Search

PURPOSE Precision medicine uses advanced molecular techniques to guide the use of targeted therapeutic drugs and is an emerging paradigm in pediatric oncology. Clinical evidence related to the efficacy of many novel targeted drugs, however, is currently very limited given the rarity of pediatric cancer and the lack of published evidence for the use of these drugs in children. This systematic review aimed to evaluate the existing evidence for the feasibility and clinical efficacy of precision medicine in pediatric oncology. METHODS A systematic review was conducted using the PubMed, Medline, and Embase databases. Clinical trials and observational studies, which used molecular assays such as whole-exome sequencing to identify molecular targets that guided the allocation of targeted cancer drugs and reported clinical outcomes, were included in this review. RESULTS Twenty-one clinical trials and observational studies were identified, collectively enrolling 1,408 pediatric patients across nine countries. Therapeutic targets were found in 647 patients (46.0%); however, only 175 of these patients (27.0%) received a targeted drug. Objective responses were recorded for 73 (41.7%) of these 175 patients, only 5.2% of the total sample. Inconsistent outcome reporting and limited comparison with conventional treatment hindered evaluation of the clinical utility of precision medicine. CONCLUSION Precision medicine can feasibly identify molecular targets in a clinical setting. However, the inaccessibility of targeted drugs is a significant barrier, restricting the exploration of its therapeutic potential in pediatric oncology. Future clinical trials should endeavor to link the molecular testing results with access to targeted drugs and standardize outcome reporting to advance understanding of the benefits of this novel paradigm in improving patient outcomes.

Objectives Iliac branch devices (IBDs) are modular, bifurcated endografts designed to preserve hypogastric flow during endovascular aortoiliac aneurysm repair. We report our single center outcomes, and describe the unique complications of these devices: inability to cannulate the hypogastric artery (technical failure), occlusion of the internal branch, and type III endoleak from separation of components between the main body and IBD. Methods A prospectively maintained institutional database of patients undergoing IBD implantation between 2014 and 2019 was reviewed. Technical and clinical outcomes were evaluated. We then identified patients having one of the IBD-specific complications and patient, anatomic, and procedural data were analyzed to identify factors associated with these failures. Results Sixty-four IBDs were placed in 59 patients during the study period. Mean age was 71.2 ± 8.6, and 92% were male. A 74.6% of patients had a current or prior abdominal aortic aneurysm, and 9.4% had a hypogastric aneurysm. Technical success was achieved in 60/64 cases (93.8%); prior endovascular aortic repair was associated with technical failure (P = 0.04). There were 5 instances of component separation between the main body and the IBD: 3 occurred intraoperatively and were repaired with additional bridging components, and 2 occurred on late follow-up and required reintervention. Increased tortuosity index of both aortoiliac (1.7 ± 0.4 vs. 1.3 ± 02, P = 0.04) and iliac-specific (3.9 ± 2.4 vs. 1.9 ± 0.9, P = 0.03) segments were significantly associated with component separation, as was the use of larger internal iliac components (13.9 ± 2.4 vs. 11.1 ± 2.3 mm, P = 0.04). Internal branch occlusions occurred in 4 patients (6.7%). Two were successfully reopened with endovascular procedures, with two being asymptomatic. No specific factors were found to be predictive of branch occlusion. Conclusions IBD-specific complications occur rarely. History of prior endovascular aortic repair is associated with technical failure, while increased aortic and iliac tortuosity are predictive of component separation and type III endoleak. Severe tortuosity should be carefully considered when planning for IBD.

Objective Hybrid lower extremity revascularization has been well described, typically consisting of common femoral endarterectomy (CFE) followed by direct patch puncture and endovascular treatment of any distal disease. We describe a modified technique that obviates the need for endovascular re-entry and simplifies treatment at the proximal and distal endpoints. Methods The REWIRE technique begins with retrograde arterial access via a patent tibial, pedal or femoropopliteal vessel. The diseased segment is crossed in the subintimal plane. Once the wire reaches the common femoral artery (CFA), the vessel is surgically exposed. Arteriotomy is performed and the wire is externalized during standard CFE. With through-wire access achieved, a sheath is inserted and the distal disease is treated. The proximal extent of the endovascular revascularization is incorporated into a standard CFE with patch angioplasty. Results Seven patients with chronic limb-threatening ischemia were treated with this approach, all with long segment occlusions of the SFA and significant CFA disease. The SFA disease was stented and bovine pericardial patch was used for CFE in all. Technical success was achieved in all patients. There were no complications related to the retrograde puncture site, which was controlled with manual pressure (4) or excluded with a covered stent (3). Thirty-Day freedom from major adverse limb events was 100%. Conclusions The REWIRE technique is an effective approach to hybrid revascularization involving the CFA. By crossing the occluded segment in a retrograde fashion and surgically externalizing the wire during CFE, the proximal and distal endpoints can be addressed with ease, the profunda femoris is protected under direct visualization, and the need for endovascular re-entry is eliminated.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

There is evidence of practice consolidation in US health care in recent years. To our knowledge, a detailed quantitative study of recent changes in radiation oncology practice size has not been performed. We aim to evaluate radiation oncology practice size changes between 2012 and 2020 in the United States.Using the Medicare Physician Compare Database, we identified practices employing radiation oncologists using their taxpayer identification number and individual radiation oncologists using their national provider identifier. We grouped individual radiation oncologists into categories by practice size (which includes the number of physicians of all specialties) and compared the number of radiation oncologists in each category between 2012 and 2020. Further analyses by US geographic census region, single-specialty practice, academic practice, and high- and low-population density areas were performed.Between 2012 and 2020, the total number of practicing radiation oncologists increased by 9%, and the number of practices employing radiation oncologists decreased by 11.5%. The number of radiation oncologists in practices of size 1 to 2, 3 to 9, 10 to 24, and 25 to 49 decreased by 3.7%, 4.7%, 4.9%, and 2%, respectively, and the number of radiation oncologists in practices of size 50 to 99, 100 to 499, and 500+ increased by 1.4%, 2.1%, and 11.8%, respectively (all 500+ practices are multispecialty groups). The increase in practice size was significant in all regions, for single-specialty and multispecialty practices, academic and nonacademic practices, and for practices in high-, middle-, and low-population density areas (P.05 for all comparisons). The proportion of single-specialty practices has decreased significantly (P.001), and the proportion of academic practices increased significantly (P = .004). Additionally, the proportion of practices and physicians in high- and low-population density regions remained stable during this period (P.05).Our analysis suggests that practice size consolidation has occurred within the US radiation oncology workforce from 2012 to 2020. The impact of this consolidation on quality, cost, and patient access deserves further attention.

Thoracic endovascular aortic repair (TEVAR) is an effective treatment of blunt thoracic aortic injury (BTAI). However, the risks and benefits of administering intraoperative heparin in trauma patients are not well-defined, especially with regard to bleeding complications.The Vascular Quality Initiative registry was queried from 2013 to 2019 to identify patients who had undergone TEVAR for BTAI with or without the administration of intraoperative heparin. Univariate analyses were performed with the Student t test, Fisher exact test, or χA total of 655 patients were included, of whom most had presented with grade III (53.3%) or IV (20%) BTAI. Patients receiving heparin were less likely to have an injury severity score (ISS) of ≥15 (70.2% vs 90.5%; P .0001) or major head or neck injury (39.6% vs 62.9%; P .0001). Patients receiving heparin also had a lower incidence of inpatient death (5.1% vs 12.9%; P .01). Across all injury grades, heparin use was not associated with the need for intraoperative transfusion or postoperative transfusion or the development of hematoma. In patients with grade III BTAI, the nonuse of heparin was associated with an increased risk of lower extremity embolization events (7.4% vs 1.8%; P .05). On multivariable logistic regression analysis for inpatient mortality, intraoperative heparin use (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.11-0.86; P .05) and female gender (OR, 0.11; 95% CI, 0.11-0.86; P .05) were associated with better survival, even after controlling for head and neck trauma and injury grade. In contrast, increased age (OR, 1.06; 95% CI, 1.03-1.1; P .001), postoperative transfusion (OR, 1.06; 95% CI, 1.02-1.11; P .01), higher ISS (OR, 1.04; 95% CI, 1.01-1.07; P .05), postoperative dysrhythmia (OR, 4.48; 95% CI, 1.10-18.18; P .05), and postoperative stroke or transient ischemic attack (OR, 5.54; 95% CI, 1.11-27.67; P .05) were associated with increased odds of inpatient mortality.Intraoperative heparin use was associated with reduced inpatient mortality for patients undergoing TEVAR for BTAI, including those with major head or neck trauma and high ISSs. Heparin use did not increase the risk of hemorrhagic complications across all injury grades. Also, in patients with grade III BTAI, heparin use was associated with a reduced risk of lower extremity embolic events. Heparin appears to be safe during TEVAR for BTAI and should be administered when no specific contraindication exists.

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia., Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.

Introduction The purpose of this study was to evaluate trends in annual arthroplasty volume among the Medicare population, as well as assess true Medicare reimbursement to physicians for all hip and knee arthroplasty procedures billed to Medicare since year 2000. Methods The publicly available Medicare Part B National Summary Data File from years 2000 to 2019 was utilized. Collected data included true physician reimbursements for all primary total hip and knee, unicompartmental knee, and revision hip/knee arthroplasty procedures from 2000 to 2019. Monetary data was adjusted for inflation to year 2019 dollars. Change was assessed and compared by procedure type. Results From 2000 to 2019, physicians billed Medicare Fee-For-Service for 8,363,821 hip and knee arthroplasty procedures. During this time, the annual number of included arthroplasty procedures billed to Medicare increased by 100%. From 2000 to 2019 across all included procedures, the mean physician reimbursement after adjusting for inflation decreased by -$729.82 (-38.9%) per procedure. This varied by procedure type. Unicompartmental knee arthroplasty was the only procedure to experience an increased mean reimbursement when adjusting for inflation, increasing by $241.40 (+16.6%) per procedure from 2000 to 2019. Conclusion This study demonstrates decreasing Medicare reimbursement to physicians within hip and knee arthroplasty from 2000 to 2019 when adjusting for inflation. This study is important for informing the potential development of more equitable payment models and maintaining access for arthroplasty care moving forward.

Maxillary hypoplasia is a commonly seen dentofacial anomaly in patients with cleft lip and palate after surgical repair of the cleft anomaly. To facilitate large horizontal movements of the maxilla, distraction osteogenesis is used to slowly stretch the soft tissue envelope with the skeletal advancement preventing tissue recoil and skeletal relapse. Internal distraction devices have the advantage of reducing the amount of physical and psychological stress placed on patients, families, and caregivers. The technique has been successful in producing stable results for large advancements of the facial skeleton when compared with conventional Le Fort I advancement and fixation of the maxilla.

Children with low-grade gliomas have excellent long-term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long-term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprasellar region, our patients commonly suffer from hormone deficiencies. In Australia, the Pharmaceutical Benefits Scheme currently restricts growth hormone therapy to patients who are not being actively treated for cancer, including those receiving targeted therapies. This viewpoint hopes to facilitate an important discussion amongst our colleagues as to whether this should be changed to allow growth hormone to become available to children on chronic tumour suppressive therapy.

Background Physical distancing required by coronavirus disease 2019 (COVID-19) has limited traditional in-person resident education. We present our novel online curriculum for incorporation into traditional surgical educational programs. Methods The online curriculum utilized weekly sub-specialty themed faculty and resident created lectures, ABSITE practice questions, and weekly sub-specialty synchronized readings. Attendance, resident and faculty surveys, and completed ABSITE practice questions evaluated for curriculum success. Curriculum was adapted as COVID-19 clinical restructuring ended. Results 77% and 80% of clinical residents attended faculty lectures and resident led topic discussions as compared to 66% and 48% attending traditional in-person grand rounds and SCORE curriculum (both p > 0.05). 71.9% of residents and 16.6% of faculty reported improved resident participation while none reported decreased levels of participation (p, Highlights • Online educational platforms are useful and effective tools for the acquisition and application of knowledge. • Successful knowledge acquisition requires multimodal approach. • Resident driven educational sessions can empower residents to take change of their education. • Online educational platforms can facilitate sharing of knowledge across large distances.

Introduction A growing body of scientific evidence points to the potentially harmful cognitive effects of anticholinergic medications among older adults. Most interventions designed to promote deprescribing of anticholinergics have directly targeted healthcare professionals and have had mixed results. Consumer-facing technologies may provide a unique benefit by empowering patients and can complement existing healthcare professional-centric efforts. Methods We initiated a randomized clinical trial to evaluate the effectiveness of a patient-facing mobile application (Brain Safe app) compared to an attention control medication list app in reducing anticholinergic exposure among community-dwelling older adults. Study participants are adults aged 60 years and above, currently using at least one prescribed strong anticholinergic, and receiving primary care. The trial plans to enroll a total of 700 participants, randomly allocated in 1:1 proportion to the two study arms. Participants will have the Brain Safe app (intervention arm) or attention control medication list app (control arm) loaded onto a smartphone (study provided or personal device). All participants will be followed for 12 months and will have data collected at baseline, at 6 months, and 12 months by blinded outcome assessors. The primary outcome of the study is anticholinergic exposure measured as total standard daily dose (TSDD) computed from medication prescription electronic records. Secondary outcomes of the study are cognitive function and health-related quality of life. Discussion A consumer-facing intervention to promote deprescribing of potentially high-risk medications can be part of a multi-pronged approach to reduce inappropriate medication use among older adult patients. Delivering a deprescribing intervention via a mobile app is a novel approach and may hold great promise to accelerate deployment of medication safety initiatives across diverse patient populations. Clinical trial registration Registered at ClinicalTrials.gov on October 10, 2019. Identifier number: NCT04121858.

Objective Although vast amounts of patient information are captured in electronic health records (EHRs), effective clinical use of this information is challenging due to inadequate and inefficient access to it at the point of care. The purpose of this study was to conduct a scoping review of the literature on the use of EHR search functions within a single patient's record in clinical settings to characterize the current state of research on the topic and identify areas for future study. Methods We conducted a literature search of four databases to identify articles on within-EHR search functions or the use of EHR search function in the context of clinical tasks. After reviewing titles and abstracts and performing a full-text review of selected articles, we included 17 articles in the analysis. We qualitatively identified themes in those articles and synthesized the literature for each theme. Results Based on the 17 articles analyzed, we delineated four themes: (1) how clinicians use search functions, (2) impact of search functions on clinical workflow, (3) weaknesses of current search functions, and (4) advanced search features. Our review found that search functions generally facilitate patient information retrieval by clinicians and are positively received by users. However, existing search functions have weaknesses, such as yielding false negatives and false positives, which can decrease trust in the results, and requiring a high cognitive load to perform an inclusive search of a patient's record. Conclusion Despite the widespread adoption of EHRs, only a limited number of articles describe the use of EHR search functions in a clinical setting, despite evidence that they benefit clinician workflow and productivity. Some of the weaknesses of current search functions may be addressed by enhancing EHR search functions with collaborative filtering.

Background There have been significant advances in Cystic Fibrosis (CF) treatment, with the introduction of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. Adherence is an important goal for CF management, as nonadherence is linked to poor health outcomes. Objective To calculate the medication adherence in patients taking CFTR modulators using a national specialty pharmacy database. Methods This retrospective observational cohort study utilized de-identified specialty pharmacy data from September 2017 to August 2018 to assess medication adherence for three CFTR modulators: ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor & ivacaftor. The primary outcome was proportion of days covered (PDC) for each medication, with mean PDC values compared across age groups and insurance characteristics. All analyses were performed using the SAS 9.4 University Edition (SAS Institute, Cary, NC). Results A total of 2,548 patients were analyzed, including 1,289 (50.59%) patients on lumacaftor/ivacaftor, 784 (30.77%) on ivacaftor, and 475 (18.64%) on tezacaftor/ivacaftor & ivacaftor. The mean PDC value for all CFTR modulators was above 0.80. Tezacaftor/ivacaftor & ivacaftor had the highest overall PDC of 0.92, while PDC values for both lumacaftor/ivacaftor and ivacaftor were 0.84. Children/adolescents on lumacaftor/ivacaftor (p = 0.0001) and tezacaftor/ivacaftor & ivacaftor (p = 0.001) had significantly higher mean PDC values compared to adults but not for ivacaftor (p = 0.3744). No statistical differences were seen in PDC across insurance characteristics. Conclusion To the best of our knowledge, this is the first study to assess the adherence of three CFTR modulators using a large nationwide specialty database. With high acquisition costs of CFTR modulator therapies, there is a need to improve rates of adherence in patients with CF.

Opioids are one of the most prescribed classes of analgesic medications. Their narrow therapeutic index and metabolism through cytochrome p450 (CYP) enzymes can result in a drug interaction when used concomitantly with rifamycins. In clinical scenarios where concurrent therapy with an opioid and a rifamycin occurs, there is no standardized guidance for managing the interaction. The objective of this review was to examine literature which evaluates the concomitant use of opioids and rifamycins with clinically relevant CYP-inducing properties. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria was performed. PubMed, Scopus, and OVID Embase were queried for studies from database inception to January 2020 related to rifamycin and opioid medications. Only full-text, peer-reviewed, English language articles addressing clinical outcomes from concomitant rifamycin and opioid therapy were included. The review isolated 12 articles for data extraction from an original 2260 citations identified. Rifampin (11; 92%) and rifabutin (2; 17%) were the rifamycins studied along with seven different opioids. Decreased effect of opioids with concomitant rifampin therapy manifested as withdrawal in numerous patients on methadone and a decreased analgesic effect from tramadol, morphine, and, most notably, oxycodone. Only the combinations of rifampin with buccal fentanyl and rifabutin with buprenorphine and methadone were found to have no clinically measurable interaction. Available literature suggests that a decrease in opioid clinical effects is appreciated with concomitant rifamycin therapy. Further research is needed to focus on specific mitigation strategies beyond opioid agent selection, such as dosing adjustment recommendations.

Biomolecular structure drives function, and computational capabilities have progressed such that the prediction and computational design of biomolecular structures is increasingly feasible. Because computational biophysics attracts students from many different backgrounds and with different levels of resources, teaching the subject can be challenging. One strategy to teach diverse learners is with interactive multimedia material that promotes self-paced, active learning. We have created a hands-on education strategy with a set of 16 modules that teach topics in biomolecular structure and design, from fundamentals of conformational sampling and energy evaluation to applications, such as protein docking, antibody design, and RNA structure prediction. Our modules are based on PyRosetta, a Python library that encapsulates all computational modules and methods in the Rosetta software package. The workshop-style modules are implemented as Jupyter Notebooks that can be executed in the Google Colaboratory, allowing learners access with just a Web browser. The digital format of Jupyter Notebooks allows us to embed images, molecular visualization movies, and interactive coding exercises. This multimodal approach may better reach students from different disciplines and experience levels, as well as attract more researchers from smaller labs and cognate backgrounds to leverage PyRosetta in science and engineering research. All materials are freely available at https://github.com/RosettaCommons/PyRosetta.notebooks.

Background As the uncertainty surrounding the future of U.S. health care policy intensifies, political advocacy and campaign contributions have become increasingly relevant. This study describes the trends of political contributions of U.S. neurosurgeons from the years 2003–2019. Methods Individual contribution data from 2003–2019 were obtained from the Federal Election Commission website. Contributions were filtered for occupation lines matching either “neurosurg,” “neurologic surgeon,” or “neurological surgeon.” Each contribution is designated to a recipient committee associated with a political candidate or group. The party designations of these committees were used to catalogue donations as “Republican,” “Democratic,” or “Independent.” Results From 2003–2019 a total of 9242 political donations were made by self-identified neurosurgeons amounting to $8,469,121. Most of these contribution dollars were directed to Independent committees (47.9%). Of all Independent contribution dollars from 2005–2019, 95.9% were directed to the American Association of Neurological Surgeons Political Action Committee. The total number of unique contributions increased from 442 contributions in 2003 to 650 in 2019. Democrats experienced the most substantial increase in support, from 4.8% of all contribution dollars in 2003 to 26.3% in 2019. Republican support was noted to be more widespread across the United States compared with Democratic support. Conclusions Political contributions from U.S. neurosurgeons have increased steadily over time. Donations were largely Independent but became increasingly partisan in recent years. Overall, this displays an increase in political involvement among the neurosurgeon community. Future studies are warranted into how this involvement translates to representative health policy.

Rivaroxaban and apixaban are direct oral anticoagulants increasing in popularity as convenient alternatives to warfarin. However, current guidelines recommend against use in patients with a BMI > 40 kg/m2 or bodyweight > 120 kg unless drug-specific levels are measured, which may not be feasible across all clinical practices. Accordingly, the objective of this study was to broadly examine literature evaluating the clinical outcomes of rivaroxaban and/or apixaban in patients with increased body mass. A systematic literature review (guided by PRISMA) was performed through January 27, 2021 using PubMed, Embase, and Scopus. Key search term clusters included drug and weight-related concepts (overweight/obese, body mass index [BMI], waist circumference). DistillerSR was utilized to review and process search results. Studies met inclusion if they analyzed the risk of bleeding and/or thrombosis in patients with increased body mass (i.e., via BMI or other criteria) receiving rivaroxaban or apixaban. Clinical guidelines, case reports/series, pharmacokinetic/dynamic analyses, and commentaries were excluded. Bias was examined qualitatively across studies. After duplicates were removed, the original search rendered 1822 abstracts and 200 full-texts for screening, ultimately providing a final set of 24 studies for qualitative review. Of these studies, 13 (54.2%) enabled comparisons between patients of increased versus normal body mass, while 11 (45.8%) reported outcomes only for patients of increased body mass. The working definition of ‘increased body mass’ varied amongst the studies, including 11 (45.8%) studies that utilized BMI, seven (29.2%) with a combination of BMI and body measurement, two (8.3%) that relied on body weight alone, and four (16.7%) that identified obesity-related ICD codes. All 13 comparative studies found similar or reduced rates of safety and efficacy outcomes with rivaroxaban and apixaban. The literature reports similar or lower bleeding and thrombotic risk for rivaroxaban and apixaban in patients of increased body mass compared to patients of normal body mass. Future prospective controlled studies are needed to further define guidelines for use in this population.

BackgroundRecent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked power to integrate molecular and clinical findings. The different proposed subgroup structures also highlighted a need to reach consensus on a robust and relevant classification system.MethodsWe performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical and genomic features of patients and samples from these pineal tumor subgroups were annotated.FindingsFour clinically and biologically relevant consensus PB subgroups were defined: PB-miRNA1 (n=96), PB-miRNA2 (n=23), PB-MYC/FOXR2 (n=34) and PB-RB1 (n=25); with PPTID (n=43) remaining as a molecularly distinct entity. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual subgroups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection and metastatic status varied significantly among tumor subgroups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 and PB-RB1.InterpretationWe systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease subgroups, laying the groundwork for future studies as well as routine use in tumor classification.

Craniometaphyseal dysplasia (CMD) is a rare genetic disease affecting bone metabolism with sclerosis of craniofacial bones. Orthognathic surgery has rarely been described in this patient population due to the bony thickness, making osteotomies challenging. We present a 19-year-old male with CMD with malocclusion, severe midface hypoplasia, and obstructive sleep apnea. With the aid virtual planning, we safely performed a combined LeFort III/I midface advancement to correct a negative overjet to improve occlusal balance, decrease scleral show, and diminish daytime sleepiness.

A massive localized trauma to the spinal cord results in complex pathologic events driven by necrosis and vascular damage which in turn leads to hemorrhage and edema. Severe, destructive and very protracted inflammatory response is characterized by infiltration by phagocytic macrophages of a site of injury which is converted into a cavity of injury (COI) surrounded by astroglial reaction mounted by the spinal cord. The tissue response to the spinal cord injury (SCI) has been poorly understood but the final outcome appears to be a mature syrinx filled with the cerebrospinal fluid with related neural tissue loss and permanent neurologic deficits. This paper reviews known pathologic mechanisms involved in the formation of the COI after SCI and discusses the integrative role of reactive astrogliosis in mechanisms involved in the removal of edema after the injury. A large proportion of edema fluid originating from the trauma and then from vasogenic edema related to persistent severe inflammation, may be moved into the COI in an active process involving astrogliosis and specifically over-expressed aquaporins.

Objective:To determine the usefulness of adjusting antibiotic use (AU) by prevalence of bacterial isolates as an alternative method for risk adjustment beyond hospital characteristics.Design:Retrospective, observational, cross-sectional study.Setting:Hospitals in the southeastern United States.Methods:AU in days of therapy per 1,000 patient days and microbiologic data from 2015 and 2016 were collected from 26 hospitals. The prevalences of Pseudomonas aeruginosa, extended-spectrum β-lactamase (ESBL)–producing bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE) were calculated and compared to the average prevalence of all hospitals in the network. This proportion was used to calculate the adjusted AU (a-AU) for various categories of antimicrobials. For example, a-AU of antipseudomonal β-lactams (APBL) was the AU of APBL divided by (prevalence of P. aeruginosa at that hospital divided by the average prevalence of P. aeruginosa). Hospitals were categorized by bed size and ranked by AU and a-AU, and the rankings were compared.Results:Most hospitals in 2015 and 2016, respectively, moved ≥2 positions in the ranking using a-AU of APBL (15 of 24, 63%; 22 of 26, 85%), carbapenems (14 of 23, 61%; 22 of 25; 88%), anti-MRSA agents (13 of 23, 57%; 18 of 26, 69%), and anti-VRE agents (18 of 24, 75%; 15 of 26, 58%). Use of a-AU resulted in a shift in quartile of hospital ranking for 50% of APBL agents, 57% of carbapenems, 35% of anti-MRSA agents, and 75% of anti-VRE agents in 2015 and 50% of APBL agents, 28% of carbapenems, 50% of anti-MRSA agents, and 58% of anti-VRE agents in 2016.Conclusions:The a-AU considerably changes how hospitals compare among each other within a network. Adjusting AU by microbiological burden allows for a more balanced comparison among hospitals with variable baseline rates of resistant bacteria.

PurposePerceptual judgments of articulatory function are commonly used by speech-language pathologists to evaluate articulatory performance in individuals with amyotrophic lateral sclerosis (ALS). The goal of this study was to evaluate the psychometric properties (e.g., reliability, validity) of these perceptual measures to inform their application as part of a comprehensive bulbar assessment tool in ALS.MethodPreexisting data from 51 individuals with ALS were obtained from a larger longitudinal study. Five independent raters provided perceptual judgments of articulatory rate and imprecision in a sentence task. Inter- and intrarater reliability of these judgments were assessed. Perceptual ratings were correlated with an acoustic measure of articulatory rate, in syllables per second, obtained from passage-reading recordings. Both perceptual and acoustic measures were correlated with gold-standard kinematic tongue and jaw movement measures, recorded from sentences using electromagnetic articulography.ResultsThe results revealed good inter- and intrarater reliability of perceptual judgments of articulatory function. Strong correlations were observed between perceptual ratings of articulatory rate and imprecision and acoustic measures of articulatory rate and kinematic measures of tongue speed.ConclusionsThese findings support the clinical application of perceptual judgments of articulatory function as valid and reliable measures of underlying articulatory changes in bulbar ALS. Additional research is needed to understand the responsiveness of these measures to clinical changes in articulatory function in ALS.

Background Reports of gabapentinoid (gabapentin and pregabalin) misuse are on the rise, but few studies have assessed this within the general US population. Objective Describe lifetime misuse/abuse/non-prescribed obtainment of gabapentinoids and descriptive characteristics associated with such actions in a US general population sample. Setting This cross-sectional questionnaire was administered online by Qualtrics® research panel aggregator via quota-based sampling. Methods Data were collected from a sample of respondents that mirrored the general US population aged 18–59 years with regards to age, geographic region, ethnicity, income, and education level, based on most recent census data. Misuse/abuse/non-prescribed obtainment was collectively defined as use of a gabapentinoid for reasons other than a diagnosed medical condition, using with the intention of altering one’s state of consciousness, or obtaining without a prescription. A multivariable logistic regression model was created to predict misuse/abuse/non-prescribed obtainment of gabapentinoids, incorporating relevant covariates. Main outcome measure Proportion of sample indicating lifetime misuse/abuse/non-prescribed obtainment of gabapentinoids. Results Among 1,843 respondents, 121 (6.6%) reported gabapentinoid misuse/abuse/non-prescribed obtainment. Specifically, 2.1% (n = 39) and 1.5% (n = 27) of respondents for gabapentin and pregabalin, respectively, met study criteria for abuse. Opioids were the most common medication co-administered with gabapentinoids (among 50–70% of respondents) for misuse/abuse. Previous treatment for addiction (OR: 2.61, 95% CI: 1.32–5.14, p = 0.005) and the total attitudinal risk score (OR: 1.14, 95% CI: 1.09–1.19, p

We describe a novel endovascular technique in which three 0.014″ guidewires are placed in parallel through a 0.035″ lumen catheter, in order to create a stiff platform to allow for delivery of 0.035″ profile devices through challenging anatomy. Three illustrative cases are presented: a difficult aortic bifurcation during lower extremity intervention, a tortuous internal iliac artery during placement of an iliac branch device, and salvage of a renal artery after inadvertent coverage during proximal cuff deployment for type 1a endoleak. We also quantify the relative stiffness of the triple 0.014″ wire configuration, using several well-known 0.035″ wires for comparison. The "triple wire technique" is an effective method for tracking endovascular devices through difficult tortuous anatomy, and can be used in a variety of clinical settings. The technique is especially useful when a traditional, stiff 0.035″ wire will not track without "kicking out." Each 0.014″ wire is reasonably soft and traverses the tortuous vessel easily, but when the 3 wires are used together as a rail it provides a stiff enough platform for delivery.

A 2017 systematic review (SR) identified 59 studies examining gabapentinoid (pregabalin and gabapentin) misuse/abuse. Evidence of gabapentinoid misuse/abuse has since grown substantially. Update previous SR and describe new insights regarding gabapentinoid abuse. A SR of PubMed was conducted to identify studies published from 7/29/2016–8/31/2020. Four searches were performed using the following terms: “gabapentin [MeSH] OR pregabalin [MeSH] OR gabapentinoid” AND one of the following substance misuse/abuse-related terms: “substance-related disorders [MeSH]”, “overdose”, “abuse”, or “misuse”. Clinicaltrials.gov and the Cochrane Library database were searched to identify ongoing studies or similar SRs. Reference lists of included studies were reviewed to identify additional literature. All studies with novel data related to pregabalin and/or gabapentin abuse, misuse, or overdose conducted during the study period were included. Articles not written in English, review articles, and animal studies were excluded. Fifty-five studies were included (29 [52.7%] from North America, 17 [30.9%] Europe, 6 [10.9%] Asia, and 3 [5.5%] Australia). Forty-six observational studies and 10 case reports/series were included (one manuscript included both). Twenty (36.4%) studied gabapentin only, 18 (32.7%) pregabalin only, and 17 (30.9%) both pregabalin/gabapentin. These studies corroborate findings from the previous SR that gabapentinoids are increasingly abused or misused to self-medicate, that gabapentinoids can produce desirable effects alone but are often used concomitantly with other drugs, and that opioid use disorder is the greatest risk factor for gabapentinoid abuse. While the original SR identified the largest studies having been published in Europe, this review identified several more generalisable US studies that have subsequently been conducted. The most concerning finding was increased evidence of associated patient harm, including increased hospital utilisation and opioid-related overdose mortality risk. Evidence suggests that gabapentinoid misuse/abuse represents a growing trend that is causing significant patient harm. Prescribers should exercise appropriate caution with use in high-risk populations and monitor for signs of misuse or abuse.

Study objective The change in reimbursement rates for emergency physician services has yet to be quantified. We attempted to fill this knowledge gap by evaluating the monetary trends in Medicare reimbursement rates over the last 20 years for the most common emergency medicine services. Methods We obtained commonly used Current Procedural Terminology (CPT) codes in emergency medicine from the American College of Emergency Physicians website. We queried the Physician Fee Schedule Look-Up Tool from the Centers for Medicare & Medicaid Services for each of the included CPT codes, and we extracted reimbursement data. We adjusted all monetary data for inflation to 2020 US dollars by using changes to the United States consumer price index. Both the average annual and the total percentage change in reimbursement were calculated on the basis of these adjusted trends for all included services. Results Reimbursement by Medicare for the services decreased by an average of 29.13% from 2000 to 2020 after adjusting for inflation. There was a stable decline in adjusted reimbursement rates throughout the study period, with an average decrease of 1.61% each year. The largest decrease was seen for laceration repairs up to 7.5 cm, with reimbursement rates for all 4 relevant CPT codes decreasing by more than 60%. Conclusion When adjusted for inflation, Medicare reimbursement declined by an average of 29% over the last 20 years for the 20 most common emergency medicine services. Knowledge of these trends is essential to address current controversies in emergency medicine billing adequately and advocate for sustainable payment system reform.

The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown. We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival. Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5–0.7). Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.

Viral infections of the central nervous system (CNS) often cause disease in an age-dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.

Ultrasound-enhanced catheter-directed thrombolysis (UET) using the Ekosonic® Endovascular System device for acute, peripheral arterial ischemia has been purported in clinical trials to accelerate the fibrinolytic process to reduce treatment time and lytic dosage. We aim to describe outcomes of UET in a real-world clinical setting.We performed a retrospective review of all patients undergoing UET for acute limb ischemia at a single institution. Data collected included patient demographics, procedural details, and 30-day and 1-year outcomes. The primary endpoints for analysis were major adverse limb events (MALEs; reintervention and/or amputation) and mortality within 30-days and 1-year. Secondary endpoints included technical success, use of adjunctive therapies, and postoperative complications.A total of 32 patients (mean age 67.4 ± 14.9 years; 25% women) underwent UET for acute limb ischemia between 2014 and 2018. The Rutherford Acute Limb Ischemia Classification was Rutherford (R) 1 in 56.3%, R2a in 31.3%, and R2b in 12.5%. Etiology was thrombosis of native artery in 12.5% of patients, prosthetic bypass in 31.3%, autogenous bypass in 6.3%, and stented native vessel in 50.0%. Mean duration of thrombolytic therapy was 22.2 ± 11.3 hr, and mean tissue plasminogen activator dose was 24.5 ± 15.3 mg. MALEs occurred in 16.7% of patients within the first 30 days and 38.9% experienced a MALE by 1 year. Limb salvage at 30 days and 1 year was 93.8% and 87.5%, respectively. Ipsilateral reintervention was required in 12.5% of patients within 30 days and 37.5% of patients within 1 year. Overall mortality was 6.2% at 30 days and 13.5% at 1 year. In-line flow to the foot was re-established in 90.6% of patients, with a significant improvement in preoperative to postoperative ankle-brachial index (0.31 ± 0.29 vs. 0.78 ± 0.34, P 0.001) and number of patent tibial runoff vessels (1.31 ± 1.20 vs. 1.96 ± 0.86, P 0.001). There was no significant difference in revascularization success between occluded vessel types. All but one patient required adjunctive therapy such as further thromboaspiration, stenting, or balloon angioplasty. Major bleeding complications occurred in 3 patients (9.4%), including 1 intracranial hemorrhage (3.1%).UET with the EKOS device demonstrates acceptable real-world outcomes in the treatment of acute limb ischemia. UET is generally safe and effective at re-establishing in-line flow to yield high limb salvage rates. However, UET is associated with a high rate of reintervention. Further investigation is needed into specific predictors of limb salvage and need for reintervention, as well as cost-efficacy of this technology compared with that of traditional methods.

Objective.Early diagnosis of systemic sclerosis (SSc) is imperative, and Raynaud phenomenon (RP) is an important component of progressive vasculopathy. Nailfold videocapillaroscopy (NVC) is a well-established tool that can quantify structural vascular abnormalities. Digital thermal monitoring (DTM) assesses microvascular functional dysfunction related to thermoregulation. In this study, we investigated the correlation of NVC patterns and DTM variables in patients with SSc.Methods.Patients with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism criteria who consented and enrolled in the clinical care registry had NVC and DTM performed. For NVC, the number of capillaries (density), measurement of apical diameter (dimension), presence or absence of hemorrhages, and number of abnormal shapes were assessed to categorize 3 different qualitative patterns: early, active, and late. For DTM, Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery, and fingertip vascular function were assessed, and a vascular reactivity index (VRI) measurement was automated. Statistical evaluation was performed by nonparametric tests to assess the correlation of NVC and VRI.Results.Thirty-one SSc subjects with interpretable NVC and DTM performed on the same day were included in the study. VRI was progressively higher in SSc patients with early, active, and late NVC patterns of microangiopathy (P < 0.0001). There was a significant negative correlation between VRI and microhemorrhages scores (r = –0.363, P = 0.044).Conclusion.Our study suggests that more advanced vasculopathy correlates to reduced microvascular function as detected by DTM and more advanced structural abnormalities detected by NVC. NVC and DTM may provide different aspects of vasculopathy quantification and complement each other as investigative tools.

Despite its recognized value, there is a gap in the assessment of patient satisfaction among patients with substance use disorder (SUD) in rehabilitation. The study objective was to determine patient satisfaction dimensions relevant to individuals receiving residential rehabilitation for SUD. Semi-structured interviews were conducted with the following: (1) adult males enrolled in the program and (2) counseling staff involved in the care of these individuals. A literature review formed the basis for interviews, which were audio recorded and transcribed. Text data was analyzed using directed content analysis to identify dimensions relevant to patient satisfaction. Eighteen individuals participated, including 14 men with SUD and four staff. Content analysis of the interview transcripts resulted in five themes: (1) counselor (skill), (2) programmatic structure (adhering), (3) skill development (personal responsibility), (4) comparison to other programs, and (5) case management facilitation. These dimensions will be utilized to create a patient satisfaction tool specific to SUD rehabilitation.

Objectives The superficial femoral artery can be used as inflow for infra-geniculate bypass, but progressive proximal occlusive disease may affect graft durability. We sought to evaluate the effect of superficial femoral artery versus common femoral artery inflow on infra-geniculate bypass patency within a large contemporary multicenter registry. Methods The vascular quality initiative was queried from 2013 to 2019 to identify patients with >30-day patency follow-up, Rutherford chronic limb ischemia stage 1–6, and an infra-geniculate bypass, excluding those with prior ipsilateral bypass. The cohort was stratified by inflow vessel, with primary, primary-assisted, and secondary patency serving as the primary outcome variables. Multivariate Cox-proportional hazard models and radius-based propensity-score matching were performed to reduce treatment-selection bias due to clinical covariates. Results A total of 11,190 bypass procedures were performed (8378 common femoral artery inflow, 2812 superficial femoral artery) on 10,110 patients, with a mean follow-up of 12.8 months (range 1–98). Patients receiving superficial femoral artery inflow bypasses were more commonly male ( p = 0.002), obese ( p Conclusions Within the vascular quality initiative, there is no significant difference in life-table determined three-year primary, primary-assisted, and secondary patency between infra-geniculate bypasses using common femoral artery inflow compared to superficial femoral artery inflow. Small, statistically significant differences exist in primary, primary-assisted, and secondary patency favoring common femoral artery inflow after propensity score matching. Long-term follow-up data are required in the vascular quality initiative to better evaluate bypass graft durability as this study was limited by a mean follow-up of one year.

Imipenem-cilastatin-relebactam (IMI-REL) is a novel β-lactam-β-lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β-lactamase inhibitor with the ability to inhibit a broad spectrum of β-lactamases such as class A and class C β-lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem-resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI-REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem-resistant bacteria. In a phase III trial comparing IMI-REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30-minute infusion of imipenem 500 mg-cilastatin 500 mg-relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI-REL represents another important step in the ongoing fight against multidrug-resistant gram-negative pathogens.

To evaluate the impact of an ambulatory clinical pharmacy service (inclusive of immunization needs assessments) on the frequency and appropriateness of pneumococcal vaccine administration in a family medicine clinic.This cohort study had an observational and retrospective design and included patients who received pneumococcal vaccines at a family medicine clinic in a medically underserved area in Southwestern Pennsylvania across a 42-month period from January 1, 2015, to June 30, 2018. The outcome measures included the administration and appropriateness of pneumococcal 13-valent conjugate (PCV13) and pneumococcal 23-valent polysaccharide (PPSV23) vaccines across 3 time cohorts including before, during, and after the establishment of a clinical pharmacy service.A total of 457 pneumococcal vaccines were administered, including 198 (43.3%) PCV13 and 259 (56.7%) PPSV23, across all time cohorts. Overall vaccine administration per month increased by 143% with the introduction of a dedicated clinical pharmacy service, including a 270% increase for PCV13 and an 87% increase for PPSV23. A strong correlation was found between recommendations made and doses administered for both pneumococcal vaccines (r = 0.89; P0.003). Across the entire time frame, PPSV23 administrations were appropriate in more than 96% of instances, whereas the appropriateness of PCV13 administrations were statistically significantly improved after the introduction of a fully dedicated clinical pharmacy service (58.5% vs. 90.8%; P0.05). The appropriateness of vaccine administration remained high even after the reduction of clinical pharmacy services.Clinical pharmacy service implementation in a family medicine clinic was associated with increased pneumococcal vaccine administration and increased appropriateness of PCV13 administrations.

This study investigated effects of rate reduction and emphatic stress cues on second formant (F2) trajectories and articulatory movements during diphthong production in 11 typically developing school-aged children. F2 extent increased in slow and emphatic stress conditions, and tongue and jaw displacement increased in the emphatic stress condition compared to habitual speech. Tongue displacement significantly predicted F2 extent across speaking conditions. Results suggest that slow rate and emphatic stress cues induce articulatory and acoustic changes in children that may enhance clarity of the acoustic signal. Potential clinical implications for improving speech in children with dysarthria are discussed.

Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.

SUMMARY Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses., Graphical Abstract, In Brief Nobre et al. analyze a clinically annotated cohort of 93 WNT-activated medulloblastoma using an integrated genomic approach. A maintenance chemotherapy regimen is the strongest predictor of relapse, and cumulative cyclophosphamide doses confer a reduced risk of relapse. Unlike other medulloblastoma subgroups, WNT-activated medulloblastoma recurs most frequently in the lateral ventricles.

BackgroundWe sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI).MethodsRetrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria.ResultsIn total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929–11.499), no medical insurance (aOR 3.451, 95% CI 1.310–9.090), ICU residence (aOR 4.398, 95% CI 1.676–11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158–7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037–1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days,p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%,p p = 0.024)ConclusionsV-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy.

Background: A vancomycin target of area under the curve to minimum inhibitory concentration (AUC:MIC) ratio ≥400 is recommended for treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Objective: To evaluate vancomycin total daily dose (TDD) achieving trough targets versus a calculated strategy achieving AUC targets based on body mass index (BMI). Methods: A retrospective cohort study was performed within a large hospital network. Patients with MRSA bacteremia were eligible if they received vancomycin with a steady-state trough (15-20 mg/L). Cockcroft-Gault was used to estimate creatinine clearance, calculating vancomycin clearance and AUC. Patients were stratified by BMI (less than/greater than 30 kg/m2). The primary outcome was vancomycin TDD for the trough-based strategy compared with an AUC-dosing strategy. Results: A total of 119 patients were included, including 51 (42.9%) and 68 (57.1%) patients with high- and low-BMI, respectively. The TDD for trough-based dosing (2390.76 ± 1224.59 mg) differed significantly from AUC-based dosing (1985.07 ± 616.18 mg) across the cohort ( P = 0.0014). For patients with high BMI, there was a significant difference ( P < 0.0001) in TDD between trough (2637.25 ± 1327.89 mg) versus AUC (1918.71 ± 625.89 mg) strategies. No difference in TDD between dosing strategies was observed among low-BMI patients. Across all patients, 46 (38.7%) experienced acute kidney injury (AKI); high-BMI patients experienced higher rates of AKI compared with low-BMI patients (54.9 vs 26.5%; P = 0.002). Conclusions and Relevance: An AUC-based dosing strategy may reduce vancomycin TDD required for MRSA bacteremia compared with trough-based dosing, particularly for patients with higher BMI.

Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. Patients and Methods: Patients ages 1 to Results: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.

Objective To evaluate for differences in time to decannulation and survival rates for pediatric tracheotomy patients based on ventilator status upon discharge. Study design Retrospective longitudinal cohort study. Methods A single-institution longitudinal study of pediatric tracheostomy patients was conducted. Patients were categorized based on mechanical ventilation status on discharge and principal reason for tracheostomy. Survival rates were determined using the Kaplan-Meier method. The Wilcoxon's Rank Sum test and Cox regression analysis evaluated differences in survival times and time to decannulation based on primary indication for tracheotomy and ventilation status. Results Chart review identified 305 patients who required a tracheostomy under the age of 3. The median age at the time of tracheotomy was 5.2 months. The indications for tracheotomy in these patients were airway obstruction in 145 (48%), respiratory failure in 214 (70%), and pulmonary toilet in 10 (3.3%). Seventy-nine percent of patients were ventilator dependent at discharge. At the conclusion of the study period, 55% of patients were alive with tracheostomy in place, 30% patients were decannulated, and 15% patients were deceased. Patients with ventilator dependence at initial discharge, bronchopulmonary dysplasia, or airway obstruction were more likely to be decannulated. Hispanic patients were less likely to be decannulated. Patients had an equal probability of death regardless of ventilator status at discharge. Conclusions This study demonstrated that the time to decannulation and likelihood of decannulation varies based on the indication for the tracheostomy. The majority of patients with a tracheostomy were not decannulated at the conclusion of this study. Median time to decannulation was 2.5 years for patients with a median death time of 6 months. Level of evidence 2b Laryngoscope, 130:2319-2324, 2020.

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Background Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide-ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity. Methods A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF-focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome. Results Thirty-three adults with CF-CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF-related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance. Conclusion Sex, CF-related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF-CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

Traumatic brain injury (TBI) is a major cause of chronic disability. Less than a quarter of moderate and severe TBI patients improved in their cognition within 5 years. Non-invasive brain stimulation, including transcranial direct current stimulation (tDCS), may help neurorehabilitation by boosting adaptive neuroplasticity and reducing pathological sequelae following TBI.we searched MEDLINE/PubMed and Web of Science databases. We used Jadad scale to assess methodological assumptions.the 14 papers included reported different study designs; 2 studies were open-label, 9 were crossover randomized clinical trials (RCTs), and 3 were parallel group RCTs. Most studies used anodal tDCS of the left dorsolateral prefrontal cortex, but montages and stimulation parameters varied. Multiple studies showed improved coma recovery scales in disorders of consciousness, and improved cognition on neuropsychological assessments. Some studies showed changes in neurophysiologic measures (electroencephalography (EEG) and transcranial magnetic stimulation (TMS), correlating with clinical findings. The main methodological biases were lack of blinding and randomization reports.tDCS is a safe, non-invasive neuromodulatory technique that can be given as monotherapy but may be best combined with other therapeutic strategies (such as cognitive rehabilitation and physical therapy) to further improve clinical cognitive and motor outcomes. EEG and TMS may help guide research due to their roles as biomarkers for neuroplasticity.A lesão cerebral traumática (TCE) é uma das principais causas de incapacidade crônica. Menos de um quarto dos pacientes com TCE moderada e grave melhoraram sua cognição dentro de cinco anos. A estimulação cerebral não invasiva, incluindo a estimulação transcraniana por corrente contínua (ETCC), pode ajudar na reabilitação neurológica, aumentando a neuroplasticidade adaptativa e reduzindo as sequelas patológicas após o TCE.pesquisamos os bancos de dados MEDLINE / PubMed e Web of Science. Usamos a escala de Jadad para avaliar os métodos utilizados nos ensaios clínicos.os 14 artigos incluídos relataram diferentes desenhos de estudo; 2 estudos foram abertos, 9 foram ensaios clínicos randomizados (ECRs) cruzados e 3 foram ECR de grupos paralelos. A maioria dos estudos utilizou a ETCC anódica do córtex pré-frontal dorsolateral esquerdo, mas os parâmetros de montagem e estimulação variaram. Múltiplos estudos mostraram melhoras nas escalas de recuperação de coma em pacientes com distúrbios da consciência e melhora da cognição. Alguns estudos mostraram alterações nas medidas neurofisiológicas (eletroencefalografia (EEG) e estimulação magnética transcraniana (EMT)), correlacionando com os achados clínicos. Os principais vieses metodológicos foram a falta de relatos de cegamento e randomização.a ETCC é uma técnica neuromodulatória segura e não invasiva que pode ser administrada em monoterapia, mas a utilização da ETCC parece impulsionar os resultados clínicos quando combinada com outras estratégias terapêuticas (como reabilitação cognitiva e fisioterapia). O EEG e o EMT podem ajudar a orientar a pesquisa e tambem mensurar os ganhos clínicos por serem potenciais biomarcadores da neuroplasticidade.

DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. Our analysis on ChIP-seq experiment in human embryonic stem cells (hESC) revealed that DNMT3B, mCA and H3K36me3 share the same genomic distribution profile. Deletion of DNMT3B or its histone-interacting domain (PWWP) demolished mCA in hESCs, suggesting that PWWP domain of DNMT3B directs the formation of mCA landscape. In contrast to the common presumption that PWWP guides DNMT3B-mediated mCG deposition, we found that deleting PWWP does not affect the mCG landscape. Nonetheless, DNMT3B knockout led to the formation of 2985 de novo hypomethylated regions at annotated promoter sites. Upon knockout, most of these promoters gain the bivalent marks, H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping the mCA landscape and for maintaining the fidelity of the bivalent promoters in hESCs.

Background Ischemia-reperfusion injury (IRI) is an antigen-independent, innate immune response to arterial occlusion and ischemia with subsequent paradoxical exacerbation after reperfusion. IRI remains a critical problem after vessel occlusion and infarction or during harvest and surgery in transplants. After transplant, liver IRI (LIRI) contributes to increased acute and chronic rejection and graft loss. Tissue loss during LIRI has been attributed to local macrophage activation and invasion with excessive inflammation together with hepatocyte apoptosis and necrosis. Inflammatory and apoptotic signaling are key targets for reducing post-ischemic liver injury. Myxomavirus is a rabbit-specific leporipoxvirus that encodes a suite of immune suppressing proteins, often with extensive function in other mammalian species. Serp-2 is a cross-class serine protease inhibitor (serpin) which inhibits the inflammasome effector protease caspase-1 as well as the apoptotic proteases granzyme B and caspases 8 and 10. In prior work, Serp-2 reduced inflammatory cell invasion after angioplasty injury and after aortic transplantation in rodents. In this report, we explore the potential for therapeutic treatment with Serp-2 in a mouse model of LIRI. Methods Wildtype (C57BL/6 J) mice were subjected to warm, partial (70%) hepatic ischemia for 90 min followed by treatment with saline or Serp-2 or M-T7, 100 ng/g/day given by intraperitoneal injection on alternate days for 5 days. M-T7 is a Myxomavirus-derived inhibitor of chemokine-GAG interactions and was used in this study for comparative analysis of an unrelated viral protein with an alternative immunomodulating mechanism of action. Survival, serum ALT levels and histopathology were assessed 24 h and 10 days post-LIRI. Results Serp-2 treatment significantly improved survival to 85.7% percent versus saline-treated wildtype mice (p = 0.0135), while M-T7 treatment did not significantly improve survival (p = 0.2584). Liver viability was preserved by Serp-2 treatment with a significant reduction in serum ALT levels (p = 0.0343) and infarct scar thickness (p = 0.0016), but with no significant improvement with M-T7 treatment. Suzuki scoring by pathologists blinded with respect to treatment group indicated that Serp-2 significantly reduced hepatocyte necrosis (p = 0.0057) and improved overall pathology score (p = 0.0046) compared to saline. Immunohistochemistry revealed that Serp-2 treatment reduced macrophage infiltration into the infarcted liver tissue (p = 0.0197). Conclusions Treatment with Serp-2, a virus-derived inflammasome and apoptotic pathway inhibitor, improves survival after liver ischemia-reperfusion injury in mouse models. Treatment with a cross-class immune modulator provides a promising new approach designed to reduce ischemia-reperfusion injury, improving survival and reducing chronic transplant damage. Electronic supplementary material The online version of this article (10.1186/s12950-019-0215-1) contains supplementary material, which is available to authorized users.

The ability to differentiate post-cancer from healthy tongue muscle coordination patterns is necessary for the advancement of speech motor control theories and for the development of therapeutic and rehabilitative strategies. A deep learning approach is presented to classify two groups using muscle coordination patterns from magnetic resonance imaging (MRI). The proposed method uses tagged-MRI to track the tongue's internal tissue points and atlas-driven non-negative matrix factorization to reduce the dimensionality of the deformation fields. A convolutional neural network is applied to the classification task yielding an accuracy of 96.90%, offering the potential to the development of therapeutic or rehabilitative strategies in speech-related disorders.

ObjectiveTo evaluate whether a quantitative speech measure is effective in identifying and monitoring motor speech impairment (MSI) in patients with primary progressive aphasia (PPA) and to investigate the neuroanatomical basis of MSI in PPA.MethodsSixty-four patients with PPA were evaluated at baseline, with a subset (n = 39) evaluated longitudinally. Articulation rate (AR), a quantitative measure derived from spontaneous speech, was measured at each time point. MRI was collected at baseline. Differences in baseline AR were assessed across PPA subtypes, separated by severity level. Linear mixed-effects models were conducted to assess groups differences across PPA subtypes in rate of decline in AR over a 1-year period. Cortical thickness measured from baseline MRIs was used to test hypotheses about the relationship between cortical atrophy and MSI.ResultsBaseline AR was reduced for patients with nonfluent variant PPA (nfvPPA) compared to other PPA subtypes and controls, even in mild stages of disease. Longitudinal results showed a greater rate of decline in AR for the nfvPPA group over 1 year compared to the logopenic and semantic variant subgroups. Reduced baseline AR was associated with cortical atrophy in left-hemisphere premotor and supplementary motor cortices.ConclusionsThe AR measure is an effective quantitative index of MSI that detects MSI in mild disease stages and tracks decline in MSI longitudinally. The AR measure also demonstrates anatomic localization to motor speech–specific cortical regions. Our findings suggest that this quantitative measure of MSI might have utility in diagnostic evaluation and monitoring of MSI in PPA.