. In this investigation, a national needs assessment survey was performed to identify strengths, weaknesses, and future opportunities of the current training landscape. Methods An online survey was distributed to all thirteen Canadian OHNS post-graduate administrators for completion by program directors and residents from February to October in 2016. Prior to distribution, the survey was vetted for face validity by a group of staff Otolaryngologists and questions were modified accordingly. Quantitative analysis was performed on SPSS (IBM Corp., Chicago) with non-parametric, two-tailed Mann-Whitney U testing performed on scaled questions. Results Of the 68 responses, 11 of 13 (84.6%) of program directors and 57 of 168 (33.9%) residents responded to the survey. All 13 programs currently utilize cadaveric laboratory dissections. Associated challenges were ranked as specimen availability, faculty participation, insufficient space, and resident time constraints. 30.8% of programs currently utilize some form of virtual reality simulator, which 90.9% of program directors felt would be a fair and effective platform for evaluation. Conclusion A discrepancy exists between the favourable attitudes of both residents and program directors towards virtual reality simulation and its actual adoption. For successful adoption to occur, the existing barriers to unconventional training must be addressed and the tangible benefits for competency based training will need to be explored

Is otologic surgery contributing to the opioid epidemic?

Abstract Background The opioid epidemic is a significant public health crisis challenging the lives of North Americans. Interestingly, this problem does not exist to the same extent in Europe. Surgeons play a significant role in prescribing opioids, especially in the context of post-operative pain management. The aim of this study was to compare the post-surgical prescribing patterns of otologists comparing Canada and Austria. Methods An online questionnaire was sent to 33 Canadian and 32 Austrian surgeons, who perform otologic surgery on a regular basis. Surgeons were asked to answer some questions about their background as well as typical prescribing patterns for postoperative pain medication for different ear surgeries (cochlear implant, stapedotomy, tympanoplasty). In addition, surgeons were asked about the typical use of local anesthetics for pain control at the end of a procedure. Otologists gave an estimate how confident they were that their therapy and prescriptions provide sufficient pain control to their patients. Results Analysis of the returned questionnaires showed that opioids are more commonly prescribed in Canada than in Austria. Nonsteroidal anti-inflammatory drugs are used for postoperative pain more regularly after ear surgery in Austria, as opposed to Canada. Some of the prescribed drugs by European otologists are not available in North America. The use of local anesthetics at the end of surgery is not common in Austria. Surgeons´ confidence that the prescribed pain medication was sufficient to control postoperative symptoms was higher in the group not prescribing opioids than in the group that did routinely prescribe opioids. Conclusion Prescribing patterns differ substantially between the two evaluated countries. This data suggests an opportunity to reduce opioid prescriptions after otologic surgeries. Studies to evaluate pain after these operations as well as efficacy of analgesics following ear surgery are an important next step. Graphical abstrac

Using augmented reality to guide bone conduction device implantation

Abstract Exact placement of bone conduction implants requires avoidance of critical structures. Existing guidance technologies for intraoperative placement have lacked widespread adoption given accessibility challenges and significant cognitive loading. The purpose of this study is to examine the application of augmented reality (AR) guided surgery on accuracy, duration, and ease on bone conduction implantation. Five surgeons surgically implanted two different types of conduction implants on cadaveric specimens with and without AR projection. Pre- and postoperative computer tomography scans were superimposed to calculate centre-to-centre distances and angular accuracies. Wilcoxon signed-rank testing was used to compare centre-to-centre (C-C) and angular accuracies between the control and experimental arms. Additionally, projection accuracy was derived from the distance between the bony fiducials and the projected fiducials using image guidance coordinates. Both operative time (4.3 ± 1.2 min. vs. 6.6 ± 3.5 min., p = 0.030) and centre-to-centre distances surgery (1.9 ± 1.6 mm vs. 9.0 ± 5.3 mm, p < 0.001) were significantly less in augmented reality guided surgery. The difference in angular accuracy, however, was not significantly different. The overall average distance between the bony fiducial markings and the AR projected fiducials was 1.7 ± 0.6 mm. With direct intraoperative reference, AR-guided surgery enhances bone conduction implant placement while reduces operative time when compared to conventional surgical planning