Atoms to Phenotypes: Molecular Design Principles of Cellular Energy Metabolism.

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

CosTaL: an accurate and scalable graph-based clustering algorithm for high-dimensional single-cell data analysis.

With the aim of analyzing large-sized multidimensional single-cell datasets, we are describing a method for Cosine-based Tanimoto similarity-refined graph for community detection using Leiden's algorithm (CosTaL). As a graph-based clustering method, CosTaL transforms the cells with high-dimensional features into a weighted k-nearest-neighbor (kNN) graph. The cells are represented by the vertices of the graph, while an edge between two vertices in the graph represents the close relatedness between the two cells. Specifically, CosTaL builds an exact kNN graph using cosine similarity and uses the Tanimoto coefficient as the refining strategy to re-weight the edges in order to improve the effectiveness of clustering. We demonstrate that CosTaL generally achieves equivalent or higher effectiveness scores on seven benchmark cytometry datasets and six single-cell RNA-sequencing datasets using six different evaluation metrics, compared with other state-of-the-art graph-based clustering methods, including PhenoGraph, Scanpy and PARC. As indicated by the combined evaluation metrics, Costal has high efficiency with small datasets and acceptable scalability for large datasets, which is beneficial for large-scale analysis.

Sternal fixation for traumatic sternal fractures demonstrates better long-term quality of life outcomes than nonoperative management: A survey analysis.

INTRODUCTION: Sternal fractures are rare, causing significant pain, respiratory compromise, and decreased upper extremity range of motion. Sternal fixation (SF) is a viable treatment option; however, there remains a paucity of literature demonstrating long-term benefits. This study examined long-term outcomes of SF, hypothesizing they have better long-term quality of life (QoL) than patients managed nonoperatively (NOM). METHODS: This was a survey study at our level 1 academic hospital. All patients diagnosed with a sternal fracture were included from January 2016 to July 2021. Patients were grouped whether they received SF or NOM. Basic demographics were obtained. Three survey phone call attempts were conducted. The time from injury to survey was recorded. Outcomes included responses to the QoL survey, which included mobility, self-care, usual activities, chest pain/discomfort, and anxiety/depression. The survey scale is 1-5 (1 = worst condition possible; 5 = best possible condition). Patients were asked to rate their current health on a scale of 0-100 (100 being the best possible health imaginable). Chi square and t-tests were used. Significance was set at p < 0.05. RESULTS: Three hundred eighty four patients were surveyed. Sixty nine underwent SF and 315 were NOM. Thirty-eight (55.1%) SF patients and 126 (40%) NOM patients participated in the survey. Basic demographics were similar. Average days from sternal fracture to survey was 1198 (±492) for the SF group and 1454 (±567) for the NOM group. The SF cohort demonstrated statistically significant better QoL than the NOM cohort for all categories except anxiety/depression. CONCLUSION: SF provides better long-term QoL and better overall health scores compared to NOM.

Lower Extremity Vascular Injury in the Pediatric Trauma Patient: Management and Outcomes at an Adult Level I Trauma Center.

BACKGROUND: Traumatic vascular injuries of the lower extremity in the pediatric population are uncommon but can result in significant morbidity. The objective of this study is to demonstrate our experience with these injuries by describing patterns of traumatic vascular injury, the initial management, and data regarding early outcomes. METHODS: In total, 506 patients presented with lower extremity vascular injury between January 1, 2009 and January 1, 2021 to Grady Memorial Hospital, an urban, adult Level I trauma center in Atlanta, Georgia. Thirty-two of the 506 patients were aged less than 18 years and were evaluated for a total of 47 lower extremity vascular injuries. To fully elucidate the injury patterns and clinical course in this population, we examined patient demographics, mechanism of injury, type of vessel injured, surgical repair performed, and early outcomes and complications. RESULTS: The median (interquartile range) age was 16 (2) years (range, 3-17 years), and the majority were male (n = 29, 90.6%). Of the vascular injuries identified, 28 were arterial and 19 were venous. Of these injuries, 14 patients had combined arterial-venous injuries. The majority of injuries were the result of a penetrating injury (n = 28, 87.5%), and of these, all but 2 were attributed to gunshot wounds. Twenty-seven vascular interventions were performed by nonpediatric surgeons: 11 by trauma surgeons, 13 by vascular surgeons, 2 by orthopedic surgeons, and 1 by an interventional radiologist. Two patients required amputation: 1 during the index admission and 1 delayed at 3 months. Overall survival was 96.9%. CONCLUSIONS: Vascular injuries as the result of trauma at any age often require early intervention, and we believe that these injuries in the pediatric population can be safely managed in adult trauma centers with a multidisciplinary team composed of trauma, vascular, and orthopedic surgeons with the potential to decrease associated morbidity and mortality from these injuries.

Protocol-in-a-Day Workshop: Expediting IRB Approval for Junior and Senior Faculty.

Delays in research protocol development may be a single factor that hinders the career progression of academic faculty. Structured educational guidance during this phase proves crucial in mitigating setbacks in Institutional Review Board (IRB) approval and expediting trial implementation. To address this, the Protocol-in-a-Day (PIAD) workshop, a comprehensive 1-day event involving members from six critical facets of RO clinical trial implementation, was established, offering significant input to individual protocols. Efficacy and satisfaction of the PIAD workshop were assessed through a 5-question survey and the average time from submission to IRB initial approval. The normality of the data was analyzed using the Shapiro-Wilk Test. Nonparametric data was analyzed using a Mann-Whitney U test for significance. A total of 18 protocols that went through the PIAD workshop were activated. The mean time to IRB approval for protocols that went through PIAD was 39.8 days compared to 58.4 days for those that did not go through the PIAD workshop. Based on survey results, 100% of PIAD participants said the PIAD workshop was useful and 94% of participants stated that the PIAD workshop improved the overall quality of their protocol. Participant surveys further highlighted substantial improvements in trial quality, language, and statistical design and revealed that all participants found the workshop helpful. Therefore, both junior and senior faculty benefitted from this educational program during protocol development, as both groups demonstrated shorter times to IRB approval than non-participants. This acceleration not only fosters efficient trial implementation but also supports academic faculty in their career development.

Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. METHODS: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. FINDINGS: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. INTERPRETATION: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. FUNDING: Bristol Myers Squibb Rare Population Malignancy Program.

The relationship of lifetime history of depression on the ovarian tumor immune microenvironment.

BACKGROUND: Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. METHODS: We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. RESULTS: We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. CONCLUSION: Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.

Tumor immune cell clustering and its association with survival in African American women with ovarian cancer.

New technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations. However, there are currently few approaches to analyze the spatial context of the TIME. Therefore, we have developed a framework for the spatial analysis of the TIME using Ripley's K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to epithelial ovarian cancer (EOC) using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 160 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 263 tissue cores; 93 subjects with 260 ROIs; 27 subjects with both TMA and ROI data). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes (CD3+), cytotoxic T-cells (CD8+CD3+), and regulatory T-cells (CD3+FoxP3+) with overall survival. Analysis was done on TMA and ROIs, treating the TMA data as validation of the findings from the ROIs. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and T-cell subsets in their tumors had the best overall survival. Additionally, patients with EOC tumors displaying high co-occurrence of cytotoxic T-cells and regulatory T-cells had the best overall survival. Grouping women with ovarian cancer based on both cell abundance and spatial contexture showed better discrimination for survival than grouping ovarian cancer cases only by cell abundance. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.

REBOA: Expanding Applications From Traumatic Hemorrhage to Obstetrics and Cardiopulmonary Resuscitation, From the AJR Special Series on Emergency Radiology.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged over the past decade as a technique to control life-threatening hemorrhage and treat hemorrhagic shock, being increasingly used to treat noncompressible traumatic torso hemorrhage. Reports during this time also support the use of a REBOA device for an expanding range of indications including nontraumatic abdominal hemorrhage, postpartum hemorrhage, placenta accreta spectrum (PAS) disorder, and cardiopulmonary resuscitation (CPR). The strongest available evidence supports REBOA as a lifesaving adjunct to definitive surgical management in trauma and as a method to help avoid hysterectomy in select patients with postpartum hemorrhage or PAS disorder. In comparison with initial descriptions of complete REBOA inflation, techniques for partial REBOA inflation have been introduced to achieve hemodynamic stability while minimizing adverse events relating to reperfusion injuries. Fluoroscopy-free REBOA has been described in various settings, including trauma, obstetrics, and out-of-hospital cardiac arrest. As the use of REBOA expands outside the trauma setting and into nontraumatic abdominal hemorrhage, obstetrics, and CPR, it is imperative for radiologists to become familiar with this technology, its proper placement, and its potential adverse sequelae.

Improved chest wall trauma taxonomy: an interdisciplinary CWIS and ASER collaboration.

PURPOSE: Chest wall injury taxonomy and nomenclature are important components of chest wall injury classification and can be helpful in communicating between providers for treatment planning. Despite the common nature of these injuries, there remains a lack of consensus regarding injury description. The Chest Wall Injury Society (CWIS) developed a taxonomy among surgeons in the field; however, it lacked consensus and clarity in critical areas and collaboration with multidisciplinary partners. We believe an interdisciplinary collaboration between CWIS and American Society of Emergency Radiology (ASER) will improve existing chest wall injury nomenclature and help further research on this topic. METHODS: A collaboration between CWIS and ASER gathered feedback on the consensus recommendations. The workgroup held a series of meetings reviewing each consensus statement, refining the terminology, and contributing additional clarifications from a multidisciplinary lens. RESULTS: After identifying incomplete definitions in the CWIS survey, the workgroup expanded on and clarified the language proposed by the survey. More precise definitions related to rib and costal cartilage fracture quality and location were developed. Proposed changes include more accurate characterization of rib fracture displacement and consistent description of costal cartilage fractures. CONCLUSIONS: The 2019 consensus survey from CWIS provides a framework to discuss chest wall injuries, but several concepts remained unclear. Creating a universally accepted taxonomy and nomenclature, utilizing the CWIS survey and this article as a scaffolding, may help providers communicate the severity of chest wall injury accurately, allow for better operative planning, and provide a common language for researchers in the future.

Exploring cryo-electron microscopy with molecular dynamics.

Single particle analysis cryo-electron microscopy (EM) and molecular dynamics (MD) have been complimentary methods since cryo-EM was first applied to the field of structural biology. The relationship started by biasing structural models to fit low-resolution cryo-EM maps of large macromolecular complexes not amenable to crystallization. The connection between cryo-EM and MD evolved as cryo-EM maps improved in resolution, allowing advanced sampling algorithms to simultaneously refine backbone and sidechains. Moving beyond a single static snapshot, modern inferencing approaches integrate cryo-EM and MD to generate structural ensembles from cryo-EM map data or directly from the particle images themselves. We summarize the recent history of MD innovations in the area of cryo-EM modeling. The merits for the myriad of MD based cryo-EM modeling methods are discussed, as well as, the discoveries that were made possible by the integration of molecular modeling with cryo-EM. Lastly, current challenges and potential opportunities are reviewed.

Organ donation after self-inflicted injury: A single institution analysis.

BACKGROUND: This study sought to determine the contribution of self-inflicted injury-related deaths to local organ donation rates and analyze contributing factors. METHODS: A retrospective review of adult patients with traumatic self-inflicted injuries was performed at a Level I trauma center from 2013 to 2017. Data were obtained from the institutional trauma registry and cross-referenced with the local organ procurement organization (OPO). Referral rates were analyzed and outcomes, demographics and injury characteristics were compared between patients who underwent donation versus those who did not. RESULTS: 142 adult patients presented with traumatic self-inflicted injury, and 100 (70.4%) had referral calls made to the local OPO. These patients were predominantly male (83%), and gunshot injuries accounted for 75% of all mechanisms. Sixty-four percent had organ referrals versus tissue referrals (34%), and 17 (26.6%) of those patients went on to donate. The median number of organs procured was 4 [IQR 0-5]. In multivariate analysis, for each year increase in age, patients were less likely to have an organ referral (OR = .96 [95% CI .93-.99]; p = .0134) and less likely to undergo donation (OR = .95 [95% CI .90-.99]; p = .0308). CONCLUSIONS: Self-inflicted injury, though tragic, may provide a significant contribution to the limited organ donor registry.

Severity of traumatic adrenal injury does not meaningfully affect clinical outcomes.

PURPOSE: There are limited data comparing the severity of traumatic adrenal injury (TAI) and the need for interventions, such as transfusions, hospitalization, or incidence of adrenal insufficiency (AI) and other clinical outcomes. The aim of this study was to analyze the relationship between the grade of TAI and the need for subsequent intervention and clinical outcomes following the injury. METHODS: After obtaining Institutional Review Board approval, our trauma registry was queried for patients with TAI between 2009 and 2017. Contrast-enhanced computed tomography (CT) examinations of the abdomen and pelvis were evaluated by a board-certified radiologist with subspecialty expertise in abdominal and trauma imaging, and adrenal injuries were classified as either low grade (American Association for the Surgery of Trauma (AAST) grade I-III) or high grade (AAST grade IV-V). Patients without initial contrast-enhanced CT imaging and those with indeterminate imaging findings on initial CT were excluded. RESULTS: A total of 129 patients with 149 TAI were included. Eight-six patients demonstrated low-grade injuries and 43 high grade. Age, gender, and Injury Severity Score (ISS) were not statistically different between the groups. There was an increased number of major vascular injuries in the low-grade vs. high-grade group (23% vs. 5%, p < 0.01). No patient required transfusions or laparotomy for control of adrenal hemorrhage. There was no statistical difference in hospital length of stay (LOS), ventilator days, or mortality. Low-grade adrenal injuries were, however, associated with shorter ICU LOS (10 days vs. 16 days, p = 0.03). CONCLUSION: The need for interventions and clinical outcomes between the low-grade and high-grade groups was similar. These results suggest that, regardless of the TAI grade, treatment should be based on a holistic clinical assessment and less focused on specific interventions directed at addressing the adrenal injury.

The role of diagnostic laparoscopy for trauma at a high-volume level one center.

BACKGROUND: The role of minimally invasive surgery in trauma has continued to evolve over the past 20 years. Diagnostic laparoscopy (DL) has become increasingly utilized for the diagnosis and management of both blunt and penetrating injuries. OBJECTIVE: While the safety and feasibility of laparoscopy has been established for penetrating thoracoabdominal trauma, it remains a controversial tool for other injury patterns due to the concern for complications and missed injuries. We sought to examine the role of laparoscopy for the initial management of traumatic injuries at our urban Level 1 trauma center. METHODS: All trauma patients who underwent DL for blunt or penetrating trauma between 2009 and 2018 were retrospectively reviewed. Demographic data, indications for DL, injuries identified, rate of conversion to open surgery, and outcomes were evaluated. RESULTS: A total of 316 patients were included in the cohort. The mean age was 34.9 years old (± 13.7), mean GCS 14 (± 3), and median ISS 10 (4-18). A total of 110/316 patients (35%) sustained blunt injury and 206/316 patients (65%) sustained penetrating injury. Indications for DL included evaluation for peritoneal violation (152/316, 48%), free fluid without evidence of solid organ injury (52/316, 16%), evaluation of bowel injury (42/316, 13%), and evaluation for diaphragmatic injury (35/316, 11%). Of all DLs, 178/316 (56%) were negative for injury requiring intervention, which was 58% of blunt cases and 55% of penetrating cases. There were no missed injuries noted. Average hospital length of stay was significantly shorter for patients that underwent DL vs conversion to open exploration (2.2 days vs. 4.5 days, p < 0.05). CONCLUSION: In this single institution, retrospective study, the high volume of cases appears to show that DL is a reliable tool for detecting injury and avoiding potential negative or non-therapeutic laparotomies. However, when injuries were present, the high rate of conversion to open exploration suggests that its utility for therapeutic intervention warrants further study.

Pharmacologic Therapy is Not Associated with Stroke Prevention in Patients with Isolated Blunt Vertebral Artery Injury.

BACKGROUND: Vertebral artery injury (VAI) is often grouped with carotid artery injury into a broader classification of blunt cerebrovascular injury, despite fundamental differences in mechanism of injury and outcome. This study seeks to evaluate the efficacy of medical therapy in preventing strokes for isolated VAI. METHODS: Patients with isolated blunt VAI (2011-2018) were identified from the trauma registry of a level I trauma center. A retrospective chart review was conducted excluding patients with concomitant carotid artery injury. Factors examined included demographics, injury characteristics, anatomic classification, and management strategy. Patients were stratified by whether they received pharmacological (antiplatelet or anticoagulation) therapy. The primary outcome was new posterior circulation stroke within 30 days of injury as confirmed by imaging studies. RESULTS: A total of 206 patients with blunt VAI were included. Median Injury Severity Score was 17 and 33 (16.0%) patients presented with Glasgow Coma Scale <8. The most common mechanism of injury was motor vehicle collision (58.7%). The injuries were bilateral in 38 (18.5%) patients and 73 (35.4%) suffered multisegmental injuries. The anatomic severity of injuries was Grade 1 = 38.8%, Grade 2 = 25.7%, Grade 3 = 4.9%, Grade 4 = 30.6%, and Grade 5 = 0.5%. There was no correlation between anatomic grade and stroke (P = 0.11) or initiation of pharmacologic therapy (P = 0.30). In total, 172 (84%) patients received pharmacological therapy with no differences in baseline characteristics between treated and untreated patients. Overall, the 30-day stroke rate was 1.9%. There was no difference in stroke rate between patients who received medical therapy versus those who did not (5.9% vs. 1.2%, P = 0.13). In subgroup analysis by injury severity, medical therapy did not improve stroke rates. Among patients treated with aspirin, there was no difference in stroke rate between doses of 81 vs. 325 mg (1.1% vs. 0%, P = 1). CONCLUSIONS: Isolated VAI is associated with a very low risk of stroke and treatment with medical therapies including antiplatelet or anticoagulation does not improve risk of stroke.

Clinical decision making involving prescription drug monitoring programs: A factorial, vignette-based study among student pharmacists.

OBJECTIVES: Prescription drug monitoring programs (PDMPs) are state-maintained databases that providers may reference when deciding to prescribe or dispense controlled substances. As more states begin to mandate PDMP use at the point of care, it is imperative to assess how pharmacists use PDMP information when determining whether to fill a controlled substance prescription (CSP). The objective of this study was to evaluate which factors affected fourth-year student pharmacists' decision to fill an opioid prescription, their level of confidence in their decision making, and familiarity with the PDMP. METHODS: We used a 24 factorial design to present a series of text-based vignettes to fourth-year student pharmacists. Each participant received 8 vignettes (5 randomly selected, 3 fixed), representing a hypothetical hydrocodone-acetaminophen combination prescription with varying levels of the following dichotomous factors: doctor shopping, dosage, pharmacy shopping, and concurrent benzodiazepine prescription. Participants were asked to decide whether or not they would fill each of the hypothetical prescriptions they received. A multilevel model was used to measure the association between each of the vignette factors, age, race, sex, experience with PDMP, and the decision to refuse to fill a prescription. Each vignette response served as an independent observation. RESULTS: A total of 87 participants yielded 696 vignette responses. Participants were significantly more likely to refuse to fill prescriptions with doctor shopping (adjusted odds ratio [aOR] 19.86 [95% CI 10.78-36.58]), pharmacy shopping (6.78 [4.13-11.12]), dosage (1.83 [1.16-2.90]), or if the student pharmacist was of female sex (1.73 [1.02-2.93]). Concomitant benzodiazepine use was not associated with a no-fill decision (1.45 [0.92-2.27]). CONCLUSION: This study reveals that student pharmacists' decision to fill a prescription is dependent on both prescription characteristics and a patient's CSP history. The importance of PDMP history cannot be downplayed and suggests that PDMP use may be effective in informing patient care decisions. Still, the variability in filling decision highlights the need to teach a formulaic approach to CSP dispensing in colleges of pharmacy.

Breast Reconstruction in the Social Media Age.

BACKGROUND: The internet and social media are sources of information regarding breast reconstruction, which can educate and influence patients. OBJECTIVES: This study aimed to evaluate internet and social media usage by breast reconstruction patients and its impact on patients. METHODS: Eighty-six breast reconstruction patients over a 7-month period answered an anonymous survey, which queried demographics, reconstruction type, internet usage, social media usage, expectations, and impact on decisions. Fisher's exact test was performed to evaluate the use of social media. RESULTS: Overall, 95% of patients used the internet for breast reconstruction information. The information was found to be easy to understand by 70% of patients, helpful by 76%, and trustworthy by 60%. The information influenced decisions regarding procedure by 23% of patients, regarding surgeon by 23%, and regarding hospital by 22%. Social media was used by 71% of the patients; 62% of patients found it easy to understand, 57% found it helpful, and 48% found it trustworthy. The information influenced decisions regarding procedure by 16% of patients, regarding surgeon by 11%, and regarding hospital by 10%. Twenty-six percent of women expected their final breast reconstruction to look better than their premastectomy breasts, 55% as good or similar, and 12% reported appearance to be unimportant. Women found social media information to be less helpful than internet information. There was no significant association between expectations and social media vs no social media usage. CONCLUSIONS: Patients who undergo breast reconstruction use the internet and social media as sources of information. Although the information is generally trusted, it does not seem to heavily influence patient decision-making. Providers remain patients' main source of information, and need to direct patients to high-quality and accessible resources.

The American Association for the Surgery of Trauma Organ Injury Scale 2018 update for computed tomography-based grading of renal trauma: a primer for the emergency radiologist.

The most widely used trauma injury grading system is the Organ Injury Scale (OIS) by the American Association for the Surgery of Trauma (AAST). The AAST OIS for renal trauma was revised in 2018 to reflect necessary updates based on decades of experience with computed tomography (CT)-based injury diagnosis and, specifically, to better incorporate vascular injuries, which were not comprehensively addressed in the original OIS. In this review article, we describe CT findings of the AAST OIS for the kidney according to the 2018 revision, with an emphasis on real-world application, and highlight important differences from the prior grading scheme. Routine use of this grading system allows for a standardized classification of the range of renal injuries to aid in management, adding value in the imaging care of trauma patients.

Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.