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Background and ObjectivesTo determine the risk of hospitalization and death associated with pimavanserin use.MethodsWe conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score–based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively.ResultsThe study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06–1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99–1.24) or with 30-day mortality (aHR 0.76, CI 0.56–1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02–1.41) that persisted after 180 days (aHR 1.28, CI 1.13–1.45) and 1 year (aHR 1.56, CI 1.42–1.72).DiscussionPimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease.Classification of EvidenceThis study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

INTRODUCTION: There is a high post-operative incidence of venous thromboembolisms (VTEs), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE), in pelvic ring and acetabular fractures, and identification of risk factors for VTEs is crucial to decrease this highly morbid complication. High altitudes have a known physiological effect on the body that may predispose patients to developing VTEs in the postoperative period. The purpose of this study was to investigate the relationship between pelvic ring and acetabular fractures occurring at high altitudes and the development of postoperative VTEs. METHODS: In this retrospective study, the Truven MarketScan claims database was used to identify patients who underwent surgical fixation of a pelvic ring and/or acetabular fracture from January 2009 to December 2018 using Current Procedural Terminology (CPT) codes. Patient characteristics, including medical comorbidities, were collected. The zip codes of where the surgeries took place were used to determine recovery altitude and patients were separated into either the high altitude (>4000 feet) or low altitude (4,000feet) are associated with increased odds of developing a PE in the first 30 days as well as developing a DVT or PE at 90 days postoperatively. Future prospective studies are needed to further elucidate the causality of altitude on the development of postoperative VTEs.

All species of large whales are susceptible to vessel strikes, but the true scale and geographical extent of such strikes is not known. This paper provides a qualitative assessment of the range-wide risks posed to gray whales Eschrichtius robustus by vessels, by comparing patterns of whale distribution with the density of vessel traffic seasonally throughout the North Pacific in 2019. Areas of very high vessel density were evident year-round near many coastlines, along inter-continental trade routes, and at hubs of commercial shipping near port entrances. Gray whales were exposed to vessel strikes throughout their range and in their feeding, southbound migration, wintering, and northbound migration periods. Areas of apparently high risk were in the Russian Far East (Kamchatka peninsula and Okhotsk Sea), Bering Sea (including the Aleutian Islands), Gulf of Alaska, and along the entire west coast of North America. Risk appeared greatest during south- and northbound migration when much of the gray whale population is moving through waters near shore. Tanker, container, and bulk-carrier ships represent considerable risk to whales in the North Pacific Ocean, but the large geographical extent of commercial fishing activities suggests that fisheries are also a substantial source of risk. Vessel-strike risk maps indicate the relative extent of exposure of gray (and other) whales to underwater vessel noise. The number of gray whales killed by ship strikes each year may be in the tens, or perhaps the low hundreds. Additional analyses, including quantitative assessments, are warranted to further clarify the risk of vessel strikes to gray whales.

This study aimed to quantify the association between pharmaceutical industry payments to physicians for pimavanserin and both pimavanserin prescription volume and Medicare expenditures.This retrospective cross-sectional study used 2016 and 2017 data from Open Payments and the Medicare Part D Prescriber Public Use Files. The authors used Poisson regression models to quantify the association between physician payments for pimavanserin and pimavanserin prescription volume and linear regression models to quantify the association with Medicare expenditures for pimavanserin.Of 1,609 physicians who prescribed pimavanserin, 45% received payments, which totaled to $6,369,922. Each $10,000 in physician payments was associated with a 14% increase in pimavanserin prescription volume (incident rate ratio=1.14, 95% confidence interval [CI]=1.13-1.14). Every $100 in physician payments was associated with a $175.84 increase in Medicare pimavanserin expenditures (95% CI=$161.55-$190.13).Extensive physician payments have been associated with increased pimavanserin prescription volume and Medicare expenditures.

BACKGROUND Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. OBJECTIVE To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. DESIGN Cross-sectional analysis. SETTING Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. PARTICIPANTS Patients with pain who participated in phase 3 pivotal trials. INTERVENTION FDA-approved opioid analgesics. MEASUREMENTS Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. RESULTS Most of the 48 NDAs evaluated were for new dosage forms (n = 25 [52.1%]) or new formulations (n = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. LIMITATIONS The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. CONCLUSION Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. PRIMARY FUNDING SOURCE None.

Objective To investigate the presence of tibial nerve dysfunction (TND) in operatively treated talar neck fractures. Design Retrospective chart review. Setting Urban Level-1 trauma center. Patients Sixty-four patients for a total of 65 talar neck fractures treated with open reduction and internal fixation between January 1, 2014, and May 1, 2018. Main outcome measures Incidence of TND. Results Evidence of TND was documented in 20 of 65 cases (30.8%) of talar neck fractures. There were no cases of TND associated with Hawkins I fractures, but TND was found in 7 of 32 Hawkins II fractures (21.9%), 10 of 24 Hawkins III fractures (41.7%), and 3 of 5 Hawkins IV fractures (60%). TND was reported in 11 of 19 open talar neck fractures (57.9%) (P = 0.002). TND was associated with tibiotalar dislocation (P = 0.017) but not subtalar dislocation (P = 0.17). TND did not occur in the absence of subtalar subluxation/dislocation. Of 18, a total of 6 (33.3%) reported partial recovery, and 6 (33.3%) reported full recovery within 6 months of the initial injury. By 12 months, of the 18, 8 (44.4%) reported partial recovery and 7 (38.9%) reported full recovery. Conclusion The tibial nerve and its distal branches are at risk of injury in the setting of displaced talar neck fracture, tibiotalar subluxation/dislocation, and open talar neck fracture with increasing risk among those with a higher Hawkins grade. Level of evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The US Food and Drug Administration (FDA) and other major regulators regularly issue safety advisories about licensed drugs with new adverse effects that have been documented through observational studies, clinical trials, and spontaneously reported adverse drug events. To assess the possible effects of a representative group of FDA Drug Safety Communications on the reporting of the specific adverse effect featured in the advisory on new cases reported to the FDA Adverse Event Reporting System (FAERS). We examined 16 FDA Drug Safety Communications issued from 2010 to 2015 that had not previously been the focus of advisories from regulators in the UK, Canada, or Australia. We compared the reports of the adverse effect in the 8 calendar quarters preceding the advisory and in the 4 quarters following. We measured change in reporting frequency by calculating the event reporting odds ratio (ROR) for the post-warning compared to the pre-warning periods. We defined a credible association of the advisory with increased reporting as a ROR ≥ 2.0 and p value of

Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.

Coral reef restoration is a rapidly growing movement galvanized by the accelerating degradation of the world's tropical coral reefs. The need for concerted and collaborative action focused on the recovery of coral reef ecosystems coalesced in the creation of the Coral Restoration Consortium (CRC) in 2017. In March 2020, the CRC leadership team met for a biennial review of international coral reef restoration efforts and a discussion of perceived knowledge and implementation bottlenecks that may impair scalability and efficacy. Herein we present six priorities wherein the CRC will foster scientific advancement and collaboration to: (1) increase restoration efficiency, focusing on scale and cost-effectiveness of deployment; (2) scale up larval-based coral restoration efforts, emphasizing recruit health, growth, and survival; (3) ensure restoration of threatened coral species proceeds within a population-genetics management context; (4) support a holistic approach to coral reef ecosystem restoration; (5) develop and promote the use of standardized terms and metrics for coral reef restoration; and (6) support coral reef restoration practitioners working in diverse geographic locations. These priorities are not exhaustive nor do we imply that accomplishing these tasks alone will be sufficient to restore coral reefs globally; rather these are topics where we feel the CRC community of practice can make timely and significant contributions to facilitate the growth of coral reef restoration as a practical conservation strategy. The goal for these collective actions is to provide tangible, local-scale advancements in reef condition that offset declines resulting from local and global stressors including climate change.

This cross-sectional study examines atezolizumab as a second-line treatment for malignant urothelial carcinoma, which received accelerated US Food and Drug Administration approval, although the manufacturer’s confirmatory trial did not identify benefits.

Significance Global change threatens the genetic diversity of economically important and foundational ecosystem-building species such as corals. We tested whether cryopreserved coral sperm could be used to transfer genetic diversity among genetically isolated populations of the critically endangered Caribbean elkhorn coral, Acropora palmata. Here we report successful assisted gene flow (AGF) in corals using cryopreserved sperm, yielding the largest living wildlife population ever created from cryopreserved cells. Furthermore, we produced direct evidence that genetically distinct populations of Caribbean coral can interbreed. Thus, we demonstrated that sperm cryopreservation can enable efficient, large-scale AGF in corals. This form of assisted genetic migration can enhance genetic diversity and help critically endangered species adapt to local environments in the face of rapid global change., Assisted gene flow (AGF) is a conservation intervention to accelerate species adaptation to climate change by importing genetic diversity into at-risk populations. Corals exemplify both the need for AGF and its technical challenges; corals have declined in abundance, suffered pervasive reproductive failures, and struggled to adapt to climate change, yet mature corals cannot be easily moved for breeding, and coral gametes lose viability within hours. Here, we report the successful demonstration of AGF in corals using cryopreserved sperm that was frozen for 2 to 10 y. We fertilized Acropora palmata eggs from the western Caribbean (Curaçao) with cryopreserved sperm from genetically distinct populations in the eastern and central Caribbean (Florida and Puerto Rico, respectively). We then confirmed interpopulation parentage in the Curaçao–Florida offspring using 19,696 single-nucleotide polymorphism markers. Thus, we provide evidence of reproductive compatibility of a Caribbean coral across a recognized barrier to gene flow. The 6-mo survival of AGF offspring was 42%, the highest ever achieved in this species, yielding the largest wildlife population ever raised from cryopreserved material. By breeding a critically endangered coral across its range without moving adults, we show that AGF using cryopreservation is a viable conservation tool to increase genetic diversity in threatened marine populations.

Background: Pivotal clinical trials provide critical evidence to regulators regarding a product’s suitability for marketing approval. The objectives of this study are (1) to characterize select features of trials for oncology products approved by the U.S. Food and Drug Administration between 2015 and 2017; and (2) to quantify the costs of these trials and how such costs varied based on trial characteristics. Methods: We identified novel oncology therapeutic drugs, and their respective pivotal trials, approved between 2015 and 2017 using annual summary reports from the Food and Drug Administration. Cost estimates for each pivotal trial were calculated using IQVIA’s CostPro, a clinical trial cost estimating tool based on executed contracts between pharmaceutical manufacturers and contract research organizations. Measures of drug and trial characteristics included trial design, end point, patient enrollment, and regulatory pathway. We also performed sensitivity analyses that varied assumptions regarding how efficiently each trial was conducted. Results: A total of 39 pivotal clinical trials provided the basis for Food and Drug Administration approval of 30 new oncology drugs from 2015 to 2017. Among these trials, primary end points were objective response rate in 20 (51.3%), progression-free survival in 13 (33.3%), and overall survival in 6 (15.4%). Twenty trials (51.3%) were single-arm studies. The median estimated cost of oncology pivotal trials was $31.7 million (interquartile range = $17.0–$60.4 million). Trials with objective response rate as primary end point had a median estimate of $17.7 million (interquartile range = $11.9–$27.1 million), compared with trials examining progression-free survival ($42.3 million, interquartile range = $34.6–$101.2 million) or overall survival ($79.4 million, interquartile range = $56.9–$97.7 million) (p Conclusions: Relative to the estimated costs of drug development, the costs of these oncology pivotal trials were modest, with trials that produced more valuable scientific information costing more than their counterparts.

Natural resource trustee agencies must determine how much, and what type of environmental restoration will compensate for injuries to natural resources that result from releases of hazardous substances or oil spills. To fulfill this need, trustees, and other natural resource damage assessment (NRDA) practitioners have relied on a variety of approaches, including habitat equivalency analysis (HEA) and resource equivalency analysis (REA). The purpose of this paper is to introduce the Habitat-Based Resource Equivalency Method (HaBREM), which integrates REA’s reproducible injury metrics and population modeling with HEA’s comprehensive habitat approach to restoration. HaBREM is intended to evaluate injury and restoration using organisms that use the habitat to represent ecological habitat functions. This paper seeks to expand and refine the use of organism-based metrics (biomass-based REA), providing an opportunity to integrate sublethal injuries to multiple species, as well as the potential to include error rates for injury and restoration parameters. Applied by NRDA practitioners in the appropriate context, this methodology can establish the relationship between benefits of compensatory restoration projects and injuries to plant or animal species within an affected habitat. HaBREM may be most effective where there are appropriate data supporting the linkage between habitat and species gains (particularly regionally specific habitat information), as well as species-specific monitoring data and predictions on the growth, density, productivity (i.e., rate of generation of biomass or individuals), and age distributions of indicator species.

Background/Aims Despite the increasing globalization of clinical trials, little is known regarding how the trial site costs vary around the world. We quantified the geographical distribution and regional cost differences for the clinical trials that established the benefits for new therapeutic drugs approved by the US Food and Drug Administration in 2015 and 2016. Methods We included all pivotal clinical trials for 59 new molecular entities approved by the US Food and Drug Administration in 2015 and 2016 that included at least one site in North America. We derived cost estimates from IQVIA’s CostPro, a global clinical trial cost-estimating tool used by pharmaceutical sponsors. We assessed the patient and site allocation of these trials across eight geographic regions. To quantify the region-specific cost differences, we conducted a within-trial comparison by expressing the estimated regional costs associated with the sites in each global region as a percent of the same costs in North America. We also estimated the percentage breakdown of regional cost components (pass-through, site management, regulatory, and study conduct costs) for each trial and for all endpoints reported the median and interquartile range. Results Overall, 127 pivotal clinical trials enrolled 91,415 patients from 13,264 sites. Most patients (60.3%) and sites (57.3%) were outside North America. A median of 66% of the total estimated trial costs (interquartile range: 60%–72%) were spent on regional tasks, with the largest share (53.3%) going directly to trial sites and the remainder going to other regional trial management tasks. Differences were greatest in four lower cost regions: Africa, with an estimated regional cost per site of 49% of North America (interquartile range: 44%–56%), Central Europe 50% (interquartile range: 41%–63%), Middle East 53% (interquartile range: 42%–64%) and Latin America 59% (interquartile range: 50%–70%). Overall, 90 (71%) of the 127 pivotal trials had a total of 3160 sites in these lower cost regions. In contrast, savings were more limited in Western Europe, Oceania, and Asia, where estimated regional costs were 78% of North America (interquartile range: 67%–89%). One-quarter of the trials with sites in Asia and Oceana did not achieve cost savings in those regions relative to North America. Conclusion Among this sample of pivotal trials for recently approved US Food and Drug Administration products, most patients and sites enrolled were outside of North America, with selection of regional sites having a significant impact on total trial costs.

Emotional intelligence (EI) has been associated with decreased burnout in surgical residents but has not been extensively studied in medical students. We hypothesized that higher EI would lead to decreased levels of burnout among medical students at a US medical school.The authors administered three separate EI measures and compiled an EI score by adding the normalized score on each test. These measures were the DRS-15, the Grit Scale, and the Reading the Mind Between the Eyes Quiz. The Professional Fulfillment Index (PFI) was used to determine levels of burnout experienced two weeks before survey completion.The population included 68 medical students. PFI and EI scores were positively correlated (The results confirmed our hypothesis that EI would be correlated with decreased levels of burnout among this group of students. Some areas of potential future study include whether these same results hold true at other medical schools and if improving EI has a benefit of decreasing burnout.

ObjectivesThe coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19.Design, setting and participantsCross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO’s International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers.Main outcome(s)Trial intervention, sponsorship, critical design elements and specified outcomesResultsOverall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020.ConclusionsWhile accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

BACKGROUND Hydroxychloroquine and chloroquine are widely used to treat hospitalized COVID-19 patients primarily based on antiviral activity in in vitro studies. Our objective was to systematically evaluate their efficacy and safety in hospitalized patients with COVID-19. METHODS We systematically reviewed PubMed, ClinicalTrials.gov, and Medrxviv for studies of hydroxychloroquine and chloroquine in COVID-19 hospitalized patients on April 26, 2020. We evaluated the quality of trials and observational studies using the Jadad criteria and Newcastle Ottawa Scale, respectively. RESULTS After a review of 175 citations, we included 5 clinical trials (total of 345 patients), 9 observational studies (n = 2529), and 6 additional studies (n = 775) reporting on the QT interval. Three studies reported treatment benefits including two studies reporting benefit on virologic outcomes, which was statistically significant in one study, and another reported significant improvement on cough symptoms. Three studies reported that treatment was potentially harmful, including an significantly increased risk of mortality in two studies and increased need for respiratory support in another. Eight studies were unable to detect improvements on virologic outcomes (n = 3) or pneumonia or transfer to ICU/death (n = 5). The proportion of participants with critical QTc intervals of ≥ 500 ms or an increase of ≥ 60 ms from baseline ranged from 8.3% to 36% (n = 8). One clinical trial and six observational studies were of good quality. The remaining studies were of poor quality. CONCLUSIONS Our systematic review of reported clinical studies did not identify substantial evidence to support the efficacy of hydroxychloroquine or chloroquine in hospitalized COVID-19 patients and raises questions about potential harm from QT prolongation and increased mortality. Key Points We conducted a systematic review of the efficacy and safety of hydroxychloroquine and chloroquine among patients hospitalized with COVID-19 and identified 14 studies reporting on clinical or virologic outcomes and 6 additional studies reporting on the QT interval. We conducted a systematic review of the efficacy and safety of hydroxychloroquine and chloroquine among patients hospitalized with COVID-19 and identified 14 studies reporting on clinical or virologic outcomes and 6 additional studies reporting on the QT interval. Hydroxychloroquine or chloroquine improved virologic outcomes in 2 clinical studies and cough in another study. We conducted a systematic review of the efficacy and safety of hydroxychloroquine and chloroquine among patients hospitalized with COVID-19 and identified 14 studies reporting on clinical or virologic outcomes and 6 additional studies reporting on the QT interval. Hydroxychloroquine or chloroquine improved virologic outcomes in 2 clinical studies and cough in another study.

The purpose of the present study was to evaluate the prevalence of closed suction drainage after a Kocher–Langenbeck (K–L) approach for surgical fixation of acetabular fractures and to determine the impact of closed suction drainage on patient outcomes. This retrospective study reports on 171 consecutive patients that presented to a single level I trauma center for surgical fixation of an acetabular fracture. Medical records were reviewed to evaluate the use of closed suction drains. The primary outcomes measures were rate of packed red blood cell (PRBC) transfusion and length of hospital stay (LOS). Secondary outcome measures were 30-day post-operative wound complication and 1-year deep infection rates. Of the 171 patients included in this study, 140 (82%) patients were treated with drains. There was a significant association between the use of closed suction drainage and post-operative blood transfusion rate (p = 0.002). Thirty-five patients (25%) treated with drains required a post-operative blood transfusion compared to 0% in the no drain cohort. Regarding the total number of drains used, for every additional closed suction drain that was placed beyond a single drain, the odds of receiving a blood transfusion doubled (p = 0.002). Use of closed suction drainage was associated with a significantly longer LOS (p = 0.015), and no difference in wound complication or deep infection rates. The use of closed suction drains for treatment of acetabular fractures using a K–L approach is associated with increased rates of blood transfusion and increased length of hospital stay, with no impact on surgical site infection rates. The results of this study suggest against routine drain usage in acetabular surgery.

Background The novel coronavirus and associated Coronavirus Disease 2019 (COVID-19) is rapidly spreading throughout the world, with robust growth in the United States. Its drastic impact on the global population and international health care is swift, evolving, and unpredictable. The effects on orthopaedic surgery departments are predominantly indirect, with widespread cessation of all nonessential orthopaedic care. Although this is vital to the system-sustaining measures of isolation and resource reallocation, there is profound detriment to orthopaedic training programs. Methods In the face of new pressures on the finite timeline on an orthopaedic residency, the Emory University School of Medicine Department of Orthopaedics has devised a 5-pronged strategy based on the following: (1) patient and provider safety, (2) uninterrupted necessary care, (3) system sustainability, (4) adaptability, and (5) preservation of vital leadership structures. Results Our 5 tenants support a 2-team system, whereby the residents are divided into cycling "active-duty" and "working remotely" factions. In observation of the potential incubation period of viral symptoms, phase transitions occur every 2 weeks with strict adherence to team assignments. Intrateam redundancy can accommodate potential illness to ensure a stable unit of able residents. Active duty residents participate in in-person surgical encounters and virtual ambulatory encounters, whereas remotely working residents participate in daily video-conferenced faculty-lead, case-based didactics and pursue academic investigation, grant writing, and quality improvement projects. To sustain this, faculty and administrative 2-team systems are also in place to protect the leadership and decision-making components of the department. Conclusions The novel coronavirus has decimated the United States healthcare system, with an unpredictable duration, magnitude, and variability. As collateral damage, orthopaedic residencies are faced with new challenges to provide care and educate residents in the face of safety, resource redistribution, and erosion of classic learning opportunities. Our adaptive approach aims to be a generalizable tactic to optimize our current landscape.

To describe differences in follow-up compliance and emergency department (ED) visits between ballistic and non-ballistic operative lower extremity fracture patients.Retrospective study.Urban level 1 trauma center.Patients age ≥18 years with ≥1 tibia or femur fractures treated with ORIF or intramedullary nailing (IMN) between September 1, 2013 and August 31, 2015.A compliance fraction calculated as ([number of attended follow-up visits] / [number of attended follow-up visits + number of missed follow-up visits]) and ED visits in the post-operative period.612 patients were studied. Patients with ballistic lower extremity fractures had a younger mean age (30.8 years v. 41.6 years; p 0.0001); a shorter length of stay (5.00 days v. 8.00 days; p 0.0001); and were more likely to be male (92.6% v. 68%; p 0.0001) and African-American (90.1% v. 63.1%; p 0.0001) when compared to non-ballistic long bone injuries. Increased follow-up compliance (defined as a compliance fraction ≥0.75) was associated with having a non-ballistic fracture (OR 1.73, 1.13-2.64; p = 0.01), not having an ED visit (OR 2.08, 1.30-3.33; p = 0.002), and being female (OR 1.82, 1.27-2.61; p = 0.001). Increased ED utilization (≥ 1 ED visit) was associated with ballistic mechanism (OR 1.95, 1.20-3.16; p = 0.006), a low follow-up compliance fraction (OR 2.08, 1.30-3.33; p = 0.0019), homelessness (OR 3.91, 1.53-9.98; p = 0.006), and African-American race (OR 2.26, 1.26-4.05; p = 0.05). Scheduling a specific follow-up visit on the discharge summary did not predict higher compliance (OR 1.51, 0.98-2.33; p = 0.06). Conversely, the lack of a specific follow-up visit scheduled on the discharge summary did not predict ED utilization (OR 0.63, 0.34-1.17; p = 0.14).The results of this study demonstrate that increased utilization of the ED was associated with ballistic fractures, homelessness, decreased clinic compliance, and African American race. Furthermore, patients with non-ballistic injuries, women, and those without any ED visit were more likely to have higher outpatient clinic compliance.

Seaborne trade continues to grow and is an important component of the global economy. Threats from shipping to marine ecosystems include oil spills and other water pollution, air pollution, anchor scouring, biological invasions, container loss, chronic noise, and collisions between ships and large whales. Shipping and its associated threats can be influenced by a suite of regulations and economic events. The dynamic nature of ship traffic can be characterized using ship tracking data from automatic identification system (AIS) technology. These data enhance our ability to analyze the ecological threats from commercial shipping as a component of spatially explicit risk assessments. We explore ship traffic variability using a case study in waters off California. AIS data from 2008 to 2015 were used to evaluate the role of vessel emission regulations and economic events on vessel routes and speeds. We document vessels navigating around emission control areas (ECAs) or reducing speed when traveling through them. Large freight vessels decreased speeds from 2008 to 2015 by about 3–6 knots in many areas, with lowered speeds observed in areas of both heavy and sparse vessel use. The timing and location of the speed reductions appear to be most influenced by state and international clean fuel standards, which required the use of more costly fuels. Therefore, the speed reductions may have provided a more cost-effective means of travel. We also found temporary speed increases off southern California when vessels used longer routes to avoid traveling through an ECA. We conclude that the establishment of ECAs had a profound influence on vessel routes and speeds, likely due to the higher costs of clean fuels. Proposals have come before the International Maritime Organization (IMO) to establish clean fuel requirements in various locations around the world to reduce air-borne emissions from vessels. Our research suggests such proposals, or other events that may affect marine fuel prices, can have key impacts on vessel behavior. Consequently, it is important to consider this variability when designing strategies to minimize threats from shipping to vulnerable biophysical systems.

Habitat-based distribution modelling is an established method for predicting species distributions and is necessary for many conservation and management applications. Cetacean habitat models have primarily been developed using data from visual surveys. However, numerous techniques exist for detecting animal presence and each capture a portion of the true population. Combining detection data gathered from multiple survey methods, such as visual and acoustic surveys, may lead to a more robust picture of a species distribution and ecology. We compare habitat models for Dall’s porpoise built with visual versus acoustic survey data from a line-transect survey in the California Current and develop a combined model, utilizing both acoustic detections and visual sightings. Combining acoustic and visual detections increases sample size and allows for detections under a greater range of oceanographic conditions. Consequently, the combined model shows a modest expansion of predicted distribution of Dall’s porpoise compared to either single-source model. However, this study reveals that acoustic and visual methods appear to be more complementary, rather than directly additive. Models built with acoustic data display differences from those built with visual data. Different predictor variables were selected across models and the acoustic model predicts a distribution shifted slightly south of the visual distribution. Results from the current study show promise for incorporating acoustics into habitat models but also identify discrepancies in population sampling between these two methods that should inform future population assessments and modelling efforts.

The sport of motocross entails off-road motorcycle racing and is associated with a high incidence of traumatic injury. While prophylactic knee braces are routinely worn, there has been anecdotal concern that brace use is linked to femoral shaft fractures. While this risk remains unreported in the medical literature, preventing this complication has played a role in new commercial knee brace designs. We present two cases in which two motocross riders sustained transverse femoral shaft fractures at the proximal portion of each respective knee brace. The fracture locations measured on anterior-posterior radiograph were 22 and 21.1 cm proximal to the center of the knee, which is also the recommended proximal extent of motocross knee braces. We propose that the rigid knee brace protects the ligamentous knee structures but may focus undue force on the proximal aspect of the brace. New knee brace designs have incorporated features to dissipate the potentially injurious force to prevent femur fracture. While knee braces undoubtedly help prevent ligamentous knee injury, these cases question the safety of standard brace design and highlight the need for further brace development to better protect the patient’s bony structures, in addition to the knee joint.

The Food and Drug Administration often requires postapproval studies to address issues such as optimal dosing, potential long-term side effects, and use in children or to confirm a drug’s clinical benefit. But many of these studies aren’t completed on time, if at all.

Assessments of ship-strike risk for large whales typically use a single year of ship traffic data and averaged predictions of species distributions. Consequently, they do not account for variability in ship traffic or species distributions. Variability could reduce the effectiveness of static management measures designed to mitigate ship-strike risk. We explore the consequences of interannual variability on ship-strike risk using multiple years of both ship traffic data and predicted fin, humpback, and blue whale distributions off California. Specifically, risk was estimated in four regions that are important for ship-strike risk management. We estimated risk by multiplying the predicted number of whales by the cumulative distance travelled by ships. To overcome the temporal mismatch between the ship traffic and whale data available off California, we classified the time series of ship traffic data into nearshore and offshore traffic scenarios using the percentage of ship traffic travelling more than 24nmi from the mainland coast, which was the boundary of a clean fuel rule implemented in 2009 that altered ship traffic patterns. We found that risk for fin and humpback whale populations off California increased as these species recovered from whaling. We also found that broad-scale, northward shifts in blue whale distributions throughout the North Pacific, likely in response to changes in oceanographic conditions, were associated with increased ship-strike risk off northern California. The magnitude of ship-strike risk for fin, humpback, and blue whales was influenced by the ship traffic scenarios. Interannual variability in predicted whale distributions also influenced the magnitude of ship-strike risk, but generally did not change whether the nearshore or offshore traffic scenario had higher risk. The consistency in the highest risk from the traffic scenarios likely occurred because areas containing the highest predicted number of whales were generally the same across years. The consistency in risk from the traffic scenarios suggests that static spatial management measures (e.g., changing shipping lanes or creating areas to be avoided) can provide an effective means of mitigating risk resulting from ship traffic variability off California.

ObjectiveTo assess the 5-year changes in the adult medical use of central nervous system (CNS) stimulants with higher risk of dependence and evaluate the population characteristics of users and their medical and/or neurological conditions.DesignCross-sectional study.SettingAnnual US Medical Expenditure Panel Survey, a stratified random sample of approximately 30 000 persons designed to produce national population estimates. It focuses on reported medical spending, medical services used, health status and prescription medications.ParticipantsAdults age 19 years and older who reported obtaining one or more prescriptions for amphetamine or methylphenidate products during two survey years, 2013 and 2018.Main outcomes measuresPrescriptions obtained, the specific stimulant product and annual treatment days of drug supplied.ResultsIn 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported prescriptions for CNS stimulants, having filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions with a mean of 226 (95% CI 210 to 242) days’ supply. Compared with 2013, the estimated number of adults reporting using CNS stimulants in 2018 increased by 1.8 million (95% CI 1.0 million to 2.7 million) or 79.8%. Most 2018 adult stimulant users reported taking psychoactive medication for one or more mental, behavioural or neurodevelopment disorders. Overall, 77.8% (95% CI 72.6% to 83.0%) reported some medication for adult attention deficit disorder, 26.8% (95% CI 22.2% to 31.5%) took medication for anxiety, 25.1% (95% CI 19.9% to 30.3%) for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug treatment for other mental or neurological disorders. Adult CNS stimulant use was higher in females, in younger age cohorts and among individuals of white race/ethnicity.ConclusionsAdult medical use of prescription stimulants increased markedly in 5 years and occurred in a population often reporting multiple mental or neurological disorders. Further action is needed to understand and manage this new resurgence in drugs with high risks of dependence.

Low-frequency noise that is part of the acoustic environment for baleen whales has increased in many areas of the Northeast Pacific Ocean that contain whale habitat. We conducted a spatially explicit risk assessment of noise from commercial shipping to blue, fin, and humpback whale habitats in Southern California waters and explored how noise is affected by several place-based management techniques: a National Marine Sanctuary, an Area to be Avoided (ATBA), and a Traffic Separation Scheme (TSS). We used shipping data to model noise at 2 frequencies that are part of the acoustic environment for these species and capture the variable contributions from shipping to noise. Predicted noise levels in Southern California waters suggest high, region-wide exposure to shipping noise. Our risk assessment identified several areas where the acoustic environment may be degraded for blue, fin, and humpback whales because their habitat overlaps with areas of elevated noise from shipping traffic and 2 places where blue and humpback whale feeding areas overlap with lower predicted noise levels. One of the places with lower predicted noise occurs in the Channel Islands National Marine Sanctuary (CINMS). Noise has not been directly managed within the CINMS; instead, reduced noise in this portion of the CINMS is likely an ancillary benefit of the ATBA surrounding most of the Sanctuary. Areas of elevated noise in the CINMS also occur, primarily where a TSS intersects the Sanctuaryís boundaries. Our risk assessment framework can be used to evaluate how shipping traffic affects acoustic environments and explore management strategies.

Aim Human activities are creating conservation challenges for cetaceans. Spatially explicit risk assessments can be used to address these challenges, but require species distribution data, which are limited for many cetacean species. This study explores methods to overcome this limitation. Blue whales (Balaenoptera musculus) are used as a case study because they are an example of a species that have well-defined habitat and are subject to anthropogenic threats. Location Eastern Pacific Ocean, including the California Current (CC) and eastern tropical Pacific (ETP), and northern Indian Ocean (NIO). Methods We used 12 years of survey data (377 blue whale sightings and c. 225,400 km of effort) collected in the CC and ETP to assess the transferability of blue whale habitat models. We used the models built with CC and ETP data to create predictions of blue whale distributions in the data-poor NIO because key aspects of blue whale ecology are expected to be similar in these ecosystems. Results We found that the ecosystem-specific blue whale models performed well in their respective ecosystems, but were not transferable. For example, models built with CC data could accurately predict distributions in the CC, but could not accurately predict distributions in the ETP. However, the accuracy of models built with combined CC and ETP data was similar to the accuracy of the ecosystem-specific models in both ecosystems. Our predictions of blue whale habitat in the NIO from the models built with combined CC and ETP data compare favourably to hypotheses about NIO blue whale distributions, provide new insights into blue whale habitat, and can be used to prioritize research and monitoring efforts. Main conclusions Predicting cetacean distributions in data-poor ecosystems using habitat models built with data from multiple ecosystems is potentially a powerful marine conservation tool and should be examined for other species and regions.

This safety assessment provides a detailed analysis of key studies and focuses on the six most widely used antipsychotic drugs. Lines of evidence include mechanisms of action, short-term treatment of psychosis, relapse prevention, early intervention in schizophrenia, long-term comparisons between first- and second-generation agents, and flexible treatment algorithms. Despite the diversity of study settings, several common features were seen. All the agents obstruct normal signaling through widely dispersed dopamine D2 receptors. Treatment failure or psychosis relapse was the most frequent outcome in most key studies, ranging from 38 to 93%. High discontinuation rates caused most trials to fail to demonstrate a substantial treatment benefit, or difference from an active comparator. Assessment of harm to the extrapyramidal motor system was confounded because of extensive neurological impairment from previous antipsychotic drug treatment measured at baseline, abrupt discontinuation effects, and high rates of concomitant medications to manage drug adverse effects. Claims that second-generation antipsychotic drugs have safety advantages over classical neuroleptic drugs and prevent relapse were not supported in these key studies. The extent of injury to and impairment of multiple body systems caused by antipsychotic drugs shows the need for a scientific, clinical, and regulatory reappraisal of the appropriate use of these agents.

Importance Biosimilar biologic products were authorized in 2010, after the US Congress established an expedited pathway for approval of clinically similar versions of approved biologic products. Unlike for most small-molecule generic drugs, approval requirements for a biosimilar included animal studies and a comparative efficacy clinical trial. Objective To analyze the evidence required to support a biosimilarity license application, examine the US Food and Drug Administration (FDA) evaluation process, and estimate the costs of the key clinical trial evidence. Design This study evaluated all biosimilar biologic products approved from January 2010 through October 2019, using the publicly available FDA review documents, disclosures from ClinicalTrials.gov, and the published peer-reviewed literature. The costs of efficacy clinical trials were estimated using licensed proprietary software. Main Outcomes and Measures The following elements of each approved biosimilar were evaluated: the extent of human clinical testing to establish that the biosimilar had no clinically meaningful differences with the reference product, results of comparative animal studies, and FDA-cited application deficiencies. The cited deficiencies included the following categories: (1) facility inspection, (2) manufacturing or product quality, (3) animal studies, (4) laboratory analytical studies, (5) phase 1 and/or immunogenicity studies, and (6) phase 3 comparative efficacy trials. Results As of October 2019, the FDA had approved 23 biosimilar biologics for 9 reference products. The 29 clinical trials that established that the efficacy of the biosimilar products was comparable to that of the reference products enrolled a median (interquartile range [IQR]) of 504 (258-612) patients, had a median (IQR) estimated cost of $20.8 ($13.8-$35.3) million, and had a median (IQR) treatment duration of 52 (28-68) weeks. Substantial deficiencies temporarily halted the review of 9 applications, and the most frequent deficits were failed facilities inspections (n = 5) and manufacturing process quality problems (n = 6). The approved biosimilar submissions included 51 animal studies on species that included mice, rats, rabbits, dogs, and cynomolgus monkeys. Negative outcomes in 2 animal studies were attributed to differences between human and test species. The FDA generally met the standard 12-month review deadlines or stopped the review clock when serious deficiencies were identified. Conclusions and Relevance This study found that most comparative efficacy trials supporting the FDA approval of biosimilars appeared to be as rigorous as and often larger, longer, and more costly than pivotal trials for new molecular entities. Further research is needed into whether less costly comparative efficacy trials could provide adequate evidence of biosimilarity and whether animal studies contribute useful scientific evidence.

We anticipate that conventional management approaches will be insufficient to protect coral reefs, even if global warming is limited to 1.5 °C. Emerging technologies are needed to stem the decline of these natural assets.

Introduction There has been a spike in recent news regarding motorized scooter injuries due to the expansion of scooter sharing companies. Given the paucity of literature on this topic, the purpose of our study was to describe and quantify emergency department encounters associated with motorized scooter related injuries. Methods The National Electronic Injury Surveillance System (NEISS) was queried for motorized scooter related injuries from 2013 to 2017. Patient demographics, diagnosis, injury location, narrative description of incident, and disposition data were collected from emergency department encounters. Results There were an estimated 32,400 motorized scooter injuries from 2013 to 2017. The estimated incidence did not change significantly over time with 1.9 cases per 100,000 in 2013 and 2.6 cases per 100,000 in 2017. A 77.0% increase in scooter injuries was noted for millennials from 2016 to 2017. Head injuries were the most common body area injured (27.6%). Fractures or dislocations (25.9%) were the most common diagnosis. The most common site of fracture was the wrist and lower arm (35.4%). There were no deaths. Major orthopaedic injury and concussion were the strongest independent predictors of hospital admission. Conclusions Head injuries were the most commonly injured body part, while fractures or dislocations were the most common diagnosis. These results highlight the importance of using protective equipment while riding motorized scooters, and lay a foundation for future policies requiring helmet use.

Global change will compromise the population sizes, species ranges, and survival of economically-important plants and animals, including crops, aquaculture species, and foundational ecosystem builders. Scleractinian reef-building corals are a particular concern because they are slow-growing, long-lived, environmentally-sensitive, and concentrated in the warmest regions of the ocean. Assisted Gene Flow (AGF) is considered a viable tool to help natural plant and animal populations, including corals, adapt to changing environments. Our goal was to test for the first time whether cryopreserved coral sperm could be used to facilitate assisted gene flow between genetically-isolated populations of a Caribbean coral. We collected, pooled, and cryopreserved coral sperm from the threatened Caribbean coral Acropora palmata in the western Caribbean (Key Largo, FL), central Caribbean (Rincon, Puerto Rico), and eastern Caribbean (Curacao). Alongside freshly-collected sperm from Curacao, the cryopreserved sperm from each of these populations was used for in vitro fertilization experiments with freshly-collected eggs from Curacao. Across five egg donors, average fertilization success was 91 to 99% for CUR x CUR (fresh sperm) crosses, 37 to 82% for CUR x CUR (frozen sperm) crosses, 3 to 19% for CUR x FL (frozen sperm) crosses and 0 to 24% for CUR x PR (frozen sperm) crosses. Notably, fertilization was achieved in all four categories of crosses, showing for the first time through direct evidence that populations of A. palmata are reproductively compatible, and that genetic diversity can be transferred from one population to another for the purposes of assisted gene flow. The resulting larvae were reared in Curacao for up to 7 days, then the swimming larvae were transported to Florida for settlement and grow-out at two separate facilities, which achieved larval settlement rates of 37 to 60% across all cohorts. Larvae were reared and settled in Florida to acclimate them to the ambient water quality, microbial environment, and temperature regimes of the western genetic A. palmata population as early in their life cycle as possible. At one month, over 54% all settlers had survived, including over 3500 settlers from CUR x CUR (frozen sperm), 1200 settlers from CUR x FL (frozen sperm), and 230 settlers from CUR x PR (frozen sperm). These experiments represent the first-ever pan-Caribbean coral crosses produced in captivity and the first direct evidence that geographically-separated and genetically-isolated populations of any Caribbean coral are reproductively compatible. Moreover, with over 4700 A. palmata settlers produced using cryopreserved sperm, this represents the largest living wildlife population ever created from cryopreserved material. Together, these findings demonstrate that cryopreservation of coral sperm can enable efficient, large-scale assisted gene flow in corals. This form of assisted migration can not only help to preserve the population-level genetic diversity of extant coral populations but also help to increase population resilience to global change.

Importance A critical question in health care is the extent of scientific evidence that should be required to establish that a new therapeutic agent has benefits that outweigh its risks. Estimating the costs of this evidence of efficacy provides an important perspective. Objective To estimate costs and assess scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) from 2015 to 2016. Design and Setting This study identified 59 novel therapeutic drugs using the annual summary reports from the FDA Center for Drug Evaluation and Research. ClinicalTrials.gov, FDA reviews, and peer-reviewed publications that were publicly available in 2017 were used to identify 52 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors. Main Outcomes and Measures Estimated mean cost and 95% CIs based on industry benchmark data from 60 countries. Measures of trials’ scientific characteristics included trial design (no control group, placebo, and active drug), end point (surrogate outcome, clinical scale, and clinical outcome), patient enrollment, and treatment duration. Results A total of 138 pivotal clinical trials provided the basis for approval of 59 new therapeutic agents by the FDA from 2015 to 2016, with a median estimated cost of $19.0 million (interquartile range, $12.2 million-$33.1 million). Estimated costs ranged from less than $5 million for trials without a control group for 3 orphan drugs with fewer than 15 patients each to $346.8 million (95% CI, $252.0 million-$441.5 million) for a noninferiority trial with end points assessing clinical benefit. Twenty-six of 138 trials (18.8%) were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million-$16.9 million). Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million). Costs also varied by trial end point, treatment duration, patient enrollment, and therapeutic area. Conclusions and Relevance The highest-cost trials were those in which the new agent had to be proved to be noninferior with clinical benefit end points compared with an agent already available or those that required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.