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Abstract Background Universal skin cancer screening for the Latino population is impractical. Objectives We focused on melanoma education by conducting an online education campaign and collected baseline, postintervention, and 3‐month follow‐up surveys to assess sun‐protective behaviors. Methods Participants were recruited through (1) social media ads and (2) emails sent to Mayo Clinic Latino patients. Results Total social media impressions were 508,442 and 413,007 in Spanish and English, respectively. There were 18,790 and 11,731 clicks for the Spanish and English ads, respectively, resulting in 175 baseline survey responses. From email distribution, 4151 emails translated to 219 baseline participants. Of the 394 patients who participated in the baseline survey, 89 completed the postintervention survey, and 57 completed the 3‐month follow‐up survey (28 from social media and 29 Mayo Clinic patients). Social media provides a unique opportunity for the medical community to promote melanoma education, distribute content quickly, and provide medical education in disparate healthcare areas. Our Spanish ad click‐through rate was 3.70% compared to 2.84% for English. The click‐to‐action rate was 0.57%, and the baseline‐to‐completion rate was 16.00%. Conclusions Our study suggests social media could be a unique tool for distributing melanoma educational materials to Latino populations. The click‐through rates for this study were several‐fold higher than other studies' reported click‐through rates (0.4%–0.93%). It is important to develop melanoma educational materials that are culturally relevant and focused on Latino populations that can provide persistent improvements in mitigating melanoma risk behaviors such as sunscreen application and self‐skin examinations.

Spinal muscular atrophy is a neurodegenerative disorder resulting from the irreversible loss of anterior horn cells secondary to homozygous mutations in the survival motor neuron gene SMN1. Gene replacement therapy using a recombinant adeno-associated virus 9 vector containing an SMN1 gene construct, onasemnogene abeparvovec-xioi, was approved by the US Food and Drug Administration in May 2019. Subacute mild elevation of liver function tests following infusion has since been shown to be a common adverse event. Additionally, there have been case reports of liver failure following administration of this therapy and two reported patient deaths. While these adverse events are relatively common, they have not been reported in the youngest treated patients. We present two cases of subacute severe elevation of liver function tests >10–20 times the upper limit of normal, without progression to liver failure, following onasemnogene abeparvovec administration in young infants less than 4 weeks old. Potential mechanisms of injury, management, and implications for future treatment with onasemnogene abeparvovec and other adeno-associated virus vector gene therapies are discussed.

Abstract Background Previous literature on cutaneous squamous cell carcinoma (cSCC) suggests that the incidence, rate of metastasis, and tumour severity of cSCC are higher in immunosuppressed patients than in immunocompetent patients. However, current literature lacks an extensive comparison of cSCC clinical characteristics and outcomes in immunosuppressed patients. Objectives We compared cSCC tumour characteristics and disease‐related outcomes to help guide the clinical management of immunosuppressed patients. Methods We conducted a retrospective review of histopathologic and clinical data from 935 cSCC cases (19.5% immunosuppressed) from the Mayo Clinic. Results Immunosuppression was associated with younger age (69.3 vs. 74.8 years old, p

We reviewed invasive Nocardia infections in 3 noncontiguous geographic areas in the United States during 2011–2018. Among 268 patients with invasive nocardiosis, 48.2% were from Minnesota, 32.4% from Arizona, and 19.4% from Florida. Predominant species were N. nova complex in Minnesota (33.4%), N. cyriacigeorgica in Arizona (41.4%), and N. brasiliensis in Florida (17.3%). Transplant recipients accounted for 82/268 (30.6%) patients overall: 14 (10.9%) in Minnesota, 35 (40.2%) in Arizona, and 33 (63.5%) in Florida. Manifestations included isolated pulmonary nocardiosis among 73.2% of transplant and 84.4% of non–transplant patients and central nervous system involvement among 12.2% of transplant and 3.2% of non–transplant patients. N. farcinica (20.7%) and N. cyriacigeorgica (19.5%) were the most common isolates among transplant recipients and N. cyriacigeorgica (38.0%), N. nova complex (23.7%), and N. farcinica (16.1%) among non–transplant patients. Overall antimicrobial susceptibilities were similar across the 3 study sites.

Objective: To determine the diagnostic accuracy of the initial telestroke consultation in a large academic hub-and-spoke telemedicine network. Patients and Methods: This retrospective study includes all patients evaluated for cerebral ischemia through video telestroke consultation in a large academic hub-and-spoke telemedicine network from January 1, 2019 to December 31, 2020. A detailed chart review was conducted to identify the initial suspected diagnosis and final diagnosis. Cerebral ischemia was defined as acute ischemic stroke and transient ischemic attack. All other diagnoses were defined as stroke mimics. Data were organized into continuous and categorical variables. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, area under the curve (AUC), and likelihood ratio (LR+) for the telestroke-consultation diagnosis were calculated while using the final diagnosis as the gold standard diagnosis. Results: A total of 1043 patients met the inclusion criteria. The final diagnosis of cerebral ischemia was made in 63.5% of all patients (539 of the 1043 with acute ischemic stroke,123 of the 1043 with transient ischemic attack). Stroke mimic was diagnosed in 36.5% patients (381 of the 1043). The sensitivity and specificity of telestroke evaluation for diagnosis of cerebral ischemia were 97.1% and 81.4%, respectively. Positive predictive value was 90.1%, and negative predictive value was 94.2%. Overall diagnostic accuracy was 91.4%, with an LR+ of 5.21 and AUC of 0.89. Conclusion: This study highlights the high diagnostic accuracy of telestroke providers in diagnosing cerebral ischemia. Further research exploring the application of teleneurology in the nonstroke setting and other medical subspecialties is warranted.

Tools used for the identification, evaluation, and monitoring of concussion have not been sufficiently studied in youth or real-world settings. Normative and reliability data on sideline concussion assessment measures in the youth athlete population is needed. Pre-season normative data for 515 athletes (93.5% male) aged 5 to 16 on the Standardized Assessment of Concussion (SAC/SAC-Child), modified Balance Errors Scoring System (mBESS), Timed Tandem Gait (TTG), and the King–Devick Test (KDT) are provided. A total of 212 non-injured athletes repeated the measures post-season to assess test–retest reliability. Mean performance on the SAC-C, mBESS, TTG, and KDT tended to improve with age. KDT was the only measure that demonstrated good to excellent stability across age ranges (ICC = 0.758 to 0.941). Concentration was the only SAC/SAC-C subtest to demonstrate moderate test–retest stability (ICC = 0.503 to 0.706). TTG demonstrated moderate to good (ICC = 0.666 to 0.811) reliability. mBESS demonstrated poor to moderate reliability (ICC = −0.309 to 0.651). Commonly used measures of concussion vary regarding test–retest reliability in youth. The data support the use of at least annual sport concussion baseline assessments in the pediatric population to account for the evolution in performance as the child ages. Understanding the variation in the stability and the evolution of baseline performance will enable improved identification of possible injury.

Objective: To determine risk factors for nonelective emergency department visits (NEDVs) and whether primary care visits incorporating risk mitigation tools prevented NEDVs among patients using long-term opioid therapy (LOT). Patients and Methods: We retrospectively searched the electronic health records at Mayo Clinic primary care outpatient practices in Arizona and Florida in all of 2018 and 2019 for the records of individual adult patients using LOT. Patient and clinician demographic characteristics and patient risk factors were compared between patients with and without risk mitigation visits. Univariate and multivariable logistic regression was used to determine risk factors for NEDVs. Results: Among 457 patients using LOT identified during the study period, most were women (n=266, 58.2%), and the median age was 69 years. Long-term opioid therapy risk mitigation visits were performed equally by family medicine and internal medicine clinicians and by a significantly higher proportion of Florida clinicians than Arizona clinicians (87.0% vs 70.5%; P

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3–4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Abstract Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10−6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Abstract Background Prescribing benzodiazepines to patients taking chronic opioid analgesic therapy increases risks of adverse events. In 2016, the Centers for Disease Control and Prevention recommended avoidance of benzodiazepine prescribing concurrently with opioids, and various organizations have instituted similar guidelines. We aimed to determine the frequency and patterns of benzodiazepine prescribing at Mayo Clinic primary care (Community Internal Medicine, Family Medicine) clinics for patients taking chronic opioid analgesic therapy and the characteristics of patients receiving the prescriptions and providers administering them. Methods This retrospective observational study included adult patients taking chronic opioid analgesic therapy for 2 full years in 2018 and 2019 at Mayo Clinic primary care practices in Arizona and Florida. We assessed electronic health records for these individual patients to determine whether they received a benzodiazepine prescription during the study period and how frequently they received a prescription. Variations in prescriptions by provider specialty, location, and sex were studied. Documented data included receipt of a benzodiazepine prescription by patients with at-risk alcohol use or alcohol use disorder, depression, anxiety, chronic obstructive pulmonary disease, falls, and psychiatric referral. Data were compared between patients who received benzodiazepines and those who did not with the Kruskal-Wallis test or χ2 test, and the Wilcoxon signed rank test was used to assess whether the change in number of benzodiazepine prescriptions (2018 vs. 2019) was different from zero. Results Study participants (N = 457) were predominantly women (n = 266, 58.2%); median age was 69 years. In total, 148 patients (32.4%) received benzodiazepine prescription. These patients were more likely to be women (P = .046) and younger (P = .02). Mean percentage change was 176.9% (P

Abstract We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p

Summary: Patient-derived xenografts (PDXs) have clinical value but are time-, cost-, and labor-intensive and thus ill-suited for large-scale experiments. Here, we present a protocol to convert PDX tumors into PDxOs for long-term cultures amenable to moderate-throughput drug screens, including in-depth PDxO validation. We describe steps for PDxO preparation and mouse cell removal. We then detail PDxO validation and characterization and drug response assay. Our PDxO drug screening platform can predict therapy response in vivo and inform functional precision oncology for patients.For complete details on the use and execution of this protocol, please refer to Guillen et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

In the United States and around the world, newborns are screened on a population basis for conditions benefiting from pre-symptomatic diagnosis and treatment. The number of screened conditions continues to expand as novel technologies for screening, diagnosing, treating, and managing disease are discovered. While screening all newborns facilitates early diagnosis and treatment, most screened conditions are treatable but not curable. Patients identified by newborn screening often require lifelong medical management and community support to achieve the best possible outcome. To advance the long-term follow-up of infants identified through newborn screening (NBS), the Long-Term Follow-up Cares and Check Initiative (LTFU-Cares and Check) designed, implemented, and evaluated a system of longitudinal data collection and annual reporting engaging parents, clinical providers, and state NBS programs. The LTFU-Cares and Check focused on newborns identified with spinal muscular atrophy (SMA) through NBS and the longitudinal health information prioritized by parents and families. Pediatric neurologists who care for newborns with SMA entered annual data, and data tracking and visualization tools were delivered to state NBS programs with a participating clinical center. In this publication, we report on the development, use of, and preliminary results from the LTFU-Cares and Check Initiative, which was designed as a comprehensive model of LTFU. We also propose next steps for achieving the goal of a national system of LTFU for individuals with identified conditions by meaningfully engaging public health agencies, clinicians, parents, families, and communities.

Abstract Background There is controversy regarding the impact of delayed graft function (DGF) on kidney transplant outcomes. We hypothesize that the duration of DGF, rather than DGF itself, is associated with long-term kidney graft function. Methods We analyzed all deceased donor kidney transplants (DDKT) done at our center between 2008 to 2020. We determined factors associated with DGF duration. DGF duration was assessed at three 14-day intervals: 28 DGF days. We studied the impact of DGF duration on survival and graft function and resource utilization, including hospital length of stay and readmissions. Results 1714 DDKT recipients were included, 59.4% (n = 1018) had DGF. The median DGF duration was 10 days IQR (6,15). The majority of recipients (95%) had resolution of DGF within 28 days. Donor factors associated with DGF days were longer cold ischemia time, donor on inotropes, older age, donation after circulatory death, higher terminal creatinine, and hypertension. Recipient factors associated with increased DGF duration included male sex, length on dialysis before transplant, and higher body mass index. There were no differences in acute rejection events or interstitial fibrosis progression by 4 months when comparing DGF days. The median length of stay was 3 days. However, readmissions increased with increasing DGF duration. Death-censored graft survival was not associated with the length of DGF except when DGF lasted > 28 days. Conclusions Inferior graft survival was observed only in recipients of DDKT with DGF lasting beyond 28 days. DGF lasting

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Introduction The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. Methods The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). Results There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to “not obtainable” (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359). Conclusions These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as “not obtainable” for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test. ClinicalTrials.gov identifier NCT02310763.

Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. Methods/design The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. Discussion To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics. Trial registration clinicaltrials.gov NCT03458832; Date of registration: 1/11/2018

Abstract Background Radiodonta, large Palaeozoic nektonic predators, occupy a pivotal evolutionary position as stem-euarthropods and filled important ecological niches in early animal ecosystems. Analyses of the anatomy and phylogenetic affinity of these large nektonic animals have revealed the origins of the euarthropod compound eye and biramous limb, and interpretations of their diverse feeding styles have placed various radiodont taxa as primary consumers and apex predators. Critical to our understanding of both radiodont evolution and ecology are the paired frontal appendages; however, the vast differences in frontal appendage morphology between and within different radiodont families have made it difficult to identify the relative timings of character acquisitions for this body part. Results Here we describe a new genus of hurdiid, Ursulinacaris, from the middle Cambrian (Miaolingian, Wuliuan) Mount Cap Formation (Northwest Territories, Canada) and Jangle Limestone (Nevada, USA). Ursulinacaris has the same organisation as other hurdiid frontal appendages, with elongate endites on the first five podomeres in the distal articulated region and auxiliary spines on the distal margin of endites only. Unlike all other hurdiid genera, which possess a single row of elongated and blade-like ventral endites, this taxon uniquely bears paired slender endites. Conclusion The blade-like endite morphology is shown to be a hurdiid autapomorphy. Two other frontal appendage characters known only in hurdiids, namely auxiliary spines on the distal margin of endites only, and elongate endites on the first five podomeres in the distal articulated region only, predate this innovation.

Abstract Background Very few studies have been conducted on the seroprevalence of syphilis in Gabon. According to the World Health Organization, the average seroprevalence of syphilis has declined from 5.5 to 1.1% in Central Africa. The aim of this study was to test the hypothesis that syphilis decreased in Gabon between 2004 and 2016 and to identify factors involved in this pattern by testing a large sample of first-time blood donors in the capital Libreville. Methods The detection of Treponema pallidum was done using a Rapid Plasma Reagin test (RPR) and confirmed by an ELISA test using the Biorad Syphilis Total Antibody EIA II kit or BioMerieux Trepanostika TP recombinant. Assays were performed by dedicated technicians according to manufacturers’ recommendations and following the laboratory standard operating procedures. Test results were manually transferred into the laboratory Excel files and hand-written in the laboratory logbook for syphilis testing. Logistic regression was used to assess the impact of sociodemographic characteristics on syphilis marker seroprevalence in both univariate and multivariable analysis. Odds ratios (OR) and 95% confidence intervals were calculated. Results The seroprevalence of syphilis markers was 8.4% (95% CI = 7.9–8.9) in 2004 and 2.4% (95% CI = 2.1–2.7) in 2016. The difference was significant [OR = 3.78; 95% CI (3.26–4.38); P

Abstract Background Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often nonspecific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet‐primed PCR (TP‐PCR) is technically challenging and cost prohibitive for population surveys. Methods Here, we present a high throughput, low‐cost screening tool for CTG repeat expansions using TP‐PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye. Results We determined that multimodal melt profiles from the TP‐PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri‐modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles. Conclusion We demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large‐scale testing programs such as population studies and newborn screening programs.

Introduction. Obesity is a common comorbidity seen in the perioperative setting and is associated with many diseases including cardiovascular disease and obstructive sleep apnea. Laparoscopic Roux-en-Y gastric bypass is the gold standard surgical treatment for patients whose weight is refractory to diet and exercise. Caring for these patients perioperatively presents unique challenges to anesthesiologists and is associated with an increased risk of adverse respiratory events. In our study, we hypothesize that a low-dose perioperative ketamine infusion will reduce opioid consumption and improve analgesia when compared to standard therapy. Methods. This is a single-center, prospective randomized controlled study enrolling 35 patients in total. Patients were randomized equally into the ketamine and control group. Preop, intraop, and postop management regimens were standardized. The ketamine group received a 0.3 mg/kg ideal body weight ketamine bolus after induction followed by a 0.2 mg/kg/hr ketamine infusion continued into the postop setting for up to 24 hours. Data collected included total perioperative opioids used converted to oral morphine equivalents (ME), pain scores, side effects, hospital length of stay, and patient satisfaction captured via postoperative questionnaires. Results. The use of perioperative opioid consumption was significantly lower in the ketamine group when compared with the control group (179.9 ME versus 248.7 ME, P=0.03). There was no statistically significant difference in pain scores or hospital length of stay postoperatively between the two groups. There were also no reported adverse respiratory events, prolonged sedation, agitation, or other side effects reported in either group. The patient satisfaction questionnaires showed a significant difference with the ketamine group reporting lower maximum pain scores, a decrease in how pain limited activities of daily living once discharged, and increased hospital pain management satisfaction scores. Conclusions. Perioperative low-dose ketamine infusions significantly reduced opioid consumption in morbidly obese patients undergoing laparoscopic gastric bypass surgery.

Abstract Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Background: Therapeutic trials are critical to improving outcomes for individuals diagnosed with Duchenne muscular dystrophy (DMD). Understanding predictors of clinical trial participation could maximize enrollment. Methods: Data from six sites (Colorado, Iowa, Piedmont region North Carolina, South Carolina, Utah, and western New York) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) were analyzed. Clinical trial participation and individual-level clinical and sociodemographic characteristics were obtained from medical records for the 2000–2015 calendar years. County-level characteristics were determined from linkage of the most recent county of residence identified from medical records and publicly available federal datasets. Fisher’s exact and Wilcoxon two-sample tests were used with statistical significance set at one-sided p-value (net site: 3.7–27.3%) of 358 individuals with DMD. Corticosteroids, tadalafil, and ataluren (PTC124) were the most common trial medications recorded. Fewer non-Hispanic blacks or Hispanics than non-Hispanic whites participated in clinical trials. Trial participants tended to reside in counties with lower percentages of non-Hispanic blacks. Conclusion: Understanding characteristics associated with clinical trial participation is critical for identifying participation barriers and generalizability of trial results. MD STARnet is uniquely able to track clinical trial participation through surveillance and describe patterns of participation.

IntroductionDuchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens.MethodsA list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach.ResultsAmong corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid.DiscussionThe options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

Background Bees and flies are the two most dominant pollinator taxa in mountain environments of the Southwest USA. Communities of both taxa change dramatically along elevation gradients. We examined whether bee and fly traits would also change along elevation gradients and if so, do they change in a predictable way related to a decrease in temperature as elevation increases. Methods We used insect body size and darkness traits as proxies for energetic requirements and indicators of cold tolerance in order to assess patterns of bee and fly community trait differences along an elevation gradient. We examined 1,922 individuals of bees and flies sampled along an elevation gradient ranging from 2,400 meters to 3,200 meters and from 9.6 °C to 5.2 °C mean annual temperature. We examined bees and flies separately using community weighted means (site-level trait values weighted by species abundance) and estimates of environmental filtering (quantified as the inverse of the standardized range of trait values). Results Bees and flies exhibited two somewhat distinct patterns; (1) Community weighted mean body volume and darkness of bees increased sharply at the highest elevation, and the intensity of environmental filtering also increased with elevation. This was due to both a change among bee populations within a species as well as species replacement at the highest elevation. (2) Community weighted mean body volume and darkness of flies also increased moderately with increasing elevation, but did not exhibit patterns of significant environmental filtering. In fact, the intensity of environmental filtering as indicated by the range of fly body volume weakened with elevation. Conclusion The increase in filter intensity at high elevations exhibited by bees suggests a significant limitation on the breadth of viable functional strategies for coping with extreme cold, at least within this regional species pool. Flies, on the other hand, do not appear to be limited by high elevations, indicating that the shift from bee to fly dominance at high elevations may be due, at least in part, to greater environmental constraints on bee adaptation to colder environments.

Sediment transfer, or connectivity, by aeolian processes between channel-proximal and upland deposits in river valleys is important for the maintenance of river corridor biophysical characteristics. In regulated river systems, dams control the magnitude and duration of discharge. Alterations to the flow regime driven by dams that increase the inundation duration of sediment, or which drive the encroachment of vegetation into areas formerly composed of labile sediment and result in channel narrowing, may reduce sediment transfer from near-channel deposits to uplands via aeolian processes. Employing spatial methods developed by Kasprak et al (2018 Prog. Phys. Geogr. ), here we use data describing the areal extent of bare (i.e. subaerially exposed and non-vegetated) sediment along 168 km of the Colorado River downstream from Glen Canyon Dam in Grand Canyon, USA, in conjunction with inundation extent modeling to forecast how future flows of this highly regulated river will drive changes in the areal extent of sediment available for aeolian transport. We also compare modern bare sediment area to that which presumably would have existed under pre-dam hydrographs. Over the next two decades, the planned flow regime from Glen Canyon Dam will result in slight decreases in bare sediment area (−1%) on an annual scale. This is in contrast to pre-dam years, when unregulated low flows led to marked increases in bare sediment area as compared to the current discharge regime. Our findings also indicate that ∼75% of bare sediment in the study reach is inundated continuously at present, owing to increased baseflows in the post-dam flow regime; consequently, any reductions in flows below modern-day low discharges have the potential to expose large areas of bare sediment. We use vegetation modeling to quantify areas susceptible to vegetation encroachment under future flows, finding that 80% of bare sediment area is suitable for colonization by invasive tamarisk under the current flow regime. Our findings imply that the Colorado River in Grand Canyon, a system marked by widespread erosion of sediment resources and encroachment of riparian vegetation in the post-dam period, is likely to continue to see decreasing bare sediment extent over the coming decades in the absence of direct intervention through flow regime modification or widespread vegetation removal.