ABSTRACT
Areas of dense population congregation are prone to experience respiratory virus outbreaks. We monitored wastewater and clinic patients for the presence of respiratory viruses on a large, public university campus. Campus sewer systems were monitored in 16 locations for the presence of viruses using next generation sequencing over 22 weeks in 2023. During this period, we detected a surge in human adenovirus (HAdV) levels in wastewater. Hence, we initiated clinical surveillance at an on-campus clinic from patients presenting with acute respiratory infection. From whole genome sequencing of 123 throat and/or nasal swabs collected, we identified an outbreak of HAdV, specifically of HAdV-E4 and HAdV-B7 genotypes overlapping in time. The temporal dynamics and proportions of HAdV genotypes found in wastewater were corroborated in clinical infections. We tracked specific single nucleotide polymorphisms (SNPs) found in clinical virus sequences and showed that they arose in wastewater signals concordant with the time of clinical presentation, linking community transmission of HAdV to the outbreak. This study demonstrates how wastewater-based epidemiology can be integrated with surveillance at ambulatory healthcare settings to monitor areas prone to respiratory virus outbreaks and provide public health guidance.
Subject(s)
Respiratory Tract Infections , Wastewater , Wastewater/virology , Universities , Humans , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Adenoviruses, Human/genetics , Adenoviruses, Human/isolation & purification , Disease Outbreaks , Genotype , Environmental Monitoring/methodsABSTRACT
INTRODUCTION: Femoral-popliteal bypass (FPB) surgery is a common lower extremity revascularization procedure. As the population continues to age, this procedure is being performed increasingly on older patients. This study investigated whether outcomes differ in this population. MATERIALS AND METHODS: Patients over and less than 80 years old who underwent FPB between 2009-2013 were queried using an existing hospital registry. Demographics, comorbidities, intraoperative complications, perioperative outcomes, and two-year patencies were compared. RESULTS: Twenty-four patients in the octogenarian cohort (OC) and 72 patients in the non-octogenarian cohort (NOC) were identified. There was a lower prevalence of smoking (p=0.018) and higher prevalence of hypertension (p=0.021) among octogenarians. Other medical characteristics were similar (p<0.05). There were no differences in use of vein versus PTFE (p=0.002) as a conduit, or above (OC 20.0% vs. NOC 36.7%), versus below knee (OC 80.0% vs. NOC 63.3%) distal anastomosis (p>0.05) between the groups. There was a difference (p<0.01) in indication for procedure (OC/NOC): claudication (0%/44%), limb salvage (71%/31%), and rest pain (29%/25%). There were no differences in 30-day readmissions (17% vs. 21%; p=0.59) or incidence of postoperative (25% vs. 19%; p=0.56) or intraoperative complications (8.3% vs. 4.2%; p=0.52). Length of stay (LOS) was longer and statistically significant in octogenarians (12 days vs. 7 days; p=0.032) and remained significant after multivariate linear regression (p=0.015). Patencies in OC were lower and dropped faster after six months; however, there were no statistically significant differences in patencies at any time interval (p>0.05). The position of the distal anastomosis relative to the knee, conduit type, and indication were not independently predictive of patency outcomes (p>0.05). CONCLUSION: The safety and efficacy of FPB in octogenarians is similar to the general population despite LOS in octogenarians being 5.98 days longer. While the difference in indication suggests that vascular surgeons are more conservative in treating octogenarians, our analysis did not reveal significant differences between populations and suggests that lower extremity bypass can be performed safely with comparable results in this cohort. A larger cohort is needed to validate these results.
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The nasopharynx and its microbiota are implicated in respiratory health and disease. The interplay between viral infection and the nasopharyngeal microbiome is an area of increased interest and of clinical relevance. The impact of SARS-CoV-2, the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, on the nasopharyngeal microbiome, particularly among individuals living with HIV, is not fully characterized. Here we describe the nasopharyngeal microbiome before, during and after SARS-CoV-2 infection in a longitudinal cohort of Kenyan women (21 living with HIV and 14 HIV-uninfected) and their infants (18 HIV-exposed, uninfected and 18 HIV-unexposed, uninfected), followed between September 2021 through March 2022. We show using genomic epidemiology that mother and infant dyads were infected with the same strain of the SARS-CoV-2 Omicron variant that spread rapidly across Kenya. Additionally, we used metagenomic sequencing to characterize the nasopharyngeal microbiome of 20 women and infants infected with SARS-CoV-2, 6 infants negative for SARS-CoV-2 but experiencing respiratory symptoms, and 34 timepoint matched SARS-CoV-2 negative mothers and infants. Since individuals were sampled longitudinally before and after SARS-CoV-2 infection, we could characterize the short- and long-term impact of SARS-CoV-2 infection on the nasopharyngeal microbiome. We found that mothers and infants had significantly different microbiome composition and bacterial load (p-values <.0001). However, in both mothers and infants, the nasopharyngeal microbiome did not differ before and after SARS-CoV-2 infection, regardless of HIV-exposure status. Our results indicate that the nasopharyngeal microbiome is resilient to SARS-CoV-2 infection and was not significantly modified by HIV.
ABSTRACT
Areas of dense population congregation are prone to experience respiratory virus outbreaks. We monitored wastewater and clinic patients for the presence of respiratory viruses on a large, public university campus. Campus sewer systems were monitored in 16 locations for the presence of viruses using next generation sequencing over 22 weeks in 2023. During this period, we detected a surge in human adenovirus (HAdV) levels in wastewater. Hence, we initiated clinical surveillance at an on-campus clinic from patients presenting with acute respiratory infection. From whole genome sequencing of 123 throat and/or nasal swabs collected, we identified an outbreak of HAdV, specifically of HAdV-E4 and HAdV-B7 genotypes overlapping in time. The temporal dynamics and proportions of HAdV genotypes found in wastewater were corroborated in clinical infections. We tracked specific single nucleotide polymorphisms (SNPs) found in clinical virus sequences and showed that they arose in wastewater signals concordant with the time of clinical presentation, linking community transmission of HAdV to the outbreak. This study demonstrates how wastewater-based epidemiology can be integrated with surveillance at ambulatory healthcare settings to monitor areas prone to respiratory virus outbreaks and provide public health guidance.
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Purpose: Organizational approaches to physician burnout are limited. Training physician leaders to influence the organizational environment is a growing area of study. This study explored perceived physician leadership behaviors in response to burnout from the viewpoint of faculty physicians not in formal leadership positions. Understanding physician leadership behaviors from the viewpoint of those faculty being led can inform organizational strategy and leadership training to address physician burnout. Subjects and Methods: Interview requests were sent to 70 randomly identified faculty physicians from a roster containing all 1145 physician faculty that excluded the Pediatric Department, at an academic health care institution in Southern California. The first ten respondents were asked to participate in a 30-to-40-minute semi-structured virtual interview via Zoom. The interviewees were asked two questions pertaining to burnout and their perception of how leadership responded. The two questions were "What has leadership done to address burnout?" and "If you had five minutes to advise your leaders on burnout, what would you say?" The recorded interviews were transcribed, redacted, and then sent to two reviewers. Thematic analysis through iterative coding was completed, and categories were constructed that aligned with the two interview questions. Results: Overall, five themes were identified. These themes were organized according to the interview questions and broadly categorized as physician leadership behaviors observed that corresponded to the interview question of what leadership had done to address burnout and physician leadership behaviors desired corresponding to the second interview question of what advice should be given. Leadership behaviors observed in the context of burnout included three themes; referral to individual wellness programs, increased number of meetings and events, and a lack of agency in addressing wellness issues. The two themes of leadership behaviors desired were the obtainment of more resources and the granting of greater appreciation and recognition for work done through enhanced communication. Conclusion: This small study of faculty physician perceptions of leadership behaviors identified several themes that had been identified in previous studies of leadership and burnout; need for relationship building through communication, need for resources to address work issues, and referral to wellness programs. However, the identification of a lack of agency in addressing factors in the wellness environment has not been identified in the previous burnout and physician leadership literature. Further study into the causes of this perceived lack of agency should be explored. Understanding the root causes of physician leaders' lack of agency can further inform physician leadership education as an organizational approach to burnout.
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3D image-guidance platforms have transformed spinal surgery by enhancing visualization, increasing precision, and improving patient outcomes. However, with high procurement, operational, and maintenance costs relative to the standard of care, the benefits of acquiring these platforms must be thoroughly assessed. This study aims to develop a model that weighs the cost of a typical 3D navigation platform against its clinical benefits to determine the facility case volume required to justify its purchase. Using Medtronic's StealthStation and O-Arm as a market example, we calculated the break-even case volume by dividing the cost of the platform by the difference in gross margins between 3D navigation and the standard of care. Total gross margins earned from first-time and revision surgeries were calculated based on each payer's reimbursement rate and covered case volume, as well as each technology's revision rate. Values reported in literature and by Centers for Medicare and Medicaid Services databases were plugged into the model to calculate variables. At a 0% reimbursement rate from private payers for revision surgeries, an annual case volume of 158 spinal surgeries would be required to justify the per-year 3D navigation cost; at 100% private payer reimbursement, 352 surgeries would be required. Given these volumes, 61% of all US inpatient facilities cannot justify 3D navigation at 0% reimbursement, and 86% cannot justify it at 100% reimbursement. Accordingly, greater pricing flexibility, such as per-procedure models, is required for 3D navigation systems to standardize clinical outcomes across medical centers.
Subject(s)
Imaging, Three-Dimensional , Surgery, Computer-Assisted , Aged , United States , Humans , Cost-Benefit Analysis , Medicare , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).
Subject(s)
Antibodies, Monoclonal, Humanized , B7-H1 Antigen , Sarcoma, Alveolar Soft Part , Adolescent , Adult , Child , Humans , Infant, Newborn , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Body Weight , Sarcoma, Alveolar Soft Part/drug therapy , Administration, IntravenousABSTRACT
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, mutations arise that will allow the virus to evade immune defenses and therapeutics. Assays that can identify these mutations can be used to guide personalized patient treatment plans. Digital PCR (dPCR) is a fast and reliable complement to whole-genome sequencing that can be used to discriminate single nucleotide polymorphisms (SNPs) in template molecules. Here, we developed a panel of SARS-CoV-2 dPCR assays and demonstrate its applications for typing variant lineages and therapeutic monoclonal antibody resistance. We first designed multiplexed dPCR assays for SNPs located at residue 3395 in the orf1ab gene that differentiate the Delta, Omicron BA.1, and Omicron BA.2 lineages. We demonstrate their effectiveness on 596 clinical saliva specimens that were sequence verified using Illumina whole-genome sequencing. Next, we developed dPCR assays for spike mutations R346T, K444T, N460K, F486V, and F486S, which are associated with host immune evasion and reduced therapeutic monoclonal antibody efficacy. We demonstrate that these assays can be run individually or multiplexed to detect the presence of up to 4 SNPs in a single assay. We perform these dPCR assays on 81 clinical saliva SARS-CoV-2-positive specimens and properly identify mutations in Omicron subvariants BA.2.75.2, BM.1.1, BN.1, BF.7, BQ.1, BQ.1.1, and XBB. Thus, dPCR could serve as a useful tool to determine if clinical specimens contain therapeutically relevant mutations and inform patient treatment. IMPORTANCE Spike mutations in the SARS-CoV-2 genome confer resistance to therapeutic monoclonal antibodies. Authorization for treatment options is typically guided by general trends of variant prevalence. For example, bebtelovimab is no longer authorized for emergency use in the United States due to the increased prevalence of antibody-resistant BQ.1, BQ.1.1, and XBB Omicron subvariants. However, this blanket approach limits access to life-saving treatment options to patients who are otherwise infected with susceptible variants. Digital PCR assays targeting specific mutations can complement whole-genome sequencing approaches to genotype the virus. In this study, we demonstrate the proof of concept that dPCR can be used to type lineage defining and monoclonal antibody resistance-associated mutations in saliva specimens. These findings show that digital PCR could be used as a personalized diagnostic tool to guide individual patient treatment.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/diagnosis , Mutation , Multiplex Polymerase Chain Reaction , Antibodies, Monoclonal , COVID-19 TestingABSTRACT
INTRODUCTION: In the spring of 2020, New York City was one of the first epicenters of the COVID outbreak. In this study, we evaluate the incidence and treatment of appendicitis in two New York City community hospitals during the COVID pandemic. METHODS: This retrospective study focused on the incidence and outcome of acute appendicitis in the adult population (>18 y old) during peak-COVID periods (March 16, 2020,-June 15, 2020) compared to pre-COVID and post-COVID periods. We compared the number of patients who underwent operative versus nonoperative management, patient demographics, length of stay (LOS), complications, and readmission rates within these time periods. Data are presented as mean ± standard deviation (analysis of variance). RESULTS: From January 1, 2020 to December 31, 2020, 393 patients presented with acute appendicitis and 321 (81.7%) were treated operatively, compared to 441 total and 366 treated operatively (83%) in 2019 (P = 0.88). During the COVID outbreak, fewer patients presented with appendicitis (mean 6.9 ± 1 pre-COVID case/week, 4.4 ± 2.4 peak-COVID cases/week and 7.6 ± 0.65 post-COVID cases/week, P = 0.018) with no significant difference in the pre-COVID and post-COVID period. There was no difference in LOS between the pre-, peak-, and post-COVID periods with a median of 1 for all the three, (interquartile range (IQR): 0.8-2, 0.6-2, 0.6-2, respectively, P = 0.43). Additionally, there was no difference in 30-day readmission rates (4.2%, 0%, 3.9%, P = 0.99) and postoperative complications (4.2%, 0%, 2.9%, P = 0.98). CONCLUSIONS: During peak-COVID, there was a significant reduction in the number of patients who presented with acute appendicitis without a post rebound increase in presentation. Those who presented during peak-COVID were able to undergo operative management safely, without affecting LOS or postoperative complications.
Subject(s)
Appendicitis , COVID-19 , Adult , Humans , COVID-19/epidemiology , COVID-19/complications , Pandemics , Retrospective Studies , Appendicitis/epidemiology , Appendicitis/surgery , Appendicitis/complications , Appendectomy/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Length of Stay , Acute DiseaseABSTRACT
BACKGROUND: Teleproctoring is an emerging method of bedside clinical teaching; however, its feasibility has been limited by the available technologies. The use of novel tools that incorporate 3-dimensional environmental information and feedback might offer better bedside teaching options for neurosurgical procedures, including external ventricular drain placement. METHODS: A platform with a camera-projector system was used to proctor medical students on placing external ventricular drains on an anatomic model as a proof-of-concept study. Three-dimensional depth information of the model and surrounding environment was captured by the camera system and provided to the proctor who could provide projected annotations in a geometrically compensated manner onto the head model in real time. The medical students were randomized to identify Kocher's point on the anatomic model with or without the navigation system. The time required to identify Kocher's point and the accuracy were measured as a proxy for determining the effectiveness of the navigation proctoring system. RESULTS: Twenty students were enrolled in the present study. Those in the experimental group identified Kocher's point an average of 130 seconds faster than did the control group (P < 0.001). The mean diagonal distance from Kocher's point was 8.0 ± 4.29 mm for the experimental group compared with 23.6 ± 21.98 mm for the control group (P = 0.053). Of the 10 students randomized to the camera-projector system arm, 70% were accurate to within 1 cm of Kocher's point compared with 40% of the control arm (P > 0.05). CONCLUSIONS: Camera-projector systems for bedside procedure proctoring and navigation are a viable and valuable technology. We demonstrated its viability for external ventricular drain placement as a proof-of-concept. However, the versatility of this technology indicates that that it could be useful for a variety of even more complex neurosurgical procedures.
Subject(s)
Drainage , Neurosurgical Procedures , Humans , Neurosurgical Procedures/methods , Drainage/methods , Computer SimulationABSTRACT
The adaptive evolution of SARS-CoV-2 variants is driven by selection for increased viral fitness in transmissibility and immune evasion. Understanding the dynamics of how an emergent variant sweeps across populations can better inform public health response preparedness for future variants. Here, we investigated the state-level genomic epidemiology of SARS-CoV-2 through baseline genomic sequencing surveillance of 27,071 public testing specimens and 1,125 hospital inpatient specimens diagnosed between November 1, 2021, and January 31, 2022, in Arizona. We found that the Omicron variant rapidly displaced Delta variant in December 2021, leading to an "Omicron surge" of COVID-19 cases in early 2022. Wastewater sequencing surveillance of 370 samples supported the synchronous sweep of Omicron in the community. Hospital inpatient COVID-19 cases of Omicron variant presented to three major hospitals 10.51 days after its detection from public clinical testing. Nonsynonymous mutations in nsp3, nsp12, and nsp13 genes were significantly associated with Omicron hospital cases compared to community cases. To model SARS-CoV-2 transmissions across the state population, we developed a scalable sequence network methodology and showed that the Omicron variant spread through intracounty and intercounty transmissions. Finally, we demonstrated that the temporal emergence of Omicron BA.1 to become the dominant variant (17.02 days) was 2.3 times faster than the prior Delta variant (40.70 days) or subsequent Omicron sublineages BA.2 (39.65 days) and BA.5 (35.38 days). Our results demonstrate the uniquely rapid sweep of Omicron BA.1. These findings highlight how integrated public health surveillance can be used to enhance preparedness and response to future variants. IMPORTANCE SARS-CoV-2 continues to evolve new variants throughout the pandemic. However, the temporal dynamics of how SARS-CoV-2 variants emerge to become the dominant circulating variant is not precisely known. Genomic sequencing surveillance offers unique insights into how SARS-CoV-2 spreads in communities and the lead-up to hospital cases during a surge. Specifically, baseline sequencing surveillance through random selection of positive diagnostic specimens provides a representative outlook of the virus lineages circulating in a geographic region. Here, we investigated the emergence of the Omicron variant of concern in Arizona by leveraging baseline genomic sequence surveillance of public clinical testing, hospitals, and community wastewater. We tracked the spread and evolution of the Omicron variant as it first emerged in the general public, and its rapid shift in hospital admissions in the state health system. This study demonstrates the timescale of public health preparedness needed to respond to an antigenic shift in SARS-CoV-2.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Arizona/epidemiology , SARS-CoV-2/genetics , COVID-19/epidemiology , Wastewater , Hospitals , COVID-19 TestingABSTRACT
INTRODUCTION: High rates of physician burnout are well documented in the USA. Identifying beneficial leadership behaviors as an organizational approach to mitigating burnout can lead to improved wellness in the physicians that they lead; however, few studies have examined which leadership behaviors are beneficial and which may be detrimental. MATERIALS AND METHODS: This survey study of academic medical center physicians and their physician leaders assessed the correlation between burnout and leadership behaviors. Data were analyzed for the strength of correlation between scores for leadership behaviors and self-reported physician burnout with analysis of variance by sex, time from training, specialty, and age. RESULTS: Of 1,145 physicians surveyed, 305 returned surveys. Among the respondents, 45% were female, 25% were 56 years or older, and 57% self-identified as practitioners of medicine or medicine subspecialties. Two transformational leadership categories of behaviors (idealized influence behaviors and individualized consideration) and one transactional leadership behavior category (contingent reward) correlated favorably with all domains of burnout (P < .0001). Conversely, two transactional leadership categories of burnout (management by exception passive and laissez-faire) correlated unfavorably with all burnout domains. CONCLUSIONS: Organizational interventions are needed to improve burnout in physicians. Adopting favorable leadership behaviors while avoiding unfavorable leadership behaviors can improve burnout in those physicians being led. These findings could inform the conceptual basis of future physician leadership training programs as transactional leadership behaviors also have an impact on physician wellness.
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Background: Artificial intelligence (AI) leverages today's exceptional computational powers and algorithmic abilities to learn from large data sets and solve complex problems. The aim of this study was to construct an AI model that can intelligently and reliably recognize the anatomy of cleft lip and nasal deformity and automate placement of nasolabial markings that can guide surgical design. Methods: We adopted the high-resolution net architecture, a recent family of convolutional neural networks-based deep learning architecture specialized in computer-vision tasks to train an AI model, which can detect and place the 21 cleft anthropometric points on cleft lip photographs and videos. The model was tested by calculating the Euclidean distance between hand-marked anthropometric points placed by an expert cleft surgeon to ones generated by our cleft AI model. A normalized mean error (NME) was calculated for each point. Results: All NME values were between 0.029 and 0.055. The largest NME was for cleft-side cphi. The smallest NME value was for cleft-side alare. These errors were well within standard AI benchmarks. Conclusions: We successfully developed an AI algorithm that can identify the 21 surgically important anatomic landmarks of the unilateral cleft lip. This model can be used alone or integrated with surface projection to guide various cleft lip/nose repairs. Having demonstrated the feasibility of creating such a model on the complex three-dimensional surface of the lip and nose, it is easy to envision expanding the use of AI models to understand all of human surface anatomy-the full territory and playground of plastic surgeons.
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Ewing sarcoma is a primitive neuroectodermal tumor which seldom presents with primary disease in people over age 40 and outside of the appendicular or axial skeleton. We examine a case of primary thoracic Ewing Sarcoma diagnosed initially by CT-guided biopsy in a woman at the age of 74 years. The disease progressed after initial combined modality therapy consisting of neoadjuvant chemotherapy, surgical resection, and adjuvant radiation therapy and two additional courses of multiagent chemotherapy. After relapse of her disease, subsequent second- and third-line systemic agents which included chemotherapy and targeted agents were given with disease stabilization achieved now over 30 months from initial diagnosis. To our knowledge, this is the first report of a primary pulmonary Ewing sarcoma diagnosed in a patient greater than 70 years of age in whom multiple remissions have been achieved with tolerable toxicities.
ABSTRACT
BACKGROUND: Tumor lysis syndrome is an oncologic emergency that involves multiple metabolic abnormalities and clinical symptoms such as acute renal failure, cardiac arrhythmias, seizures, and multiorgan failure, and may be fatal if not promptly recognized. Tumor lysis syndrome occurs most often in patients with hematologic malignancies, and relatively few cases have been described in patients with sarcoma. CASE PRESENTATION: A 64-year-old male of Asian heritage presented to his primary care physician with a right lower-extremity mass and was ultimately diagnosed with widely metastatic osteosarcoma. He was treated with one cycle of cisplatin and doxorubicin that was complicated by hypervolemia and hypoxic respiratory failure. Given concerns for volume overload, therapy was changed to single-agent, dose-reduced ifosfamide. After receiving one dose of ifosfamide 1 g/m2 (1.8 g total) intravenously over 1 hour, the patient developed renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and lactic acidosis. The patient ultimately died from severe electrolyte abnormalities associated with tumor lysis syndrome. CONCLUSION: This is the first instance of tumor lysis syndrome described in a patient with osteosarcoma undergoing ifosfamide monotherapy. Clinicians must be vigilant in identifying tumor lysis syndrome regardless of the malignancy type or chemotherapy regimen in order to prevent potentially fatal complications.
Subject(s)
Bone Neoplasms , Neoplasms, Second Primary , Osteosarcoma , Tumor Lysis Syndrome , Bone Neoplasms/pathology , Cisplatin/therapeutic use , Humans , Ifosfamide/adverse effects , Male , Middle Aged , Neoplasms, Second Primary/complications , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Tumor Lysis Syndrome/diagnosis , Tumor Lysis Syndrome/etiologyABSTRACT
Biotherapeutic optimization, whether to improve general properties or to engineer specific attributes, is a time-consuming process with uncertain outcomes. Conversely, Consensus Protein Design has been shown to be a viable approach to enhance protein stability while retaining function. In adapting this method for a more limited number of protein sequences, we studied 21 consensus single-point variants from eight publicly available CD3 binding sequences with high similarity but diverse biophysical and pharmacological properties. All single-point consensus variants retained CD3 binding and performed similarly in cell-based functional assays. Using Ridge regression analysis, we identified the variants and sequence positions with overall beneficial effects on developability attributes of the CD3 binders. A second round of sequence generation that combined these substitutions into a single molecule yielded a unique CD3 binder with globally optimized developability attributes. In this first application to therapeutic antibodies, adapted Consensus Protein Design was found to be highly beneficial within lead optimization, conserving resources and minimizing iterations. Future implementations of this general strategy may help accelerate drug discovery and improve success rates in bringing novel biotherapeutics to market.
Subject(s)
Antibodies, Monoclonal , Drug Discovery , Amino Acid Sequence , Antibodies, Monoclonal/chemistry , Consensus , Drug Discovery/methods , Protein StabilityABSTRACT
Total knee arthroplasty (TKA) is one of the most commonly performed, major elective surgeries in the USA. African American TKA patients on average experience worse clinical outcomes than whites, including lower improvements in patient-reported outcomes and higher rates of complications, hospital readmissions, and reoperations. The mechanisms leading to these racial health disparities are unclear, but likely involve patient, provider, healthcare system, and societal factors. Lower physical and mental health at baseline, lower social support, provider bias, lower rates of health insurance coverage, higher utilization of lower quality hospitals, and systemic racism may contribute to the inferior outcomes that African Americans experience. Limited evidence suggests that improving the quality of surgical care can offset these factors and lead to a reduction in outcome disparities.
Subject(s)
Arthroplasty, Replacement, Knee , Humans , United States/epidemiology , Healthcare Disparities , White People , Black or African American , Patient ReadmissionABSTRACT
PURPOSE: Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population. PATIENTS AND METHODS: We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints. RESULTS: Six (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome. CONCLUSIONS: Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.
Subject(s)
Sarcoma , Vascular Endothelial Growth Factor A , Anilides/administration & dosage , Humans , Protein Kinase Inhibitors/therapeutic use , Pyridines , Sarcoma/drug therapy , Sarcoma/pathologyABSTRACT
Pulmonary embolism can occur following dislodgement of deep venous thrombosis into the pulmonary artery circulation, which results in obstruction of the pulmonary artery system and can be fatal. The consequences of pulmonary embolism include hypotension, right heart strain, and hypoxia. In the long term, pulmonary embolism may lead to Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Patients who develop hypotensive massive and submassive pulmonary embolism can be treated with large-bore aspiration thrombectomy. In the acute setting, this improves short-term outcomes by decreasing the ICU stay. It can also reduce the risk of CTEPH. Options for large-bore aspiration thrombectomy include the FlowTriever™ system (Inari Medical, Irvine, CA) and the Lightning 12 vascular thrombectomy system (Penumbra Inc., Alameda, CA). This review discusses the pathophysiology of pulmonary embolism, management, and options for large-bore aspiration thrombectomy.
Subject(s)
Pulmonary Embolism , Venous Thromboembolism , Venous Thrombosis , Humans , Thrombectomy , Treatment Outcome , Venous Thromboembolism/surgeryABSTRACT
Carotid artery atherosclerotic disease impacts over 2 million Americans annually. Since the advent of the carotid endarterectomy by Debakey in 1953, the surgical management of carotid artery stenosis has prevented cerebrovascular accidents. The technology utilized to manage carotid artery stenosis continued to evolve with the utilization of carotid artery stenting in 1989 and more recently transcarotid artery revascularization (TCAR). This review discusses the modern management of carotid artery stenosis with an emphasis on transcarotid artery revascularization (TCAR) and reversal of flow for reversal of flow for embolic protection.