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Background: In patients with severe traumatic brain injury (TBI), clinicians must balance preventing venous thromboembolism (VTE) with the risk of intracranial hemorrhagic expansion (ICHE). We hypothesized that low molecular weight heparin (LMWH) would not increase risk of ICHE or VTE as compared to unfractionated heparin (UH) in patients with severe TBI., Methods: Patients ≥ 18 years of age with isolated severe TBI (AIS ≥ 3), admitted to 24 level I and II trauma centers between January 1, 2014 to December 31, 2020 and who received subcutaneous UH and LMWH injections for chemical venous thromboembolism prophylaxis (VTEP) were included. Primary outcomes were VTE and ICHE after VTEP initiation. Secondary outcomes were mortality and neurosurgical interventions. Entropy balancing (EBAL) weighted competing risk or logistic regression models were estimated for all outcomes with chemical VTEP agent as the predictor of interest., Results: 984 patients received chemical VTEP, 482 UH and 502 LMWH. Patients on LMWH more often had pre-existing conditions such as liver disease (UH vs LMWH 1.7 % vs. 4.4 %, p = 0.01), and coagulopathy (UH vs LMWH 0.4 % vs. 4.2 %, p < 0.001). There were no differences in VTE or ICHE after VTEP initiation. There were no differences in neurosurgical interventions performed. There were a total of 29 VTE events (3 %) in the cohort who received VTEP. A Cox proportional hazards model with a random effect for facility demonstrated no statistically significant differences in time to VTE across the two agents (p = 0.44). The LMWH group had a 43 % lower risk of overall ICHE compared to the UH group (HR = 0.57: 95 % CI = 0.32-1.03, p = 0.062), however was not statistically significant., Conclusion: In this multi-center analysis, patients who received LMWH had a decreased risk of ICHE, with no differences in VTE, ICHE after VTEP initiation and neurosurgical interventions compared to those who received UH. There were no safety concerns when using LMWH compared to UH., Level of Evidence: Level III, Therapeutic Care Management., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The hospital environment is a complex and unpredictable workplace where different providers share the responsibility of patient care. Differences in opinions, values, and experiences between resident physicians and other care team members may trigger conflicts that affect the safety and quality of patient care. Thus, developing conflict competencies may help to negotiate the complexities of different conflict situations and resolve these conflicts. However, the extent of the knowledge and perception of conflict competence among resident physicians remains to be determined., Methods: A survey and qualitative semi-structured interviews of resident physicians were conducted. Participants were recruited voluntarily. Survey results were analyzed using SPSS 21, and MAXQDA 24 was used to evaluate the interview transcripts with thematic analysis., Results: Sixty-five resident physicians completed the survey, and 15 resident physicians were interviewed. 61.5% of the survey respondents identified as female, 76.9% were Caucasian, 35.4% of the respondents were from surgical specialties, and 43.1% of the residents were in their second year of training. 53.8% of the participants reported witnessing or experiencing conflicts weekly, with 44.6% reporting resident physician-nurse conflicts. 63.1% of the conflicts were reported as unresolved, with 16.9% reporting that the conflict affected future working relationships, 25.5% of the conflicts were due to failure of communication, 75.4%residents did not have any form of prior training on conflict management, and 83.1% of them reported interest in conflict competence training. Conflicts mainly affected the quality of care (87.3%) compared to patient safety concerns (12.3%). Participants with prior training in conflict competence were more likely to resolve their reported conflict (p = 0.047). The interviews highlighted 5 main themes: sources of conflict, awareness of conflict resolution styles, addressing conflict and outcomes, and the effect on patient care. Sources of conflict included hierarchy and different priorities. 52.2% of the respondents did not know any style of conflict resolution. Addressing conflict included collaboration, avoidance, competition, and prevention. Avoidance was the most common style used by interviewees, followed by collaboration. While most felt that the conflicts affected the quality of patient care, 1 interviewee reported severe adverse events on the patient., Conclusion: Conflicts are rife in the hospital environment and can affect patient care when unresolved. Resident physicians' knowledge of conflict competence is low and does not reflect the complexity of their working environment. Future training in conflict competence and resolution is warranted., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol use is frequent in trauma patients and alcohol withdrawal syndrome (AWS) is associated with significant morbidity. Benzodiazepines are commonly used for AWS, but may cause neurologic and respiratory adverse events (AEs). The objective was to evaluate the effectiveness and safety of a phenobarbital-based protocol for the treatment of AWS in non-intensive care unit (ICU) trauma patients., Methods: Adult non-ICU trauma patients at high risk of or experiencing AWS PRE and POST implementation of a phenobarbital-based protocol were included. Outcomes were AWS-related complications (AWS-RC), benzodiazepine use, adjunctive medication use, hospital length of stay (HLOS), and medication-related AEs. Subgroup analyses were performed on patients with traumatic brain injury (TBI), rib fractures, and at high risk of severe AWS., Results: Overall, 110 patients were included (51 PRE, 59 POST). AWS-RC developed in 17 PRE patients compared to 10 POST patients (33% vs 17%; P = .05). PRE patients were more likely to receive benzodiazepines (88% vs 42%, P < .0001) and higher total dose (11 vs 4 mg lorazepam equivalent; P = .001). No difference noted in HLOS (8 vs 8 days, P = .27), adjunctive medication use (49% vs 54%, P = .60), or AEs (57% vs 39%, P = .06). There was no difference in AWS-RC in the TBI subgroup ( P = .19), less AEs in the rib fracture POST subgroup ( P = .04), and less AWS-RC in the high risk of severe AWS POST subgroup ( P = .03)., Discussion: A phenobarbital-based protocol in trauma patients is effective in preventing AWS-RC and decreasing benzodiazepine use without increasing AEs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To assess the educational of value of teaching assistant (TA) cases from the perspectives of attending, chief resident, and junior resident. We hypothesized the greatest educational value of TA cases would be for chief residents more so than other team members., Design: A prospective survey was designed and collected for TA cases separately from attendings, chief residents, and junior residents to assess operative details and educational value. The study period ran from August 2021 through December 2022. Qualitative and quantitative analysis was undertaken to compare answers and discover themes in the free-text responses of attendings and residents., Setting: Single center, tertiary care institution, Maine Medical Center, Department of Surgery, Portland, ME PARTICIPANTS: Sixty-nine teaching assistant cases were captured from a total of 117 completed surveys that were completed by 44 chief residents, 49 junior residents, 22 attendings (n = 22) and 2 APPs., Results: A wide variety of TA cases were included in the study with the most common reason for performing a TA case being resident request 68%. Operative complexity was most commonly rated easiest third (50%) and middle third (41%) of overall cases. Both junior and chief residents felt that compared to working with an attending alone, TA cases contributed more or much more to their procedural independence >80% of the time. Attendings reported learning something about the resident's skills that they were not expecting in 59% of the cases. Thematic analysis: attendings focused on the steps of the procedure, including the technical aspects, particularly regarding opening while residents largely focused on communication and preparation., Conclusions: Teaching assistant cases seem to have more educational value for chief and junior residents than attendings. Both junior and chief residents felt that compared to working with an attending alone, TA cases contributed more or much more to their procedural independence >80% of the time., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Patients with traumatic brain injury (TBI) are at high risk of venous thromboembolism events (VTE). We hypothesized that early chemical VTE prophylaxis initiation (≤24 hours of a stable head CT) in severe TBI would reduce VTE without increasing risk of intracranial hemorrhage expansion (ICHE)., Methods: A retrospective review of adult patients 18 years or older with isolated severe TBI (Abbreviated Injury Scale score, ≥ 3) who were admitted to 24 Level I and Level II trauma centers from January 1, 2014 to December 31 2020 was conducted. Patients were divided into those who did not receive any VTE prophylaxis (NO VTEP), who received VTE prophylaxis ≤24 hours after stable head CT (VTEP ≤24) and who received VTE prophylaxis >24 hours after stable head CT (VTEP>24). Primary outcomes were VTE and ICHE. Covariate balancing propensity score weighting was utilized to balance demographic and clinical characteristics across three groups. Weighted univariate logistic regression models were estimated for VTE and ICHE with patient group as predictor of interest., Results: Of 3,936 patients, 1,784 met inclusion criteria. Incidences of VTE was significantly higher in the VTEP>24 group, with higher incidences of DVT in the group. Higher incidences of ICHE were observed in the VTEP≤24 and VTEP>24 groups. After propensity score weighting, there was a higher risk of VTE in patients in VTEP >24 compared with those in VTEP≤24 (odds ratio, 1.51; 95% confidence interval, 0.69-3.30; p = 0.307), however was not significant. Although, the No VTEP group had decreased odds of having ICHE compared with VTEP≤24 (odds ratio, 0.75; 95% confidence interval, 0.55-1.02, p = 0.070), the result was not statistically significant., Conclusion: In this large multi-center analysis, there were no significant differences in VTE based on timing of initiation of VTE prophylaxis. Patients who never received VTE prophylaxis had decreased odds of ICHE. Further evaluation of VTE prophylaxis in larger randomized studies will be necessary for definitive conclusions., Level of Evidence: Therapeutic Care Management; Level III., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo., Competing Interests: MF, HF, MK, AD, CM, CF, RP, AC, JD, LM, CG, RI, EJ, VD, CV No competing interests declared, CM GRAIL Inc: Research Funding; JBF Legal: Consultancy, MR Reviewing editor, eLife, (© 2023, Farrell et al.)

Objectives: The application of surgical stabilization of rib fractures (SSRF) remains inconsistent due to evolving indications and perceived associated morbidity. By implementing thoracoscopic-assisted rib plating (TARP), a minimally invasive SSRF approach, we expanded our SSRF application to patients who otherwise might not be offered fixation. This report presents our initial experience, including fixation in super elderly (aged ≥85 years), and technical lessons learned., Methods: This was a retrospective cohort study at a level 1 trauma center of admitted patients who underwent TARP between August 2019 and October 2020. Patient demographics, injury characteristics, surgical indications and outcomes are represented as mean±SD, median or percentage., Results: A total of 2134 patients with rib fractures were admitted. In this group, 39 SSRF procedures were performed, of which 54% (n=21) were TARP. Average age was 68.5±16 years. Patients had a median of 5 fractured ribs, with an average of 1 rib that was bicortically displaced, and 19% presented with 'clicking' on inspiration. Patient outcomes were a mean hospital length of stay (LOS) of 11±3.7 days, mean postoperative LOS of 8 days, and mean intensive care unit LOS of 6.6±2.9 days. Five patients were ≥85 years old with a mean age of 90.8±4.7 years. They presented with an average of 4 rib fractures, of which an average of 2.4 ribs were plated. The procedure was well tolerated in this age group with a hospital LOS of 9.4±2 days, and all five patients were discharged to a rehab facility with no in-hospital mortalities., Conclusion: Our experience incorporating TARP at our institution demonstrated feasibility of the technique and application across a broad range of patients. This approach and its application warrants further evaluation and potentially expands the application of SSRF.., Competing Interests: Competing interests: FS is a member of a Zimmer Biomet SSRF advisory panel. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis., (© 2022 AABB.)

Introduction: Under current law in our rural state, there is no universal requirement for motorcyclists to wear helmets. Roughly 500 motorcycle crashes are reported by the state each year and only a fraction of those riders wear helmets. We sought to determine the difference in injury patterns and severity in helmeted versus non-helmeted riders., Methods: Retrospective review (2014-2018) of a single level 1 trauma center's registry was done for subjects admitted after a motorcycle collision. Demographic, injury and patient outcome data were collected. Patients were stratified by helmet use (n = 81), no helmet use (n = 144), and unknown helmet use (n = 194). Statistical analysis used Student's t-test or Pearson's χ 2 p-value ≤0.05 as significant. State Department of Transportation data registry for state level mortality and collision incidence over the same time period was also obtained., Results: Of the 2,022 state-reported motorcycle collisions, 419 individuals admitted to our trauma center were analyzed (21% capture). State-reported field fatality rate regardless of helmet use was 4%. Our inpatient mortality rate was 2% with no differences between helmet uses. Helmeted riders were found to have significantly fewer head and face injuries, higher GCS, lower face, neck, thorax and abdomen AIS, fewer required mechanical ventilation, shorter ICU length of stay, and had a greater number of upper extremity injuries and higher upper extremity AIS., Conclusions: Helmeted motorcyclists have fewer head, face, and cervical spine injuries, and lower injury severities: GCS and face, neck, thorax, abdomen AIS. Helmeted riders had significantly less mechanical ventilation requirement and shorter ICU stays. Non-helmeted riders sustained worse injuries. Practical Applications: Helmets provide safety and motorcycle riders have a 34-fold higher risk of death following a crash. Evaluating injury severities and patterns in motorcycle crash victims in a rural state with no helmet laws may provide insight into changing current legislation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021.)

Objective: Unintentional window falls represent a preventable source of injury and death in children. Despite major campaigns in some larger cities, there continue to be unintentional falls from windows throughout the United States. We aimed to identify risk factors and trends in unintentional window falls in the pediatric population in a national and regional sample., Methods: A retrospective analysis of annual emergency department (ED) visits from the National Electronic Injury Surveillance System using product codes specific to windows, as well as patient encounters for unintentional window falls from January 2007 to August 2017 using site-specific trauma registries from 10 tertiary care children's hospitals in New England. National and state-specific census population estimates were used to compute rates per 100,000 population., Results: There were 38,840 ED visits and 496 regional patients who unintentionally fell from a window across the study period between 0 and 17 years old. The majority of falls occurred in children under the age of 6 and were related to falls from a second story or below. A decreased trend in national ED visits was seen, but no change in rates over time for regional trauma center encounters. A high number of falls was found to occur in smaller cities surrounding metropolitan areas and from single family residences., Conclusions: Falls from windows represent a low proportion of overall types of unintentional sources of injury in children but are a high risk for severe disability. These results provide updated epidemiologic data for targeted intervention programs, as well as raise awareness for continued education and advocacy., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including  Il-6  and  Cxcl12  (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism.  In vitro  experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fairfield, Costa, Falank, Farrell, Murphy, D’Amico, Driscoll and Reagan.)

Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo , senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. SIGNIFICANCE: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions., (©2020 American Association for Cancer Research.)

Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Objective: To assess the association between level of resident autonomy and operative times for appendectomies., Design: A single center retrospective analysis of electronic medical record data of patients who underwent an appendectomy from 1/1/2017 to 12/31/2018. Medical record numbers s were matched with cases entered in the ACGME Resident Case Log system. Cases were stratified by resident role ("First Assistant," "Surgeon Junior," "Surgeon Chief," or "Teaching Assistant") and operative times were compared to cases without resident participation using student's t test., Setting: Maine Medical Center, Department of Surgery, Portland, Maine., Participants: Inclusion criteria: ≥5 years old, underwent appendectomy at a tertiary medical center during the study duration, and either had corresponding Case-log data or had no resident involvement. Patients who underwent appendectomy as part of a larger procedure were excluded., Results: Six hundred eighty-eight patients met inclusion criteria, with residents participating in 574 (83.5%) cases. Overall mean operating time was 51 ± 21.5 minutes. Attending physicians without resident participation had the shortest OR times (43 ± 19.1 minutes). There was no difference in operating time between chief resident involvement and attending physicians without resident participation (45 ± 21; p = 0.43). Cases with residents involved as "First Assistant" (53 ± 18.6 minutes; p = 0.04) "Surgeon Junior" (52 ± 24.0 minutes; p < 0.001), or "Teaching Assistant" (57 ± 21.6 minutes; p < 0.001) were found to have longer operating times as compared to attending physicians operating without a resident., Conclusions: Operative times for appendectomies are impacted by resident role. Chief residents' operative times approach that of attendings when operating as Surgeon Chief, however they are significantly longer when operating as Teaching Assistant. Involvement of junior residents in any role lengthen operating times. This suggests that surgical education influences operating room efficiency., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Frostbite is a cold injury that has the potential to cause considerable morbidity and long-term disability. Despite the complexity of these patients, diagnostic and treatment practices lack standardization. Thrombolytic therapy has emerged as a promising treatment modality, demonstrating impressive digit salvage rates. We review our experience with thrombolytic therapy for severe upper extremity frostbite., Methods: Retrospective data on all frostbite patients evaluated at our institution from December 2017 to March 2018 was collected. A subgroup of patients with severe frostbite treated with intra-arterial thrombolytic therapy (IATT) were analysed., Results: Of the 17 frostbite patients treated at our institution, 14 (82%) were male and the median age was 31 (range: 19-73). Substance misuse was involved in a majority of the cases (58.8%). Five (29.4%) patients with severe frostbite met inclusion criteria for IATT and the remaining patients were treated conservatively. Angiography demonstrated a 74.5% improvement in perfusion after tissue plasminogen activator thrombolysis. When comparing phalanges at risk on initial angiography to phalanges undergoing amputation, the phalangeal salvage rate was 83.3% and the digit salvage rate was 80%. Complications associated with IATT included groin hematoma, pseudoaneurysm and retroperitoneal hematoma., Conclusions: Thrombolytic therapy has the potential to greatly improve limb salvage and functional recovery after severe frostbite when treated at an institution that can offer comprehensive, protocoled thrombolytic therapy. A multi-center prospective study is warranted to elucidate the optimal treatment strategy in severe frostbite., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved.)

Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 β-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3F ax -Neu5Ac delivered as a per-acetylated methyl ester pro-drug. Specifically, we show in vivo that 3F ax -Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3F ax -Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone marrow (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interactions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggesting that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3F ax -Neu5Ac alters the post-translational modification of the α4 integrin, which may explain the reduced affinity of α4β1/α4β7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as bortezomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications., (Copyright© 2020 Ferrata Storti Foundation.)

Carbon nanotubes (CNTs) hold great potential as drug delivery transporters given their large drug-binding surface area. Herein, we designed novel, multi-walled, discrete CNTs (dMWCNTs), PEGylated dMWCNTs (PEG-dMWCNTs), and bone-targeting (BT), alendronate-conjugated PEG-dMWCNTs (BT-PEG-dMWCNTs). Using zeta potential, thermogravimetric analysis, TEM, SEM, and FTIR, dMWCNTs were characterized as individual, uniform, and stable. Drug binding and release assays validated dMWCNTs as effective doxorubicin (DOX) transporters. The mass ratio of DOX loading onto dMWCNTs was 35% wt/wt with a ~95% wt/wt efficiency. DOX release was ~51% w/w after 48 hours. Neoplastic transformation, chromosomal aberration, and cytotoxicity assays, confirmed biocompatibility for all dMWCNTs. PEG-dMWCNTs were well tolerated and modulated drug pharmacokinetics in mice. In mice with Burkitt's lymphoma, DOX-loaded PEG-dMWCNTs and BT-PEG-dMWCNTs reduced tumor burden and increased survival similarly to free drug. Importantly, DOX toxicity was abrogated when DOX was loaded onto PEG-dMWCNTs or BT-PEG-dMWCNTs. Overall, PEG-dMWCNTs and BT-PEG-dMWCNTs represent a promising new nanocarrier platform., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Our group has developed a 'Step Up' approach to the application of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in a rural trauma system. This incorporates viewing REBOA as a spectrum of technology. Examples of REBOA technology use to improve outcomes and provision of our system's clinical practice guideline for the Step-Up application of REBOA technology in the care of trauma patients are presented., Competing Interests: Competing interests: JH has the following disclosures: He is a founder and on the Board of Directors of Decisio Health, on the Board of Directors of Zibrio and QinFlow, a Co-inventor of the Junctional Emergency Tourniquet Tool and an advisor to Cellphire Therapeutics, Arsenal Medical and Prytime Medical.

The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signaling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signaling molecules are discussed in this review.

Over the past twenty years, evidence has accumulated that biochemically and spatially defined networks of extracellular matrix, cellular components, and interactions dictate cellular differentiation, proliferation, and function in a variety of tissue and diseases. Modeling in vivo systems in vitro has been undeniably necessary, but when simplified 2D conditions rather than 3D in vitro models are used, the reliability and usefulness of the data derived from these models decreases. Thus, there is a pressing need to develop and validate reliable in vitro models to reproduce specific tissue-like structures and mimic functions and responses of cells in a more realistic manner for both drug screening/disease modeling and tissue regeneration applications. In adipose biology and cancer research, these models serve as physiologically relevant 3D platforms to bridge the divide between 2D cultures and in vivo models, bringing about more reliable and translationally useful data to accelerate benchtop to bedside research. Currently, no model has been developed for bone marrow adipose tissue (BMAT), a novel adipose depot that has previously been overlooked as "filler tissue" but has more recently been recognized as endocrine-signaling and systemically relevant. Herein we describe the development of the first 3D, BMAT model derived from either human or mouse bone marrow (BM) mesenchymal stromal cells (MSCs). We found that BMAT models can be stably cultured for at least 3 months in vitro, and that myeloma cells (5TGM1, OPM2 and MM1S cells) can be cultured on these for at least 2 weeks. Upon tumor cell co-culture, delipidation occurred in BMAT adipocytes, suggesting a bidirectional relationship between these two important cell types in the malignant BM niche. Overall, our studies suggest that 3D BMAT represents a "healthier," more realistic tissue model that may be useful for elucidating the effects of MAT on tumor cells, and tumor cells on MAT, to identify novel therapeutic targets. In addition, proteomic characterization as well as microarray data (expression of >22,000 genes) coupled with KEGG pathway analysis and gene set expression analysis (GSEA) supported our development of less-inflammatory 3D BMAT compared to 2D culture. In sum, we developed the first 3D, tissue-engineered bone marrow adipose tissue model, which is a versatile, novel model that can be used to study numerous diseases and biological processes involved with the bone marrow., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Biological models are necessary tools for gaining insight into underlying mechanisms governing complex pathologies such as cancer in the bone. Models range from in vitro tissue culture systems to in vivo models and can be used with corresponding epidemiological and clinical data to understand disease etiology, progression, driver mutations, and signaling pathways. In bone cancer, as with many other cancers, in vivo models are often too complex to study specific cell-cell interactions or protein roles, and 2D models are often too simple to accurately represent disease processes. Consequently, researchers have increasingly turned to 3D in vitro tissue engineered models as a useful compromise. In this review, tissue engineered 3D models of bone and cancer are described in depth and compared to 2D models. Biomaterials and cell types used are described, and future directions in the field of tissue engineered bone cancer models are proposed., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt-inhibitory molecule secreted from bone matrix-embedded osteocytes, can induce adipogenesis in 3T3-L1 cells, mouse ear- and BM-derived MSCs, and human BM-derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre-adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM-adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti-sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications., (© 2017 Wiley Periodicals, Inc.)

This review highlights the recent advances in our understanding of adipocyte contributions to carcinogenesis or cancer disease progression for cancers in the bone., Purpose: In this review, we aim to describe bone marrow adipose tissue and discuss the soluble adipocyte-derived cytokines (adipokines) or endocrine factors, adipocyte-derived lipids, and the actual or putative juxtacrine signaling between bone marrow adipocytes and tumor cells in the bone marrow. This relationship likely affects tumor cell initiation, proliferation, metastasis, and/or drug resistance., Recent Findings: Bone marrow adipose may affect tumor proliferation, drug resistance, or cancer-induced bone disease and hence may be a new target in the fight against cancer., Summary: Overall, evidence is mixed regarding the role of bone marrow adipose and adipocytes in cancer progression, and more research in this arena is necessary to determine how these bone marrow microenvironmental cells contribute to malignancies in the marrow to identify novel, potentially targetable pathways., Competing Interests: Conflict of Interest Carolyne Falank, Heather Fairfield, and Michaela R. Reagan each declare no potential conflicts of interest.

Obesity during maturation can affect the growing skeleton directly and indirectly, although these effects and the mechanisms behind them are not fully understood. Our objective was to determine how a high-fat diet with or without metformin treatment affects skeletal development. We also sought to characterize changes that occur in white adipose tissue, circulating metabolites, lipids, and gut microbiota. A diet-induced obesity C57BL/6J mouse model was used to test the effects of obesity and metformin on bone using bone histomorphometry and microcomputed tomography. Bone marrow adipose tissue was quantified with osmium tetroxide microcomputed tomography and histology. Dual-energy x-ray absorptiometry was used to analyze body composition. Hematoxylin and eosin staining was used to assess changes in white adipose depots, mass spectrometry was used for circulating lipids and protein metabolite analysis, and ribosomal RNA sequencing was used for gut microbiome analysis. Mice fed a high fat-diet since wean displayed increased medullary areas and decreased osteoblast numbers in the long bones; this phenotype was partially normalized by metformin. Marrow and inguinal adipose expansion was also noted in obese mice, and this was partially normalized by metformin. A drug-by-diet interaction was noted for circulating lipid molecules, protein metabolites, and gut microbiome taxonomical units. Obesity was not detrimental to trabecular bone in growing mice, but bone marrow medullary expansion was observed, likely resulting from inhibition of osteoblastogenesis, and this was partially reversed by metformin treatment., (Copyright © 2017 Endocrine Society.)

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM., (© 2017 by The American Society of Hematology.)

Purpose of Review: Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth., Recent Findings: MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics.

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.

Cancers that metastasize or grow in the bone marrow are typically considered incurable and cause extensive damage to the bone and bone marrow. The bone is a complex, dynamic, three-dimensional (3D) environment composed of a plethora of cells that may contribute to, or constrain, the growth of tumor cells and development of bone disease. The development of safe and effective drugs is currently hampered by pre-clinical two-dimensional (2D) models whose poor predictive power does not accurately predict the success or failure of therapeutics. These inadequate models often result in drugs proceeding through extensive pre-clinical studies only to fail clinically. Consistently, 3D co-culture systems prove superior to 2D mono-cultures in modeling in vivo cell phenotypes, disease progression and response to therapeutics. As a complex, multicellular, multidimensional bone microenvironment, 3D models allow for more accurate predictions of tumor growth, cell-cell and cell-matrix interactions, and resulting therapeutic responses. In this review we will discuss various 3D models available and describe step-by-step protocols for two of the most well-established 3D culture models for studying tumor-induced bone disease., Competing Interests: The authors declare no conflict of interest.

In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT.

Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM., (© 2016 New York Academy of Sciences.)

Cadmium is a non-essential, toxic metal found accumulated in the organs of stranded cetaceans. Currently, there is no baseline cadmium concentration reported in a free-ranging, pelagic cetacean. The aim was to determine cadmium concentrations in the skin of free-ranging sperm whales (n=340) collected from 16 regions around the world during the voyage of the Odyssey (2000-2005) considering region, gender, and age in males. Cadmium was detected in 81% of skin biopsies with a mean of 0.3±0.04μg/g ww (0.02 to 12.4μg/g ww). These concentrations were higher than reported in literature in toothed whale skin (0.002-0.1μg/g ww). Concentrations by region were significantly different (p<0.0001) with the highest mean in Maldives and the Sea of Cortez (0.8 and 0.6μg/g ww, respectively). There was no significant difference in cadmium concentration by gender (p=0.42). Cadmium is known to have a long biological half-life, and cadmium concentrations in males were significantly higher in adults with a mean of 0.3μg/g ww compared to subadults with 0.2μg/g ww (p=0.03). Selenium, an element that binds to cadmium inhibiting its toxicity, had a moderately positive correlation with cadmium (r=0.41). Mercury, a toxic metal that positively correlates with cadmium in cetacean tissue, had a weakly positive relationship (r=0.20). The regional baselines reported in this study may be used to develop residue criteria for prediction of toxicological risk in sperm whale skin. Additionally, this study shows the extent of cadmium exposure in a pelagic cetacean that has global distribution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Arsenic is an oceanic pollutant of global concern due to its toxicity, ability to bioaccumulate and continued input into the environment by anthropogenic activities. The sperm whale (Physeter macrocephalus) is an emerging aquatic model for both human disease and ocean health having global distribution and high trophic level. The aim of this study was to establish global and regional baselines of total arsenic concentrations using free-ranging sperm whales. Skin biopsies (n=342) were collected during the voyage of the Odyssey (2000-2005) from 17 regions considering gender and age in males. Arsenic was detectable in 99% of samples with a global mean of 1.9μg/g ww ranging from 0.1 to 15.6μg/g ww. Previous work in toothed whale skin found mean concentrations 3 fold lower with 0.6μg/g ww. A significant gender-related effect was found with males having higher mean arsenic concentrations than females. There was no significant age-related effect between adult and subadult males. Arsenic concentrations in sloughed skin samples were similar to levels in skin biopsies indicating that arsenic excretion can occur by skin sloughing. Regional mean concentrations were highest in the Maldives, Seychelles and Sri Lanka with 3.5, 2.5, and 2.4μg/g ww, respectively, raising concern for arsenic pollution in the Indian Ocean. Literature suggests that arsenic exposure is emitted from natural sources and the heavy use of arsenic-containing pesticides and herbicides in this region. These data suggest that research is needed in determining the extent and source of arsenic pollution in the Indian Ocean., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive. DU is genotoxic, inducing DNA double strand breaks, chromosome damage and mutations, but the mechanisms of genotoxicity or repair pathways involved in protecting cells against DU-induced damage remain unknown. The purpose of this study was to investigate the effects of homologous recombination repair deficiency on DU-induced genotoxicity using RAD51D and XRCC3-deficient Chinese hamster ovary (CHO) cell lines. Cells deficient in XRCC3 (irs1SF) exhibited similar cytotoxicity after DU exposure compared to wild-type (AA8) and XRCC3-complemented (1SFwt8) cells, but DU induced more break-type and fusion-type lesions in XRCC3-deficient cells compared to wild-type and XRCC3-complemented cells. Surprisingly, loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. DU induced selective X-chromosome fragmentation irrespective of RAD51D status, but loss of XRCC3 nearly eliminated fragmentation observed after DU exposure in wild-type and XRCC3-complemented cells. Thus, XRCC3, but not RAD51D, protects cells from DU-induced breaks and fusions and also plays a role in DU-induced chromosome fragmentation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Lead (Pb) is an oceanic pollutant of global concern. Anthropogenic activities are increasing oceanic levels, but to an unknown extent. The sperm whale (Physeter macrocephalus) has a global distribution and high trophic level. The aim of this study was to establish a global baseline of oceanic Pb concentrations using free-ranging sperm whales as an indicator species. Skin biopsies (n=337) were collected during the voyage of the Odyssey (2000-2005) from 17 regions considering gender and age. Pb was detectable in 315 samples with a global mean of 1.6 ug/gww ranging from 0.1 to 129.6 ug/gww. Papua New Guinea, Bahamas and Australia had the highest regional mean with 6.1, 3.4, and 3.1 ug/gww, respectively. Pb concentrations were not significantly different between sex and age in males. This is the first global toxicological dataset for Pb in a marine mammal and confirms Pb is widely distributed with hotspots in some regions., (Copyright © 2014. Published by Elsevier Ltd.)

Concern regarding the Deepwater Horizon oil crisis has largely focused on oil and dispersants while the threat of genotoxic metals in the oil has gone largely overlooked. Genotoxic metals, such as chromium and nickel, damage DNA and bioaccumulate in organisms, resulting in persistent exposures. We found chromium and nickel concentrations ranged from 0.24 to 8.46 ppm in crude oil from the riser, oil from slicks on surface waters and tar balls from Gulf of Mexico beaches. We found nickel concentrations ranged from 1.7 to 94.6 ppm wet weight with a mean of 15.9 ± 3.5 ppm and chromium concentrations ranged from 2.0 to 73.6 ppm wet weight with a mean of 12.8 ± 2.6 ppm in tissue collected from Gulf of Mexico whales in the wake of the crisis. Mean tissue concentrations were significantly higher than those found in whales collected around the world prior to the spill. Given the capacity of these metals to damage DNA, their presence in the oil, and their elevated concentrations in whales, we suggest that metal exposure is an important understudied concern for the Deepwater Horizon oil disaster.

Pollution of the ocean by mercury (Hg) is a global concern. Hg persists, bioaccumulates and is toxic putting high trophic consumers at risk. The sperm whale (Physeter macrocephalus), is a sentinel of ocean health due to its wide distribution, longevity and high trophic level. Our aim was to survey Hg concentrations worldwide in the skin of free-ranging sperm whales considering region, gender and age. Samples were collected from 343 whales in 17 regions during the voyage of the research vessel, Odyssey, between 1999 and 2005. Skin was analyzed for total Hg and detected in all but three samples with a global mean of 2.5±0.1 μg g(-1) ranging from 0.1 to 16.0 μg g(-1). The Mediterranean Sea had the highest regional mean with 6.1 μg g(-1) followed by Australia with 3.5 μg g(-1). Considering gender, females and males did not have significantly different global Hg concentrations. The variation among regions for females was significantly different with highest levels in the Mediterranean and lowest in Sri Lanka; however, males were not significantly different among regions. Considering age in males, adults and subadults did not have significantly different Hg concentrations, and were not significantly different among regions. The toxic effects of these Hg concentrations are uncertain. Selenium (Se), an essential element, antagonizes Hg at equimolar amounts. We measured total Se concentrations and found detectable levels in all samples with a global mean of 33.1±1.1 μg g(-1) ranging from 2.5 to 179 μg g(-1). Se concentrations were found to be several fold higher than Hg concentrations with the average Se:Hg molar ratio being 59:1 and no correlation between the two elements. It is possible Hg is being detoxified in the skin by another mechanism. These data provide the first global analysis of Hg and Se concentrations in a free-ranging cetacean., (Copyright © 2013 Elsevier B.V. All rights reserved.)