Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Independent infections of porcine deltacoronavirus among Haitian children.

Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, the emergence of coronavirus in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae, human infections reported so far have been limited to alphacoronaviruses and betacoronaviruses3-5. Here we identify porcine deltacoronavirus strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the genes encoding Nsp15 and the spike glycoprotein. In particular, structural analysis predicts that one of the changes in the spike S1 subunit, which contains the receptor-binding domain, may affect the flexibility of the protein and its binding to the host cell receptor. Our findings highlight the potential for evolutionary change and adaptation leading to human infections by coronaviruses outside of the previously recognized human-associated coronavirus groups, particularly in settings where there may be close human-animal contact.

Mapping the differential impact of spontaneous and conversational laughter on brain and mind: an fMRI study in autism.

Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.

The #HOPE4LIVER Single-Arm Pivotal Trial for Histotripsy of Primary and Metastatic Liver Tumors.

Background Histotripsy is a nonthermal, nonionizing, noninvasive, focused US technique that relies on cavitation for mechanical tissue breakdown at the focal point. Preclinical data have shown its safety and technical success in the ablation of liver tumors. Purpose To evaluate the safety and technical success of histotripsy in destroying primary or metastatic liver tumors. Materials and Methods The parallel United States and European Union and England #HOPE4LIVER trials were prospective, multicenter, single-arm studies. Eligible patients were recruited at 14 sites in Europe and the United States from January 2021 to July 2022. Up to three tumors smaller than 3 cm in size could be treated. CT or MRI and clinic visits were performed at 1 week or less preprocedure, at index-procedure, 36 hours or less postprocedure, and 30 days postprocedure. There were co-primary end points of technical success of tumor treatment and absence of procedure-related major complications within 30 days, with performance goals of greater than 70% and less than 25%, respectively. A two-sided 95% Wilson score CI was derived for each end point. Results Forty-four participants (21 from the United States, 23 from the European Union or England; 22 female participants, 22 male participants; mean age, 64 years ± 12 [SD]) with 49 tumors were enrolled and treated. Eighteen participants (41%) had hepatocellular carcinoma and 26 (59%) had non-hepatocellular carcinoma liver metastases. The maximum pretreatment tumor diameter was 1.5 cm ± 0.6 and the maximum post-histotripsy treatment zone diameter was 3.6 cm ± 1.4. Technical success was observed in 42 of 44 treated tumors (95%; 95% CI: 84, 100) and procedure-related major complications were reported in three of 44 participants (7%; 95% CI: 2, 18), both meeting the performance goal. Conclusion The #HOPE4LIVER trials met the co-primary end-point performance goals for technical success and the absence of procedure-related major complications, supporting early clinical adoption. Clinical trial registration nos. NCT04572633, NCT04573881 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Nezami and Georgiades in this issue.

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

Combination and Optimal Sequencing of Systemic and Locoregional Therapies in Hepatocellular Carcinoma: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

Hepatocellular carcinoma, historically, has had a poor prognosis with very few systemic options. Furthermore, most patients at diagnosis are not surgical candidates. Therefore, locoregional therapy (LRT) has been widely used, with strong data supporting its use. Over the last 15 years, there has been progress in the available systemic agents. This has led to the updated Barcelona Clinic Liver Cancer (BCLC) algorithm's inclusion of these new systemic agents, with advocacy of earlier usage in those who progress on LRT or have tumor characteristics that make them less likely to benefit from LRT. However, neither the adjunct of LRT nor the specific sequencing of combination therapies is addressed directly. This Research Consensus Panel sought to highlight research priorities pertaining to the combination and optimal sequencing of LRT and systemic therapy, assessing the greatest needs across BCLC stages.

Effects of state opioid prescribing laws on rates of fatal crashes in the USA.

BACKGROUND: State opioid prescribing cap laws, mandatory prescription drug monitoring programme query or enrolment laws and pill mill laws have been implemented across US states to curb high-risk opioid prescribing. Previous studies have measured the impact of these laws on opioid use and overdose death, but no prior work has measured the impact of these laws on fatal crashes in a multistate analysis. METHODS: To study the association between state opioid prescribing laws and fatal crashes, 13 treatment states that implemented a single law of interest in a 4-year period were identified, together with unique groups of control states for each treatment state. Augmented synthetic control analyses were used to estimate the association between each state law and the overall rate of fatal crashes, and the rate of opioid-involved fatal crashes, per 100 000 licensed drivers in the state. Fatal crash data came from the Fatality Analysis Reporting System. RESULTS: Results of augmented synthetic control analyses showed small-in-magnitude, non-statistically significant changes in all fatal crash outcomes attributable to the 13 state opioid prescribing laws. While non-statistically significant, results attributable to the laws varied in either direction-from an increase of 0.14 (95% CI, -0.32 to 0.60) fatal crashes per 100 000 licensed drivers attributable to Ohio's opioid prescribing cap law, to a decrease of 0.30 (95% CI, -1.17 to 0.57) fatal crashes/100 000 licensed drivers attributable to Mississippi's pill mill law. CONCLUSION: These findings suggest that state-level opioid prescribing laws are insufficient to help address rising rates of fatally injured drivers who test positive for opioids. Other options will be needed to address this continuing injury problem.

'Quitlink': Outcomes of a randomised controlled trial of peer researcher facilitated referral to a tailored quitline tobacco treatment for people receiving mental health services.

OBJECTIVE: The aim of this study was to test the effectiveness of a tailored quitline tobacco treatment ('Quitlink') among people receiving support for mental health conditions. METHODS: We employed a prospective, cluster-randomised, open, blinded endpoint design to compare a control condition to our 'Quitlink' intervention. Both conditions received a brief intervention delivered by a peer researcher. Control participants received no further intervention. Quitlink participants were referred to a tailored 8-week quitline intervention delivered by dedicated Quitline counsellors plus combination nicotine replacement therapy. The primary outcome was self-reported 6 months continuous abstinence from end of treatment (8 months from baseline). Secondary outcomes included additional smoking outcomes, mental health symptoms, substance use and quality of life. A within-trial economic evaluation was conducted. RESULTS: In total, 110 participants were recruited over 26 months and 91 had confirmed outcomes at 8 months post baseline. There was a difference in self-reported prolonged abstinence at 8-month follow-up between Quitlink (16%, n = 6) and control (2%, n = 1) conditions, which was not statistically significant (OR = 8.33 [0.52, 132.09] p = 0.131 available case). There was a significant difference in favour of the Quitlink condition on 7-day point prevalence at 2 months (OR = 8.06 [1.27, 51.00] p = 0.027 available case). Quitlink costs AU$9231 per additional quit achieved. CONCLUSION: The Quitlink intervention did not result in significantly higher rates of prolonged abstinence at 8 months post baseline. However, engagement rates and satisfaction with the 'Quitlink' intervention were high. While underpowered, the Quitlink intervention shows promise. A powered trial to determine its effectiveness for improving long-term cessation is warranted.

Maternal Sepsis.

Sepsis is the second leading cause of pregnancy-related mortality in the United States. Early recognition, treatment, and escalation of care for the obstetric patient affected by sepsis mitigate the risk of mortality and improve patient outcomes. In this article, we provide an overview of maternal sepsis and address topics of maternal pathophysiology, early warning signs, diagnostic criteria, early goal-directed therapy, and contemporary critical care practices. We also present an overview of common etiologies of maternal sepsis and suggested treatment approaches.

Implementing peer support into practice in mental health services: a qualitative comparative case study.

BACKGROUND: Peer workers are people with personal experience of mental distress, employed within mental health services to support others with similar experiences. Research has identified a range of factors that might facilitate or hinder the introduction of new peer worker roles into mental health services. While there is mixed evidence for the effectiveness of peer worker delivered interventions, there are no studies exploring how implementation might be associated with effect. METHODS: This was a qualitative comparative case study using data from interviews with 20 peer workers and their five supervisors. Peer workers delivered peer support for discharge from inpatient to community mental health care as part of a randomised controlled trial. In the trial, level of participant engagement with peer support was associated with better outcome (hospital readmission). Study sites with higher levels of engagement also had higher scores on a measure of fidelity to peer support principles. We compared data from sites with contrasting levels of engagement and fidelity using an analytical framework derived from implementation theory. RESULTS: In high engagement-high fidelity sites, there was regular work with clinical teams preparing for working alongside peer workers, and a positive relationship between staff on inpatient wards and peer workers. The supervisor role was well resourced, and delivery of peer support was highly consistent with the intervention manual. In low engagement-low fidelity sites peer workers were employed in not-for-profit organisations to support people using public mental health services and in rural areas. Supervisors faced constrained resources and experienced barriers to joint working between organisations. In these sites, peer workers could experience challenging relationships with ward staff. Issues of geography and capacity limited opportunities for supervision and team-building, impacting consistency of delivery. CONCLUSIONS: This study provides clear indication that implementation can impact delivery of peer support, with implications for engagement and, potentially, outcomes of peer worker interventions. Resourcing issues can have knock-on effects on consistency of delivery, alongside challenges of access, authority and relationship with clinical teams, especially where peer workers were employed in not-for-profit organisations. Attention needs to be paid to the impact of geography on implementation. TRIAL REGISTRATION: ISRCTN registry number ISRCTN10043328, registered 28 November 2016.

Effects of U.S. State Medical Cannabis Laws on Treatment of Chronic Noncancer Pain.

BACKGROUND: State medical cannabis laws may lead patients with chronic noncancer pain to substitute cannabis in place of prescription opioid or clinical guideline-concordant nonopioid prescription pain medications or procedures. OBJECTIVE: To assess effects of state medical cannabis laws on receipt of prescription opioids, nonopioid prescription pain medications, and procedures for chronic noncancer pain. DESIGN: Using data from 12 states that implemented medical cannabis laws and 17 comparison states, augmented synthetic control analyses estimated laws' effects on receipt of chronic noncancer pain treatment, relative to predicted treatment receipt in the absence of the law. SETTING: United States, 2010 to 2022. PARTICIPANTS: 583 820 commercially insured adults with chronic noncancer pain. MEASUREMENTS: Proportion of patients receiving any opioid prescription, nonopioid prescription pain medication, or procedure for chronic noncancer pain; volume of each treatment type; and mean days' supply and mean morphine milligram equivalents per day of prescribed opioids, per patient in a given month. RESULTS: In a given month during the first 3 years of law implementation, medical cannabis laws led to an average difference of 0.05 percentage points (95% CI, -0.12 to 0.21 percentage points), 0.05 percentage points (CI, -0.13 to 0.23 percentage points), and -0.17 percentage points (CI, -0.42 to 0.08 percentage points) in the proportion of patients receiving any opioid prescription, any nonopioid prescription pain medication, or any chronic pain procedure, respectively, relative to what we predict would have happened in that month had the law not been implemented. LIMITATIONS: This study used a strong nonexperimental design but relies on untestable assumptions involving parallel counterfactual trends. Statistical power is limited by the finite number of states. Results may not generalize to noncommercially insured populations. CONCLUSION: This study did not identify important effects of medical cannabis laws on receipt of opioid or nonopioid pain treatment among patients with chronic noncancer pain. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse.

"Sorry for Holding You Up": Surgeons' Apologies for Lateness in Clinic Settings.

Doctors running late may convey a lack of respect which can impair the therapeutic relationship. This study examines how surgeons address lateness in consultations with patients. We analyzed 52 consultation recordings from a range of surgical specialties in an Australian metropolitan setting. Conversation analysis was used to analyze interactional sequences where lateness was addressed. Six sequences were identified within four recordings. The two consultations with two apologies include a surgeon and registrar apologizing in a neurosurgical consultation and a surgeon apologizing twice within a colorectal consultation. Apologies were either accepted or responded to with an account for not accepting the apology. When these accounts were made, consultations could only progress when patients accepted an explanation for lateness or the degree of complainability about lateness was reduced. The infrequent occurrence of apologies for lateness, and the way in which these sequences unfolded when they did occur, suggest that there is greater acceptability of lateness for surgeons than in ordinary social situations.

Examining the Effectiveness of Social Media for the Dissemination of Research Evidence for Health and Social Care Practitioners: Systematic Review and Meta-Analysis.

BACKGROUND: Social media use has potential to facilitate the rapid dissemination of research evidence to busy health and social care practitioners. OBJECTIVE: This study aims to quantitatively synthesize evidence of the between- and within-group effectiveness of social media for dissemination of research evidence to health and social care practitioners. It also compared effectiveness between different social media platforms, formats, and strategies. METHODS: We searched electronic databases for articles in English that were published between January 1, 2010, and January 10, 2023, and that evaluated social media interventions for disseminating research evidence to qualified, postregistration health and social care practitioners in measures of reach, engagement, direct dissemination, or impact. Screening, data extraction, and risk of bias assessments were carried out by at least 2 independent reviewers. Meta-analyses of standardized pooled effects were carried out for between- and within-group effectiveness of social media and comparisons between platforms, formats, and strategies. Certainty of evidence for outcomes was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. RESULTS: In total, 50 mixed-quality articles that were heterogeneous in design and outcome were included (n=9, 18% were randomized controlled trials [RCTs]). Reach (measured in number of practitioners, impressions, or post views) was reported in 26 studies. Engagement (measured in likes or post interactions) was evaluated in 21 studies. Direct dissemination (measured in link clicks, article views, downloads, or altmetric attention score) was analyzed in 23 studies (8 RCTs). Impact (measured in citations or measures of thinking and practice) was reported in 13 studies. Included studies almost universally indicated effects in favor of social media interventions, although effect sizes varied. Cumulative evidence indicated moderate certainty of large and moderate between-group effects of social media interventions on direct dissemination (standardized mean difference [SMD] 0.88; P=.02) and impact (SMD 0.76; P<.001). After social media interventions, cumulative evidence showed moderate certainty of large within-group effects on reach (SMD 1.99; P<.001), engagement (SMD 3.74; P<.001), and direct dissemination (SMD 0.82; P=.004) and low certainty of a small within-group effect on impacting thinking or practice (SMD 0.45; P=.02). There was also evidence for the effectiveness of using multiple social media platforms (including Twitter, subsequently rebranded X; and Facebook), images (particularly infographics), and intensive social media strategies with frequent, daily posts and involving influential others. No included studies tested the dissemination of research evidence to social care practitioners. CONCLUSIONS: Social media was effective for disseminating research evidence to health care practitioners. More intense social media campaigns using specific platforms, formats, and strategies may be more effective than less intense interventions. Implications include recommendations for effective dissemination of research evidence to health care practitioners and further RCTs in this field, particularly investigating the dissemination of social care research. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022378793; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=378793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/45684.

Phosphorus uptake and release patterns in overwintering constructed floating wetlands.

Understanding nutrient cycling patterns in plants deployed within constructed floating wetlands (CFWs) is critical for improving CFWs' design and management practices. This study evaluated phosphorus (P) uptake and release patterns during fall/winter plant senescence and spring regrowth. Two mesocosm-scale CFW experiments were conducted characterizing plant growth, plant tissue P levels, and water quality (nutrients and phytoplankton). Experiment 1 quantified P uptake during spring regrowth after overwintering, and experiment 2 quantified P release during fall senescence. Plant treatments (CFWs with Pontederia cordata or Juncus effusus) were compared to an open-water control. In spring, J. effusus removed 0.056 g P m-2 d-1 (19.4% of the load), P. cordata removed 0.034 g P m-2 d-1 (10%), and the open-water control removed 0.03 g P m-2 d-1 (10%). In fall, J. effusus fixed 0.008 g P m-2 d-1 (2.1% of the load), P. cordata released 0.014 g P m-2 d-1 (-2.1%), and controls fixed 0.023 g P m-2 d-1 (6.3%). P was consistently released during the fall experiment and occasionally released in the spring experiment, likely from senescing plant tissues (fall) and from roots sloughing after new root growth (spring). Results demonstrate the potential for multi-season deployment of CFWs using J. effusus for reducing P loads year-round.

Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Developing evidence-based guidelines for the safety of symptomatic drugs in multiple sclerosis during pregnancy and breastfeeding: A systematic review and Delphi consensus.

BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in people of reproductive age, many of whom will become pregnant following diagnosis. Although many women report an improvement in symptoms and relapses during pregnancy, symptoms such as fatigue and spasticity are commonly reported and can worsen. Prescribing medications during pregnancy and breastfeeding presents unique challenges and guidance on the use of symptomatic therapies is limited. OBJECTIVES: This paper aims to provide a consensus on the current evidence base to facilitate informed decision-making and optimise pre-conception counselling. METHODS: A list of most commonly prescribed medications for symptom management in MS was created using pregnancy and MS-related READ codes in the Welsh GP Dataset, followed by a review by MS neurologists. RESULTS: A final list of 24 medications was generated for review. Searches were performed on each medication, and evidence graded using standardised criteria. Evidence-based recommendations were developed and distributed to experts in the field and revised according to feedback using modified Delphi criteria. CONCLUSIONS: Our guidelines provide evidence-based recommendations on the safety of symptomatic therapies during pregnancy and breastfeeding for general practitioners and specialist teams working with people with MS who are hoping to embark on pregnancy or are currently pregnant. Individual risk-benefit ratios should be considered during pre-conception counselling to optimise symptom burden and minimise harm to both parent and child.

Comparison of Fibered versus Nonfibered Coils for Venous Embolization in an Ovine Model.

PURPOSE: To compare nylon fibered (F) with nonfibered (NF) coils for embolization in an ovine venous model. MATERIALS AND METHODS: Four- to 8-mm-diameter, 0.035-inch F and NF coils were deployed in 24 veins in 6 sheep. The number of coils, total length of the coils, and length of implanted coil pack required to achieve complete stasis were recorded, as were vessel diameter, radiation dose, ease of packing, damage to embolized vessel, and time to stasis. Venography at 1 and 3 months was used to assess the migration and durability of vessel occlusion. Veins were harvested at 3 months. RESULTS: F and NF coils were deployed in 24 veins, and stasis was achieved, without immediate coil migration or vessel damage. The mean numbers of F and NF coils per vein were 5 and 8.75, respectively (P = .007). The vessel diameter between the groups was not statistically different. The total coil length (F, 70 cm vs NF, 122.5 cm; P = .0007), coil pack length (F, 29.3 mm vs NF, 39.4 mm; P = .003), time to stasis (F, 5.3 minutes vs NF, 9.0 minutes; P = .008), and radiation dose (F, 25.3 mGy vs NF, 34.9 mGy; P = .037) were significantly different between the groups. Challenges with the animal model prevented conclusive long-term results. Migration occurred with 8 of 11 (72%) coil packs in the femoral veins and 0 of 13 (0%) coil packs in the internal iliac and deep femoral veins. Venography demonstrated that of 16 remaining coil packs, 11 were occluded at 1 month and 10 remained occluded at 3 months. CONCLUSIONS: Fibers allow for significantly fewer coils to achieve immediate venous occlusion.

Vertebral Body Bone Ablation with and without a Saline-Infused System in a Porcine Model.

The purpose of this study was to evaluate the effect of bone radiofrequency (RF) ablation in the spine with and without controlled saline infusion. RF ablation with and without controlled saline infusion was performed in the vertebral bodies of 2 swine with real-time temperature and impedance recordings. Histology and magnetic resonance (MR) imaging results were reviewed to evaluate the ablation zone size, breach of spinal canal, and damage to the spinal cord and nerves. There was no difference in maximum and mean temperatures between controlled saline and noninfusion groups. The impedance and power output were not significantly different between the groups. MR imaging and histopathology demonstrated ablation zones confined within the vertebral bodies. Ablation zone size correlated on MR imaging and histopathology by groups. No ablation effect, breach of posterior cortex, spinal cord injury, or nerve or ganglion injury was observed at any level using MR imaging or histology. Controlled saline infusion does not appear to impact bone RF ablation and, specifically, does not increase the ablation zone size.

Effects of state opioid prescribing cap laws on providers' opioid prescribing patterns among patients with chronic non-cancer pain.

Prior work suggests opioid prescribing cap laws are not associated with changes in opioid prescribing among patients with chronic pain. It is unknown how these effects differ by provider specialty, provider opioid prescribing volume, or patient insurer. This study assessed effects of state opioid prescribing cap laws on opioid prescribing among providers of patients with chronic non-cancer pain, by high volume prescribing, provider specialty, and patient insurer. We identified 224,290 providers of patients with low back pain, fibromyalgia, or headache from the IQVIA administrative database. Using a difference-in-differences approach, we examined impacts of opioid prescribing cap laws implemented between 2016 and 2018 on the annual proportion of a provider's patient panel who received any opioid prescription, as well as on dose and duration of opioid prescriptions. For providers overall, high volume prescribers, all specialties, and patient insurance categories, prescribing cap laws were associated with non-significant changes of <1.0, 1.5, and 3.5 percentage points in the proportion of chronic non-cancer patients receiving any opioid prescription, a prescription with 7 days' supply, or with >50 morphine milligram equivalents (MME)/day, per year, respectively. There were two exceptions with high dose prescribing: prescribing cap laws were associated with a 1.5 percentage point increase in the proportion of high-volume prescribers' patient panel receiving an opioid prescription with ≥50 MME/day, and a 3.0 percentage point decrease in the same measure among surgeons. Among nearly all measured subgroups of providers and patient insurers, opioid prescribing cap laws were not associated with changes in opioid prescribing.

Assessing the reliability and cross-sectional and longitudinal validity of fifteen bioelectrical impedance analysis devices.

The purpose of this investigation was to expand upon the limited existing research examining the test-retest reliability, cross-sectional validity and longitudinal validity of a sample of bioelectrical impedance analysis (BIA) devices as compared with a laboratory four-compartment (4C) model. Seventy-three healthy participants aged 19-50 years were assessed by each of fifteen BIA devices, with resulting body fat percentage estimates compared with a 4C model utilising air displacement plethysmography, dual-energy X-ray absorptiometry and bioimpedance spectroscopy. A subset of thirty-seven participants returned for a second visit 12-16 weeks later and were included in an analysis of longitudinal validity. The sample of devices included fourteen consumer-grade and one research-grade model in a variety of configurations: hand-to-hand, foot-to-foot and bilateral hand-to-foot (octapolar). BIA devices demonstrated high reliability, with precision error ranging from 0·0 to 0·49 %. Cross-sectional validity varied, with constant error relative to the 4C model ranging from -3·5 (sd 4·1) % to 11·7 (sd 4·7) %, standard error of the estimate values of 3·1-7·5 % and Lin's concordance correlation coefficients (CCC) of 0·48-0·94. For longitudinal validity, constant error ranged from -0·4 (sd 2·1) % to 1·3 (sd 2·7) %, with standard error of the estimate values of 1·7-2·6 % and Lin's CCC of 0·37-0·78. While performance varied widely across the sample investigated, select models of BIA devices (particularly octapolar and select foot-to-foot devices) may hold potential utility for the tracking of body composition over time, particularly in contexts in which the purchase or use of a research-grade device is infeasible.