Low mutation rate in epaulette sharks is consistent with a slow rate of evolution in sharks.

Sharks occupy diverse ecological niches and play critical roles in marine ecosystems, often acting as apex predators. They are considered a slow-evolving lineage and have been suggested to exhibit exceptionally low cancer rates. These two features could be explained by a low nuclear mutation rate. Here, we provide a direct estimate of the nuclear mutation rate in the epaulette shark (Hemiscyllium ocellatum). We generate a high-quality reference genome, and resequence the whole genomes of parents and nine offspring to detect de novo mutations. Using stringent criteria, we estimate a mutation rate of 7×10-10 per base pair, per generation. This represents one of the lowest directly estimated mutation rates for any vertebrate clade, indicating that this basal vertebrate group is indeed a slowly evolving lineage whose ability to restore genetic diversity following a sustained population bottleneck may be hampered by a low mutation rate.

Outpatient cross-titration to buprenorphine for chronic pain: A retrospective analysis.

OBJECTIVE: To determine the effectiveness and safety of the University of Washington's buprenorphine cross-titration protocol for chronic pain in the outpatient setting. METHODS: Retrospective chart review was performed on 150 patients transitioned from full µ-opioid agonist therapy to buprenorphine using the University of Washington Medical Center Pain Clinic's cross-titration protocol between September 1, 2020, and December 31, 2021, in an outpatient setting. Primary outcome was to determine the percentage of patients who completed the cross-titration and continued buprenorphine without full µ-opioid agonists 4 weeks after completion. Secondary outcomes included final buprenorphine dose, days needed to complete cross-titration, deviation rates from the protocol, and opioid-related adverse events. RESULTS: Fifteen of 31 (48.4 percent) included patients successfully converted to buprenorphine. Median duration of successful cross-titration was 29 days (interquartile range 19-57). Average end-titration dose for patients on buprenorphine/naloxone sublingual films was 7.9 ± 5.7 mg/day, while for buprenorphine transdermal (TD) patches, it was 11.9 ± 4.8 mcg/h. Morphine equivalent daily dose (MEDD) prior to induction varied widely. All patients transitioned to TD buprenorphine were taking ≤30 mg MEDD. Patients previously taking >120 mg MEDD stabilized on 8-16 mg/day buprenorphine. Most common reasons for cross-titration failure were inadequate pain control and intolerable adverse effects. DISCUSSION: The University of Washington's buprenorphine cross-titration protocol for chronic pain was successful in about half of included patients undergoing conversion from chronic full µ-opioid agonist therapy and generally well tolerated. Clinical responses were widely variable, and many required slower taper and higher end-titration buprenorphine dose than anticipated. Although protocols provide structure for cross-titration, each course should be monitored closely and individualized.

Comparison of PACU length of stay and opioid requirements of patients maintained on buprenorphine or methadone for opioid use disorder.

OBJECTIVES: Literature supporting best practice of perioperative buprenorphine management for opioid use disorder is evolving with more recent studies trending toward maintenance of home dose. To guide treatment protocols at our institution, we evaluated patients taking medication for opioid use disorder (MOUD) undergoing similar surgeries. Patients were maintained on either their outpatient buprenorphine or methadone. PATIENTS AND PARTICIPANTS: Data were collected on 46 patients maintained on buprenorphine MOUD who underwent surgery. A subset of these patients (n = 24) was compared with 24 patients maintained on methadone MOUD, matched on surgical procedure, admission date, age, and sex. DESIGN: This is a retrospective matched control study. SETTING: An academic, tertiary, Level 1 trauma center. MAIN OUTCOME MEASURES: Primary outcomes were post-operative opioid use and post-anesthesia care unit (PACU) length of stay. RESULTS: No significant differences in demographic characteristics, physical status, comorbid psychiatric diagnoses, or illicit substance use history were observed between patient groups. A higher proportion of patients taking methadone was admitted due to infection (41.7 percent vs 16.7 percent, p = 0.031) and underwent nonelective surgery (75.0 percent vs 45.8 percent, p = 0.039). No significant differences were observed between patients taking buprenorphine versus methadone with respect to PACU length of stay, post-operative opioid consumption, time-to-transition to oral opioids, or discharge opioid prescriptions. Patients taking buprenorphine were more likely to receive intravenous lidocaine (25.0 percent vs 0.0 percent, p = 0.031) and ketamine (83.3 percent vs 54.2 percent, p = 0.039). CONCLUSION: Findings from this study support accumulating evidence that patients should be maintained on buprenorphine MOUD throughout the perioperative period.

Pain Medicine Fellowship Video Interviews: A COVID-19 Trend or Here to Stay?

BACKGROUND: The COVID-19 pandemic ushered in a shift to a video format for pain medicine fellowship interviews for the 2021-2022 academic year, which represented a major change in the fellowship interview paradigm. OBJECTIVES: Our aim was to assess the experience of a video-only format in place of in-person interviews for Pain Medicine fellowship program directors and applicants after the 2020 fellowship interview season to determine the feasibility for continuation beyond COVID-19 travel restrictions. STUDY DESIGN: Survey via Qualtrics. SETTING: Academic pain medicine programs. METHODS: A consortium of program directors converged to discuss methods for determining the effectiveness and future direction of the video format for pain medicine fellowship interviews. Two surveys were formulated, one targeting pain medicine fellowship program directors and the other for candidates interviewing for the year 2021-2022. RESULTS: For applicants, 55 out of 170 responded for a response rate of 32.3%, and for program directors, 38 out of 95 responded for a response rate of 40%. Of the applicants, 45.7% stated that they would prefer video interviews, whereas 27.3% of program directors preferred video interviews. Savings of time and money were the most common reason for preferring video interviews. LIMITATIONS: The number of pain fellowship applicants invited was limited to those who interviewed at a subset of pain fellowships, which may not have been representative of all pain fellow applicants. CONCLUSIONS: The video format for pain medicine fellowship interviews was viewed positively by both candidates and program directors. We suspect that the video format alone or as a part of a hybrid model will become a routine method for the interview process in the future, given its time and cost benefits.

Comparison Between Preoperative Methadone and Buprenorphine Use on Postoperative Opioid Requirement: A Retrospective Cohort Study.

OBJECTIVES: Buprenorphine is a partial agonist at mu-opioid receptors and competes for these receptors with other opioids in vitro. Whether patients on buprenorphine maintenance require high doses of opioid analgesics to attain adequate postoperative pain control has not been determined. We evaluated differences in acute postoperative opioid consumption and pain burden between patients taking buprenorphine and those taking methadone preoperatively. MATERIALS AND METHODS: A retrospective review of medical records of 928 patients, of whom 195 were on buprenorphine and 733 were on methadone preoperatively, was performed. Among methadone and buprenorphine patients, 615 and 89, respectively, continued to receive the medications postoperatively. Buprenorphine patients were compared with methadone patients for the first 48 hours postoperatively with regard to acute opioid dose requirements (morphine milligram equivalents [MME] above their baseline buprenorphine and methadone doses) and time-weighted average (TWA) pain scores (using targeted maximum likelihood estimation). RESULTS: Opioid dose requirements for 48 hours postoperatively were 150 (22 to 297) (median [interquartile range]) and 220 [90 to 360] MME for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with a 59.9% lower postoperative MME (95% confidence interval: 46.6%-69.8%, P<0.0001) compared with methadone. Postoperative TWA pain scores for the first 48 hours were 5.0±2.7 (mean±SD), and 5.4±2.3 for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with a 0.37-point lower TWA pain score (95% confidence interval: 0.14-0.61, P=0.002) compared with methadone. DISCUSSION: Preoperative buprenorphine use was associated with >50% reduction in postoperative opioid dose requirement and a statistically significant, though clinically unimportant, reduction in acute pain burden in comparison to methadone. The study is limited by several important factors such as the exclusion of patients requiring intravenous patient-controlled analgesia, small number of patients were on higher dose of buprenorphine, and a large percentage of methadone patients were not on a stable dose of methadone yet.

An Acute Pain Service experience initiating methadone for opioid use disorder in hospitalized patients with acute pain.

OBJECTIVE: Inform readers of the use of a clinical pathway that includes initiation of methadone in hospitalized patients with acute pain who have untreated opioid use disorder (OUD). DESIGN: A retrospective chart review with frequency distributions and descriptive statistics calculated to describe demo-graphic and clinical characteristics of the sample. SETTING: Urban academic hospital. PATIENTS: One hundred twenty consecutive patients with untreated OUD cared for by the Acute Pain Service (APS). INTERVENTIONS: APS leadership spearheaded development of a clinical pathway to standardize pain management and optimize outcomes. The authors outline pathway development and describe 120 patients managed using this pathway, initiated on methadone for OUD. RESULTS: The sample included patients, average age 40 years, predominantly non-Hispanic white (74.2 percent), male (61.7 percent), unemployed (88.2 percent), and on Medicaid (84.2 percent). 96.7 percent had a history of heroin use, and 52.1 percent had engaged in previous medication-assisted treatment (MAT). Methadone or other opioids were held for signs of intoxication/sedation in 10.9 percent or for prolonged corrected QT interval in 1.7 percent. The majority received at least one other analgesic agent. For those prescribed opioids upon discharge, the average maximum morphine equivalent dose was 68.2 mg/day for approximately 3 days. 68.3 percent agreed to schedule post-discharge MAT, and of these, 68 percent attended their intake appointment. A small percentage (4.7 percent) left the hospital against medical advice. CONCLUSION: This pathway provides an example of an effective and safe response to address the opioid epidemic and pro-vide quality care to patients with OUD and pain.

A pedometer-based walking intervention in 45- to 75-year-olds, with and without practice nurse support: the PACE-UP three-arm cluster RCT.

BACKGROUND: Guidelines recommend walking to increase moderate to vigorous physical activity (MVPA) for health benefits. OBJECTIVES: To assess the effectiveness, cost-effectiveness and acceptability of a pedometer-based walking intervention in inactive adults, delivered postally or through dedicated practice nurse physical activity (PA) consultations. DESIGN: Parallel three-arm trial, cluster randomised by household. SETTING: Seven London-based general practices. PARTICIPANTS: A total of 11,015 people without PA contraindications, aged 45-75 years, randomly selected from practices, were invited. A total of 6399 people were non-responders, and 548 people self-reporting achieving PA guidelines were excluded. A total of 1023 people from 922 households were randomised to usual care (n = 338), postal intervention (n = 339) or nurse support (n = 346). The recruitment rate was 10% (1023/10,467). A total of 956 participants (93%) provided outcome data. INTERVENTIONS: Intervention groups received pedometers, 12-week walking programmes advising participants to gradually add '3000 steps in 30 minutes' most days weekly and PA diaries. The nurse group was offered three dedicated PA consultations. MAIN OUTCOME MEASURES: The primary and main secondary outcomes were changes from baseline to 12 months in average daily step counts and time in MVPA (in ≥ 10-minute bouts), respectively, from 7-day accelerometry. Individual resource-use data informed the within-trial economic evaluation and the Markov model for simulating long-term cost-effectiveness. Qualitative evaluations assessed nurse and participant views. A 3-year follow-up was conducted. RESULTS: Baseline average daily step count was 7479 [standard deviation (SD) 2671], average minutes per week in MVPA bouts was 94 minutes (SD 102 minutes) for those randomised. PA increased significantly at 12 months in both intervention groups compared with the control group, with no difference between interventions; additional steps per day were 642 steps [95% confidence interval (CI) 329 to 955 steps] for the postal group and 677 steps (95% CI 365 to 989 steps) for nurse support, and additional MVPA in bouts (minutes per week) was 33 minutes per week (95% CI 17 to 49 minutes per week) for the postal group and 35 minutes per week (95% CI 19 to 51 minutes per week) for nurse support. Intervention groups showed no increase in adverse events. Incremental cost per step was 19p and £3.61 per minute in a ≥ 10-minute MVPA bout for nurse support, whereas the postal group took more steps and cost less than the control group. The postal group had a 50% chance of being cost-effective at a £20,000 per quality-adjusted life-year (QALY) threshold within 1 year and had both lower costs [-£11M (95% CI -£12M to -£10M) per 100,000 population] and more QALYs [759 QALYs gained (95% CI 400 to 1247 QALYs)] than the nurse support and control groups in the long term. Participants and nurses found the interventions acceptable and enjoyable. Three-year follow-up data showed persistent intervention effects (nurse support plus postal vs. control) on steps per day [648 steps (95% CI 272 to 1024 steps)] and MVPA bouts [26 minutes per week (95% CI 8 to 44 minutes per week)]. LIMITATIONS: The 10% recruitment level, with lower levels in Asian and socioeconomically deprived participants, limits the generalisability of the findings. Assessors were unmasked to the group. CONCLUSIONS: A primary care pedometer-based walking intervention in 45- to 75-year-olds increased 12-month step counts by around one-tenth, and time in MVPA bouts by around one-third, with similar effects for the nurse support and postal groups, and persistent 3-year effects. The postal intervention provides cost-effective, long-term quality-of-life benefits. A primary care pedometer intervention delivered by post could help address the public health physical inactivity challenge. FUTURE WORK: Exploring different recruitment strategies to increase uptake. Integrating the Pedometer And Consultation Evaluation-UP (PACE-UP) trial with evolving PA monitoring technologies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98538934. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 37. See the NIHR Journals Library website for further project information.

Effect of a Primary Care Walking Intervention with and without Nurse Support on Physical Activity Levels in 45- to 75-Year-Olds: The Pedometer And Consultation Evaluation (PACE-UP) Cluster Randomised Clinical Trial.

BACKGROUND: Pedometers can increase walking and moderate-to-vigorous physical activity (MVPA) levels, but their effectiveness with or without support has not been rigorously evaluated. We assessed the effectiveness of a pedometer-based walking intervention in predominantly inactive adults, delivered by post or through primary care nurse-supported physical activity (PA) consultations. METHODS AND FINDINGS: A parallel three-arm cluster randomised trial was randomised by household, with 12-mo follow-up, in seven London, United Kingdom, primary care practices. Eleven thousand fifteen randomly selected patients aged 45-75 y without PA contraindications were invited. Five hundred forty-eight self-reporting achieving PA guidelines were excluded. One thousand twenty-three people from 922 households were randomised between 2012-2013 to one of the following groups: usual care (n = 338); postal pedometer intervention (n = 339); and nurse-supported pedometer intervention (n = 346). Of these, 956 participants (93%) provided outcome data (usual care n = 323, postal n = 312, nurse-supported n = 321). Both intervention groups received pedometers, 12-wk walking programmes, and PA diaries. The nurse group was offered three PA consultations. Primary and main secondary outcomes were changes from baseline to 12 mo in average daily step-counts and time in MVPA (in ≥10-min bouts), respectively, measured objectively by accelerometry. Only statisticians were masked to group. Analysis was by intention-to-treat. Average baseline daily step-count was 7,479 (standard deviation [s.d.] 2,671), and average time in MVPA bouts was 94 (s.d. 102) min/wk. At 12 mo, mean steps/d, with s.d. in parentheses, were as follows: control 7,246 (2,671); postal 8,010 (2,922); and nurse support 8,131 (3,228). PA increased in both intervention groups compared with the control group; additional steps/d were 642 for postal (95% CI 329-955) and 677 for nurse support (95% CI 365-989); additional MVPA in bouts (min/wk) were 33 for postal (95% CI 17-49) and 35 for nurse support (95% CI 19-51). There were no significant differences between the two interventions at 12 mo. The 10% (1,023/10,467) recruitment rate was a study limitation. CONCLUSIONS: A primary care pedometer-based walking intervention in predominantly inactive 45- to 75-y-olds increased step-counts by about one-tenth and time in MVPA in bouts by about one-third. Nurse and postal delivery achieved similar 12-mo PA outcomes. A primary care pedometer intervention delivered by post or with minimal support could help address the public health physical inactivity challenge. CLINICAL TRIAL REGISTRATION: isrctn.com ISRCTN98538934.

Opioid risk assessment in palliative medicine.

Pain management with opioids is an integral part of palliative medicine. As the doses and durations of opioid therapy increase, the inherent risks of opioid therapy rise. Although opioids are effective analgesics, they bring with them complex medical and psychological side effects. Aberrant behavior is dangerous and can be difficult to identify as it results in a splitting in the goals of treatment between the patient and providers. One effective strategy in preventing that situation is through the early identification of at-risk patients. There are several tools that can help identify patients at higher risk of addiction and aberrant behaviors during opioid therapy. Structured use of these tools in conjunction with the clinic exam, regular follow-up visits, and lab testing can further reduce patient risk and improve success in opioid therapy. This article will review the background behind a structured strategy for opioid risk assessment using the Opioid Risk Tool, SOAPP-R, and DIRE tools. In addition, example aberrant behaviors and follow-up strategies will be reviewed. It will be demonstrated that careful screening and follow-up allow risk factors to be recognized and addressed early.

Empowering and protecting children by enhancing knowledge, skills and well-being: A randomized trial of Learn to BE SAFE with Emmy.

Australia needs effective programs to protect children and prevent abuse, but there is little information available for policymakers or families. Using a randomized controlled trial, Learn to BE SAFE with Emmy, a school-based protection program for young children designed by Act for Kids, was evaluated to determine its effectiveness for promoting young children's knowledge and skills. Grade one children (n=245) from 15 classrooms across 5 primary schools completed assessment measures. A subset of these children received the program (n=131) or acted as a comparison group (n=114). Parents (n=72) completed questionnaires about their child's participation in the program. When compared with children who had not received the program, children who completed Learn to BE SAFE with Emmy demonstrated increased knowledge of interpersonal safety and were more likely to choose a safe response option to hypothetical unsafe scenarios 6 months after participation than at both pre- and post-intervention. Parents reported their children who participated used more safety strategies immediately and 6 months after participation compared to pre-intervention. Outcomes can assist in guiding future policies around the prevention of child abuse and protect the well-being of Australian children.

Multimodal Treatment of Chronic Pain.

Most patients with chronic pain receive multimodal treatment. There is scant literature to guide us, but when approaching combination pharmacotherapy, the practitioner and patient must weigh the benefits with the side effects; many medications have modest effect yet carry significant side effects that can be additive. Chronic pain often leads to depression, anxiety, and deconditioning, which are targets for treatment. Structured interdisciplinary programs are beneficial but costly. Interventions have their place in the treatment of chronic pain and should be a part of a multidisciplinary treatment plan. Further research is needed to validate many common combination treatments.

PACE-UP (Pedometer and consultation evaluation--UP)--a pedometer-based walking intervention with and without practice nurse support in primary care patients aged 45-75 years: study protocol for a randomised controlled trial.

BACKGROUND: Most adults do not achieve the 150 minutes weekly of at least moderate intensity activity recommended for health. Adults' most common physical activity (PA) is walking, light intensity if strolling, moderate if brisker. Pedometers can increase walking; however, most trials have been short-term, have combined pedometer and support effects, and have not reported PA intensity. This trial will investigate whether pedometers, with or without nurse support, can help less active 45-75 year olds to increase their PA over 12 months. DESIGN: Primary care-based 3-arm randomized controlled trial with 12-month follow-up and health economic and qualitative evaluations. PARTICIPANTS: Less active 45-75 year olds (n = 993) will be recruited by post from six South West London general practices, maximum of two per household and households randomised into three groups. Step-count and time spent at different PA intensities will be assessed for 7 days at baseline, 3 and 12 months by accelerometer. Questionnaires and anthropometric assessments will be completed. INTERVENTION: The pedometer-alone group will be posted a pedometer (Yamax Digi-Walker SW-200), handbook and diary detailing a 12-week pedometer-based walking programme, using targets from their baseline assessment. The pedometer-plus-support group will additionally receive three practice nurse PA consultations. The handbook, diary and consultations include behaviour change techniques (e.g., self-monitoring, goal-setting, relapse prevention planning). The control group will receive usual care. OUTCOMES: Changes in average daily step-count (primary outcome), time spent sedentary and in at least moderate intensity PA weekly at 12 months, measured by accelerometry. Other outcomes include change in body mass index, body fat, self-reported PA, quality of life, mood and adverse events. Cost-effectiveness will be assessed by the incremental cost of the intervention to the National Health Service and incremental cost per change in step-count and per quality adjusted life year. Qualitative evaluations will explore reasons for trial non-participation and the interventions' acceptability. DISCUSSION: The PACE-UP trial will determine the effectiveness and cost-effectiveness of a pedometer-based walking intervention delivered by post or practice nurse to less active primary care patients aged 45-75 years old. Approaches to minimise bias and challenges anticipated in delivery will be discussed. TRIAL REGISTRATION: ISRCTN98538934.