The degree of aortic occlusion in the setting of trauma alters the extent of acute kidney injury associated with mitochondrial preservation.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to control noncompressible hemorrhage not addressed with traditional tourniquets. However, REBOA is associated with acute kidney injury (AKI) and subsequent mortality in severely injured trauma patients. Here, we investigated how the degree of aortic occlusion altered the extent of AKI in a porcine model. Female Yorkshire-cross swine (n = 16, 68.1 ± 0.7 kg) were anesthetized and had carotid and bilateral femoral arteries accessed for REBOA insertion and distal and proximal blood pressure monitoring. Through a laparotomy, a 6-cm liver laceration was performed and balloon inflation was performed in zone 1 of the aorta for 90 min, during which animals were randomized to target distal mean arterial pressures of 25 or 45 mmHg via balloon volume adjustment. Blood draws were taken at baseline, end of occlusion, and time of death, at which point renal tissues were harvested 6 h after balloon deflation for histological and molecular analyses. Renal blood flow was lower in the 25-mmHg group (48.5 ± 18.3 mL/min) than in the 45-mmHg group (177.9 ± 27.2 mL/min) during the occlusion phase, which recovered and was not different after balloon deflation. AKI was more severe in the 25-mmHg group, as evidenced by circulating creatinine, blood urea nitrogen, and urinary neutrophil gelatinase-associated lipocalin. The 25-mmHg group had increased tubular necrosis, lower renal citrate synthase activity, increased tissue and circulating syndecan-1, and elevated systemic inflammatory cytokines. The extent of renal ischemia-induced AKI is associated with the magnitude of mitochondrial biomass and systemic inflammation, highlighting potential mechanistic targets to combine with partial REBOA strategies to prevent AKI.NEW & NOTEWORTHY Large animal models of ischemia-reperfusion acute kidney injury (IR-AKI) are lacking. This report establishes a titratable IR-AKI model in swine in which a balloon catheter can be used to alter distal pressures experienced by the kidney, thus controlling renal blood flow. Lower blood flow results in greater renal dysfunction and structural damage, as well as lower mitochondrial biomass, elevated systemic inflammation, and vascular dysfunction.

Functional traits of fossil plants.

A minuscule fraction of the Earth's paleobiological diversity is preserved in the geological record as fossils. What plant remnants have withstood taphonomic filtering, fragmentation, and alteration in their journey to become part of the fossil record provide unique information on how plants functioned in paleo-ecosystems through their traits. Plant traits are measurable morphological, anatomical, physiological, biochemical, or phenological characteristics that potentially affect their environment and fitness. Here, we review the rich literature of paleobotany, through the lens of contemporary trait-based ecology, to evaluate which well-established extant plant traits hold the greatest promise for application to fossils. In particular, we focus on fossil plant functional traits, those measurable properties of leaf, stem, reproductive, or whole plant fossils that offer insights into the functioning of the plant when alive. The limitations of a trait-based approach in paleobotany are considerable. However, in our critical assessment of over 30 extant traits we present an initial, semi-quantitative ranking of 26 paleo-functional traits based on taphonomic and methodological criteria on the potential of those traits to impact Earth system processes, and for that impact to be quantifiable. We demonstrate how valuable inferences on paleo-ecosystem processes (pollination biology, herbivory), past nutrient cycles, paleobiogeography, paleo-demography (life history), and Earth system history can be derived through the application of paleo-functional traits to fossil plants.

Are There More HER2 FISH in the Sea? An Institution's Experience in Identifying HER2 Positivity Using Fluorescent In Situ Hybridization in Patients with HER2 Negative Immunohistochemistry.

BACKGROUND: Approximately 20% of breast cancers express HER2-positive receptors in the USA. HER2 receptor immunohistochemistry (IHC) staining with equivocal (2+) results commonly undergoes fluorescence in-situ hybridization (FISH) for further classification. Current guidelines do not recommend routine FISH testing in IHC-negative (0 or 1+) cases. This study investigates an institution that performs both IHC and FISH testing on all cases to identify the true HER2-positive rate. PATIENTS AND METHODS: A retrospective chart review from 2015 to 2021 was conducted at an institution where both HER2 IHC and FISH testing were performed at the time of diagnosis for all invasive breast cancers. The rate of true HER2-positive patients was determined, and patient and tumor characteristics were further explored. RESULTS: A total of 1835 invasive breast cancer cases were primarily treated at this institution. A total of 289 cases were HER2 positive on IHC and FISH testing (15.7%). An additional 38 cases were identified as HER2 negative on IHC, but reclassified as HER2 positive on reflex FISH testing. Total HER2 positive cases increased from 289 (15.7%) to 327 cases (17.8%) with reflex FISH testing. CONCLUSIONS: The additional HER2-positive cases after completing FISH testing on IHC-negative tumors suggests there may be a role for routine FISH testing in addition to standard IHC staining to determine HER2 status for breast cancer. The ethical, prognostic and even  benefits of a correct diagnosis outweigh the added expense of FISH testing.

Woody plant encroachment drives population declines in 20% of common open ecosystem bird species.

Grassy ecosystems cover more than 40% of the world's terrestrial surface, supporting crucial ecosystem services and unique biodiversity. These ecosystems have experienced major losses from conversion to agriculture with the remaining fragments threatened by global change. Woody plant encroachment, the increase in woody cover threatening grassy ecosystems, is a major global change symptom, shifting the composition, structure, and function of plant communities with concomitant effects on all biodiversity. To identify generalisable impacts of encroachment on biodiversity, we urgently need broad-scale studies on how species respond to woody cover change. Here, we make use of bird atlas, woody cover change data (between 2007 and 2016) and species traits, to assess: (1) population trends and woody cover responses using dynamic occupancy models; (2) how outcomes relate to habitat, diet and nesting traits; and (3) predictions of future occupancy trends, for 191 abundant, southern African bird species. We found that: (1) 63% (121) of species showed a decline in occupancy, with 18% (34) of species' declines correlated with increasing woody cover (i.e. losers). Only 2% (4) of species showed increasing population trends linked with increased woody cover (i.e. winners); (2) Open habitat specialist, invertivorous, ground nesting birds were the most frequent losers, however, we found no definitive evidence that the selected traits could predict outcomes; and (3) We predict open habitat loser species will take on average 52 years to experience 50% population declines with current rates of encroachment. Our results bring attention to concerning region-wide declining bird population trends and highlight woody plant encroachment as an important driver of bird population dynamics. Importantly, these findings should encourage improved management and restoration of our remaining grassy ecosystems. Furthermore, our findings show the importance of lands beyond protected areas for biodiversity, and the urgent need to mitigate the impacts of woody plant encroachment on bird biodiversity.

Freeze tolerance influenced forest cover and hydrology during the Pennsylvanian.

The distribution of forest cover alters Earth surface mass and energy exchange and is controlled by physiology, which determines plant environmental limits. Ancient plant physiology, therefore, likely affected vegetation-climate feedbacks. We combine climate modeling and ecosystem-process modeling to simulate arboreal vegetation in the late Paleozoic ice age. Using GENESIS V3 global climate model simulations, varying pCO2, pO2, and ice extent for the Pennsylvanian, and fossil-derived leaf C:N, maximum stomatal conductance, and specific conductivity for several major Carboniferous plant groups, we simulated global ecosystem processes at a 2° resolution with Paleo-BGC. Based on leaf water constraints, Pangaea could have supported widespread arboreal plant growth and forest cover. However, these models do not account for the impacts of freezing on plants. According to our interpretation, freezing would have affected plants in 59% of unglaciated land during peak glacial periods and 73% during interglacials, when more high-latitude land was unglaciated. Comparing forest cover, minimum temperatures, and paleo-locations of Pennsylvanian-aged plant fossils from the Paleobiology Database supports restriction of forest extent due to freezing. Many genera were limited to unglaciated land where temperatures remained above -4 °C. Freeze-intolerance of Pennsylvanian arboreal vegetation had the potential to alter surface runoff, silicate weathering, CO2 levels, and climate forcing. As a bounding case, we assume total plant mortality at -4 °C and estimate that contracting forest cover increased net global surface runoff by up to 6.1%. Repeated freezing likely influenced freeze- and drought-tolerance evolution in lineages like the coniferophytes, which became increasingly dominant in the Permian and early Mesozoic.

A Novel Sutureless Anastomotic Device in a Swine Model: A Proof of Concept Study.

INTRODUCTION: Vascular reconstruction requires technical expertise and is often time consuming. As a novel alternative to traditional hand-sewn vascular anastomoses, the VasoLock (VL), is a nonabsorbable, sutureless anastomosis device with traction anchors designed to hold free artery ends together. These anchors do not penetrate the vessel wall but adhere by leveraging the elasticity of the vessels to fasten blood vessels together. This pilot study assesses the performance and patency of this novel device in a porcine model of femoral artery injury. METHODS: Female swine (n = 7) underwent femoral artery exposure for a total of 10 VL implanted. Study animals underwent hemodilution to a target hematocrit of 15% and ROTEM was used to assess coagulopathy, followed by an arterial injury via transection. The VL was inserted without any sutures. Flow-probe monitors were positioned proximal and distal to the device and flow rates were measured continuously for a total of 90 min. Flow was analyzed and presented as a ratio of distal to proximal flow with the slope of this ratio across time subsequently determined. Angiographic assessment was completed to evaluate for patency and technical complications after 90 min of implant. RESULTS: The average animal weight was 44.1 ± 3.2 kg. The average mean arterial pressure at the time of implant was 51.2 ± 7.8 mmHg, median heart rate was 77.4 (IQR = 77.25-157.4) beats per minute, and average temperature was 36.1 ± 1.5°C. The baseline hematocrit was 13.5 ± 3.0%, average pH was 7.20 ± 0.1, average clotting time was 154.1 ± 58.7 s and average clot formation time was 103.4 ± 10.9 s all demonstrating the acidotic, hypothermic, and coagulopathic state of the swine at the time of insertion. During the 90-min observation period, the average flow gradient identified across the VL was 0.99 ± 0.24, indicating no significant change in flow across the VL. The average slope of the gradients was 0.0005 (P = 0.22), suggesting the ratio of proximal and distal flow did not change over the 90 min. Following 90 min of dwell time, all VL were patent without technical complication. Angiographic assessment at 90 min demonstrated no evidence of dissection, device migration, arterial extravasation, or thromboembolism with any of the 10 devices. CONCLUSIONS: This pilot study demonstrated technical feasibility of the novel VL device over a 90-min observation period. All VL were patent and no negative events or complications were identified. This technology demonstrated significant promise in a coagulopathic state: additional investigation, involving long-term survival, is warranted for further validation.

Postoperative antiplatelet and/or anticoagulation use does not impact complication or reintervention rates after vein repair of arterial injury: A PROOVIT study.

INTRODUCTION: The use of antiplatelet (AP) and anticoagulation (AC) therapy after autogenous vein repair of traumatic arterial injury is controversial. The hypothesis in this study was that there is no difference in early postoperative outcomes regardless of whether AC, AP, both, or neither are used. METHODS: The American Association for the Surgery of Trauma (AAST) PROspective Observational Vascular Injury Treatment (PROOVIT) registry was queried from November, 2013, to January, 2019, for arterial injuries repaired with a vein graft. Demographics and injury characteristics were compared. Need for in-hospital reoperation was the primary outcome in this four-arm study, assessed with two ordinal logistic regression models (1. no therapy vs. AC only vs. AC and AP; 2. no therapy vs. AP only vs. AC and AP). RESULTS: 373 patients (52 no therapy, 88 AP only, 77 AC only, 156 both) from 19 centers with recorded Injury Severity Scores (ISS) were identified. Patients who received no therapy were younger than those who received AP (27.0 vs. 34.2, p = 0.02), had higher transfusion requirement (p < 0.01 between all groups) and a different distribution of anatomic injury (p < 0.01). After controlling for age, sex, ISS, platelet count, hemoglobin, pH, lactate, INR, transfusion requirement and anatomic location, there was no association with postoperative medical therapy and in-hospital operative reintervention, or any secondary outcome, including thrombosis (p = 0.67, p = 0.22). CONCLUSIONS: Neither AC nor AP alone, nor in combination, impact complication rate after arterial repair with autologous vein. These patients can be safely treated with or without antithrombotics, recognizing that this study did not demonstrate a beneficial effect.

What predicts suicidality among psychologists? An examination of risk and resilience.

Psychologists may have a uniquely high risk for suicide. We examined whether, among 172 psychologists, factors predicting suicide risk among the general population (e.g., gender and mental illness), occupational factors (e.g., burnout and secondary traumatic stress), and past trauma predicted suicidality. We also tested whether resilience and meaning in life were negatively related to suicidality and whether resilience buffered relationships between risk factors and suicidality. Family history of mental illness, number of traumas, and lifetime depression/anxiety predicted higher suicidality, whereas resilience predicted lower suicidality. At higher levels of resilience, the relationship between family history of suicide and suicidality was stronger.

Impact of Ischemia Duration on Lower Limb Salvage in Combat Casualties.

INTRODUCTION: The 6-hour threshold to revascularization of an ischemic limb is ubiquitous in the trauma literature, however, contemporary evidence suggests that this threshold should be less. This study aims to characterize the relationship between the duration of limb ischemia and successful limb salvage following lower extremity arterial trauma. METHODS: This is a cohort study of the United States and UK military service members injured while serving in Iraq or Afghanistan between 2003 and 2013. Consecutive patients who sustained iliac, femoral, or popliteal artery injuries, and underwent surgery to attempt revascularization, were included. The association between limb outcome and the duration of limb ischemia was assessed using the Kaplan-Meier method. RESULTS: One hundred twenty-two patients (129 limbs) who sustained iliac (2.3%), femoral (56.6%), and popliteal (41.1%) arterial injuries were included. Overall, 87 limbs (67.4%) were successfully salvaged. The probability of limb salvage was 86.0% when ischemia was ≤1 hour; 68.3% when between 1 and 3 hours; 56.3% when between 3 and 6 hours; and 6.7% when >6 hours ( P <0.0001). Shock more than doubled the risk of failed limb salvage [hazard ratio=2.42 (95% confidence interval: 1.27-4.62)]. CONCLUSIONS: Limb salvage is critically dependent on the duration of ischemia with a 10% reduction in the probability of successful limb salvage for every hour delay to revascularization. The presence of shock significantly worsens this relationship. Military trauma systems should prioritize rapid hemorrhage control and early limb revascularization within 1 hour of injury.

Characterizing Brain Perfusion in a Swine Model of Raised Intracranial Pressure.

INTRODUCTION: Perfusion of the brain is critical, but this can be compromised due to focal space occupying lesions (SOL). SOLs can raise intracranial pressure (ICP), resulting in reduced cerebral blood flow (CBF). Most gyrencephalic models of brain injury focus on parenchymal injury, with few models of acutely elevated ICP. We hypothesized that we could employ a SOL technique to develop a titratable ICP model and sought to quantitate the resulting decrease in brain perfusion. METHODS: Six swine were anesthetized and instrumented. A Fogarty balloon catheter was inserted intracranially. Blood CO2 partial pressure was maintained between 35 and 45 mmHg. The Fogarty balloon was infused with normal saline at 1 mL/min to ICP targets of 10, 20, 30, and 40 mmHg. CBF (mL/100 g/min) were assessed at each ICP level using computed tomography perfusion (CTP). Data are presented as the mean ± standard deviation with all pressures measured in mmHg. CBF values were compared between baseline and each ICP level using analysis of variance. RESULTS: Baseline ICP was 5 ± 2 and systolic blood pressure was 106 ± 7. Balloon volumes (mL) required to achieve each incremental ICP level were 2.4 ± 0.5, 4.9 ± 1.7, 7.6 ± 1.6, and 9.9 ± 1.7. CBF decreased with each raised ICP level, with CBF being significantly less than baseline at ICP values of 30 (56.1 ± 34.7 versus 20.6 ± 11.0, P < 0.05) and 40 (56.1 ± 34.7 versus 6.5 ± 10.6, P < 0.05). CONCLUSIONS: An intracranial balloon catheter can be used to increase ICP, delivering a proportionate reduction in CBF. This model can be used in the future studies to examine adjuncts that manipulate intracranial pressure and their effect on brain perfusion.

Next-Generation REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) Device Precisely Achieves Targeted Regional Optimization in a Porcine Model of Hemorrhagic Shock.

INTRODUCTION: Limitations such as time-dependent distal ischemia have slowed the adoption of resuscitative endovascular balloon occlusion of the aorta (REBOA) for noncompressible hemorrhage. Next-generation REBOA technologies may allow for controlled partial flow, known as targeted regional optimization, to reduce distal ischemia. We aimed to characterize the efficacy of one such catheter in a porcine model of lethal hemorrhagic shock. METHODS: Noncompressible hemorrhage from an iliac injury was induced in anesthetized swine (Sus scrofa) (70-90 kg), targeting 30% total blood volume. Animals were then randomized to partial aortic occlusion (PO) with targeted distal mean arterial pressure (MAP) of 35-40 mm of mercury (mm Hg) and complete aortic occlusion (CO) (n = 8 per group) for 90 min. All groups were then resuscitated during a two-h critical care (CC) phase, with flow rate and MAP recorded continuously at the distal infrarenal aorta and proximal carotid artery, and analyzed with two-way repeated measures analysis of variance with S-N-K post-hoc test. RESULTS: During aortic occlusion, MAP distal to the balloon was consistently maintained at 35.8 ± 0.3 mm Hg in the PO group compared to 27.1 ± 0.3 mm Hg in the CO group (P < 0.05), which also corresponded to higher flow rates (202.9 ± 4.8 mL/min PO versus 25.9 ± 0.8 mL/min CO; P < 0.05). MAP proximal to the balloon was significantly higher with CO versus PO (109.2 ± 2.3 mm Hg versus 85.2 ± 2.3 mm Hg; P < 0.05). During the CC phase, distal aortic flow and MAP were not significantly different between groups. However, creatinine returned to baseline levels by the end of the study in the PO group, but not the CO group. One animal died in the CO group, whereas none died in the PO group. CONCLUSIONS: This is the first examination of the next-generation pREBOA-PRO in a porcine model of lethal hemorrhagic shock. We show technical feasibility of this technique to precisely achieve targeted regional optimization without device failure or complication. The ability to titrate balloon inflation and thus distal flow/pressure may extend the therapeutic window of REBOA by mitigating distal ischemia.

Preliminary Experience With the Human Acellular Vessel: A Descriptive Case Series Detailing Early Use of a Bioengineered Blood Vessel for Arterial Repair.

BACKGROUND: An infection-resistant, immediately available conduit for trauma and urgent vascular reconstruction remains a critical need for successful limb salvage. While autologous vein remains the gold standard, vein-limited patients and size mismatch are common issues. The Human Acellular Vessel (HAV) (Humacyte, Inc., Durham, NC) is a bioengineered conduit with off-the-shelf availability and resistance to infection, ideal characteristics for patients with challenging revascularization scenarios. This report describes HAV implantation in patients with complex limb-threatening ischemia and limited conduit options who may have otherwise faced limb loss. METHODS: The Food and Drug Administration (FDA) expanded-access program was used to allow urgent implantation of the HAV for arterial reconstruction. Electronic medical records were reviewed with extraction of relevant data including patient demographics, surgical implantation, patency, infectious complications, and mortality. RESULTS: The HAV was implanted in 8 patients requiring vascular reconstruction. Graft or soft tissue infection was present in 2 patients. One patient with severe penetrating pelvic injury had 4 HAV placed to repair bilateral external iliac artery and vein injuries. There was 1 technical failure due to poor outflow, 2 patients died unrelated to HAV use, and 5 lower extremity bypasses maintained patency at an average of 11.4 months (range: 4-20 months). No HAV infectious complications were identified. CONCLUSIONS: This report is the first United States series describing early outcomes using the HAV under the FDA expanded-access program for urgent vascular reconstruction. The HAV demonstrates resistance to infection, reliable patency, and offers surgeons an immediate option when confronted with complex revascularization scenarios. Assessment of long-term outcomes will be important for future studies.

Insulin Shocks.

Some of the news about insulin is shocking. In the United States, people have died because they were rationing a life-saving medication discovered in the 1920s. How could this happen? Perhaps a better question is why anyone should be surprised. The insulin story both illustrates and challenges many understandings of the problems with insurance, treatment, payment, and politics in the US health care system. It particularly highlights consequences of structuring price discounts as rebates to health plans or government instead of as lower individual prices to patients. Perversely, this encourages higher list prices, which, for patients without insurance or with high cost sharing, make insulin less affordable than it would be without the rebates.

Efficient scarless genome editing in human pluripotent stem cells.

Scarless genome editing in human pluripotent stem cells (hPSCs) represents a goal for both precise research applications and clinical translation of hPSC-derived therapies. Here we established a versatile and efficient method that combines CRISPR-Cas9-mediated homologous recombination with positive-negative selection of edited clones to generate scarless genetic changes in hPSCs.

Temporary intravascular shunt use improves early limb salvage after extremity vascular injury.

OBJECTIVE: The use of temporary intravascular shunts (TIVSs) allow for restoration of distal perfusion and reduce ischemic time in the setting of arterial injury. As a damage control method, adjunct shunts restore perfusion during treatment of life-threatening injuries, or when patients require evacuation to a higher level of care. Single-center reports and case series have demonstrate that TIVS use can extend the opportunity for limb salvage. However, few multi-institutional studies on the topic have been reported. The objective of the present study was to characterize TIVS use through a multi-institutional registry and define its effects on early limb salvage. METHODS: Data from the Prospective Observation Vascular Injury Treatment registry was analyzed. Civilian patients aged ≥18 years who had sustained an extremity vascular injury from September 2012 to November 2018 were included. Patients who had a TIVS used in the management of vascular injury were included in the TIVS group and those who had received treatment without a TIVS served as the control group. An unadjusted comparison of the groups was conducted to evaluate the differences in the baseline and outcome characteristics. Double robust estimation combining logistic regression with propensity score matching was used to evaluate the effect of TIVS usage on the primary end point of limb salvage. RESULTS: TIVS use was identified in 78 patients from 24 trauma centers. The control group included 613 patients. Unmatched analysis demonstrated that the TIVS group was more severely injured (mean ± standard deviation injury severity score, 18.83 ± 11.76 for TIVS vs 14.93 ± 10.46 for control; P = .002) and had more severely mangled extremities (mean ± standard deviation abbreviated injury scale, extremity, score 3.23 ± 0.80 for TIVS vs 2.95 ± 0.87 for control; P = .008). Logistic regression demonstrated that propensity-matched control patients had a three times greater likelihood of amputation compared with the TIVS patients (odds ratio, 3.6; 95% confidence interval, 1.2-11.1; P = .026). Concomitant nerve injury and orthopedic fracture were associated with a greater risk of amputation. The median follow-up for the TIVS group was 12 days (interquartile range, 4-25 days) compared with 9 days (interquartile range, 4-18 days) for the control group. CONCLUSIONS: To the best of our knowledge, the present study is the first multicenter, matched-cohort study to characterize early limb salvage as a function of TIVS use in the setting of extremity vascular injury. Shunts expedite limb perfusion and resulted in lower rates of amputation during the early phase of care. The use of TIVS should be one part of a more aggressive approach to restore perfusion in the most injured patients and ischemic limbs.

Partial Resuscitative Endovascular Balloon Occlusion of the Aorta: A Systematic Review of the Preclinical and Clinical Literature.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has become a standard adjunct for the management of life-threatening truncal hemorrhage, but the technique is limited by the sequalae of ischemia distal to occlusion. Partial REBOA addresses this limitation, and the recent Food and Drug Administration approval of a device designed to enable partial REBOA will broaden its application. We conducted a systematic review of the available animal and clinical literature on the methods, impacts, and outcomes associated with partial REBOA as a technique to enable targeted proximal perfusion and limit distal ischemic injury. We hypothesize that a systematic review of the published animal and human literature on partial REBOA will provide actionable insight for the use of partial REBOA in the context of future wider clinical implementation of this technique. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols guidelines, we conducted a search of the available literature which used partial inflation of a REBOA balloon catheter. Findings from 22 large animal studies and 14 clinical studies met inclusion criteria. RESULTS: Animal and clinical results support the benefits of partial REBOA including extending the resuscitative window extended safe occlusion time, improved survival, reduced proximal hypertension, and reduced resuscitation requirements. Clinical studies provide practical physiologic targets for partial REBOA including a period of total occlusion followed by gradual balloon deflation to achieve a target proximal pressure and/or target distal pressure. CONCLUSIONS: Partial REBOA has several benefits which have been observed in animal and clinical studies, most notably reduced ischemic insult to tissues distal to occlusion and improved outcomes compared with total occlusion. Practical clinical protocols are available for the implementation of partial REBOA in cases of life-threatening torso hemorrhage.

Quantifying the effect of shade on cuticle morphology and carbon isotopes of sycamores: present and past.

PREMISE: Reconstructing the light environment and architecture of the plant canopy from the fossil record requires the use of proxies, such as those derived from cell wall undulation, cell size, and carbon isotopes. All approaches assume that plant taxa will respond predictably to changes in light environments. However, most species-level studies looking at cell wall undulation only consider "sun" or "shade" leaves; therefore, we need a fully quantitative taxon-specific method. METHODS: We quantified the response of cell wall undulation, cell size, and carbon isotopes of Platanus occidentalis using two experimental setups: (1) two growth chambers at low and high light and (2) a series of outdoor growth experiments using green and black shade cloth at different densities. We then developed and applied a proxy for daily light integral (DLI) to fossil Platanites leaves from two early Paleocene floras from the San Juan Basin in New Mexico. RESULTS: All traits responded to light environment. Cell wall undulation was the most useful trait for reconstructing DLI in the geological record. Median reconstructed DLI from early Paleocene leaves was ~44 mol m-2 d-1 , with values from 28 to 54 mol m-2 d-1 . CONCLUSIONS: Cell wall undulation of P. occidentalis is a robust, quantifiable measurement of light environment that can be used to reconstruct the paleo-light environment from fossil leaves. The distribution of high DLI values from fossil leaves may provide information on canopy architecture; indicating that either (1) most of the canopy mass is within the upper portion of the crown or (2) leaves exposed to more sunlight are preferentially preserved.

Aquaporin-3 in the epidermis: more than skin deep.

The skin is essential for terrestrial life. It is responsible for regulating water permeability and functions as a mechanical barrier that protects against environmental insults such as microbial infection, ultraviolet light, injury, and heat and cold, which could damage the cells of the body and compromise survival of the organism. This barrier is provided by the outer layer, the epidermis, which is composed predominantly of keratinocytes; keratinocytes undergo a program of differentiation to form the stratum corneum comprising the cornified squame "bricks" and lipid "mortar." Dysregulation of this differentiation program can result in skin diseases, including psoriasis and nonmelanoma skin cancers, among others. Accumulating evidence in the literature indicates that the water-, glycerol-, and hydrogen peroxide-transporting channel aquaporin-3 (AQP3) plays a key role in various processes involved in keratinocyte function, and abnormalities in this channel have been observed in several human skin diseases. Here, we discuss the data linking AQP3 to keratinocyte proliferation, migration, differentiation, and survival as well as its role in skin properties and functions like hydration, water retention, wound healing, and barrier repair. We also discuss the mechanisms regulating AQP3 levels, localization, and function and the anomalies in AQP3 that are associated with various skin diseases.

Novel small-molecule LG1836 inhibits the in vivo growth of castration-resistant prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance. METHODS: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models. RESULTS: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice. CONCLUSIONS: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.

Carboniferous plant physiology breaks the mold.

How plants have shaped Earth surface feedbacks over geologic time is a key question in botanical and geological inquiry. Recent work has suggested that biomes during the Carboniferous Period contained plants with extraordinary physiological capacity to shape their environment, contradicting the previously dominant view that plants only began to actively moderate the Earth's surface with the rise of angiosperms during the Mesozoic Era. A recently published Viewpoint disputes this recent work, thus here, we document in detail, the mechanistic underpinnings of our modeling and illustrate the extraordinary ecophysiological nature of Carboniferous plants.