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\"Flashpoint has changed the DC Universe, and nothing is as it was before. Now Batman is Thomas Wayne, driven by the death of his son Bruce to punish criminals, and in pursuit of a Joker whose twisted crimes will bring him to the brink of madness himself ... Now, Dick Grayson travels with his parents and the death-defying Deadman across war-torn Europe, performing in their circus until an Amazon attack leads them to their true fate ... In this world, Deathstroke is a pirate on the world's most dangerous waters, questing for the only treasure that really matters ... Shade the Changing Man leads a secret team of bizarre heroes, but will he lead them to their deaths?\"--P. [4] of cover.

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure ( p O 2 ) and decreased O 2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine–threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis -acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3′-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR’s regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

IntroductionPeriprosthetic joint infection (PJI) is the most serious and feared complication in total knee arthroplasty (TKA) and can have catastrophic consequences. The number of total knee arthroplasties is increasing, so infections could also be greater in the future. The aim of this study is to identify the most relevant risk factors associated with infection after a total knee arthroplasty.MethodsThis is a case–control study of patients who underwent total knee arthroplasty at the University Hospital of Salamanca. We included 66 TKA PJI patients and 66 control TKA patients. Demographic and clinical variables were collected. A descriptive and inferential analysis was performed by logistic regression and attributable risk fraction assessed.ResultsProlonged operative time (> 90′) and tourniquet time (> 60′) were the most relevant risk factors described (OR 40.77, AFE 0.97, p > 0.001 and OR 37.14, AFE 0.97, p < 0.001, respectively). The use of non-antibiotic-laded cement (OR 3.62), obesity (BMI > 30, OR 8.86), diabetes (OR 2.33), high ASA grade (III–IV, OR 15.30), and blood transfusion requirement (OR 4.60) were also statistically significant risk factors for TKA PJI.ConclusionsOur study provides evidence concerning that operative time, tourniquet time, cement type, diabetes, obesity, ASA grade, and blood transfusion requirement as independently associated risk factors for TKA PJI. Modifiable risk factors were specifically relevant, so we should be able to reduce the infection rate.

The 30-day mortality rate after hip fracture surgery has been considered as an indirect indicator of the quality of care. The aim of this work is to analyse preoperative and postoperative factors potentially related to early 30-day mortality in patients over 65 undergoing hip fracture surgery. Prospective cohort study including all consecutive primary hip fracture patients over 65 admitted to Trauma and Orthopaedics department from January 1, 2018 to December 31, 2019. Bed-ridden, non- surgically treated patients, and high energy trauma or tumoral aetiology fractures were excluded. A total of 943 patients were eligible (attrition rate: 2.1%). Follow-up included 30-days after discharge. We noted the 30-day mortality after hip fracture surgery, analysing 130 potentially related variables including biodemographic, fracture-related, preoperative, and postoperative clinical factors. Qualitative variables were assessed by χ2, and quantitative variables by non-parametric tests. Odds ratio determined by binary logistic regression. We selected preventable candidate variables for multivariate risk assessment by logistic regression. A total of 923 patients were enrolled (mean age 86.22±6.8, 72.9% women). The 30-day mortality rate was 6.0%. We noted significant increased mortality on men (OR = 2.381[1.371-4.136], p = 0.002), ageing patients (ORyear = 1.073[1.025-1.122], p = 0.002), and longer time to surgery (ORday = 1.183[1.039-1146], p<0.001), on other 20 preoperative clinical variables, like lymphopenia (lymphocyte count <103/μl, OR = 1.842[1.063-3.191], p = 0.029), hypoalbuminemia (≤3.5g/dl, OR = 2.474[1.316-4.643], p = 0.005), and oral anticoagulant intake (OR = 2.499[1.415-4.415], p = 0.002), and on 25 postoperative clinical variables, like arrhythmia (OR = 13.937[6.263-31.017], p<0.001), respiratory insufficiency (OR = 7.002[3.947-12.419], p<0.001), hyperkalaemia (OR = 10.378[3.909-27.555], p<0.001), nutritional supply requirement (OR = 3.576[1.894-6.752], p = 0.021), or early arthroplasty dislocation (OR = 6.557[1.206-35.640], p = 0.029). We developed a predictive model for early mortality after hip fracture surgery based on postoperative factors with 96.0% sensitivity and 60.7% specificity (AUC = 0.863). We revealed that not only preoperative, but also postoperative factors have a great impact after hip fracture surgery. The influence of post-operative factors on 30-day mortality has a logical basis, albeit so far they have not been identified or quantified before. Our results provide an advantageous picture of the 30-day mortality after hip fracture surgery.

Background Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. Materials A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10 6 or 100 × 10 6 cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. Results No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009). BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01). Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly. Conclusions The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10 6 cells are administered. These results pave the way for a future phase III clinical trial. Clinical Trials.gov identifier NCT02123368. Nº EudraCT: 2009-017624-72

Background Mesenchymal stromal cells are a safe and promising option to treat knee osteoarthritis as previously demonstrated in different clinical trials. However, their efficacy, optimal dose and addition of adjuvants must be determined. Here, we evaluated the clinical effects of a dose of 100 × 10 6 bone marrow mesenchymal stromal cells (BM-MSCs) in combination with Platelet Rich Plasma (PRGF®) as adjuvant in a randomized clinical trial. Methods A phase II, multicenter, randomized clinical trial with active control was conducted. Sixty patients diagnosed with knee OA were randomly assigned to 3 weekly doses of PRGF® or intraarticular administration of 100 × 10 6 cultured autologous BM-MSCs plus PRGF®. Patients were followed up for 12 months, and pain and function were assessed using VAS and WOMAC and by measuring the knee range of motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. Results No adverse effects were reported after BM-MSC administration or during follow-up. According to VAS, the mean value (SD) for PRGF® and BM-MSC with PRGF® went from 5 (1.8) to 4.5 (2.2) (p = 0.389) and from 5.3 (1.9) to 3.5 (2.5) (p = 0.01), respectively at 12 months. In WOMAC, the mean (SD) baseline and 12-month overall WOMAC scores in patients treated with PRGF® was 31.9 (16.2) and 22.3 (15.8) respectively (p = 0.002) while that for patients treated with BM-MSC plus PRGF® was 33.4 (18.7) and 23.0 (16.6) (p = 0.053). Although statistical significances between groups have been not detected, only patients being treated with BM-MSC plus PRGF® could be considered as a OA treatment responders following OARSI criteria. X-ray and MRI (WORMS protocol) revealed no changes in knee joint space width or joint damage. Conclusions Treatment with BM-MSC associated with PRGF® was shown to be a viable therapeutic option for osteoarthritis of the knee, with clinical improvement at the end of follow-up. Further phase III clinical trials would be necessary to confirm the efficacy. Trial registration Clinical Trials.gov identifier NCT02365142. Nº EudraCT: 2011-006036-23

Background Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is available on the long-term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical effect. Materials A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 10 6 or 100 × 10 6 cultured autologous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse effects and clinical evolution, assessed using VAS and WOMAC scorings are reported. Results No adverse effects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-administered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p = 0.01; High-dose vs Control group, p = 0.004). Patients receiving BM-MSCs also improved clinically according to WOMAC. Control group showed an increase median value of 4 points (− 11;10) while Low-dose and High-dose groups exhibited values of − 18 (− 28;− 9) and − 10 (− 21;− 3) points, respectively (Low-dose vs Control group p = 0.043). No clinical differences between the BM-MSCs receiving groups were found. Conclusions Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible procedure that results in long-term clinical and functional improvement of knee OA.

PurposeMen and women typically display different neuromuscular characteristics, force–velocity relationships, and differing strength deficit (upper vs. lower body). Thus, it is not clear how previous recommendations for training with velocity-loss resistance training based on data in men will apply to women. This study examined the inter-sex differences in neuromuscular adaptations using 20% and 40% velocity-loss protocols in back squat and bench press exercises.MethodsThe present study employed an 8-week intervention (2 × week) comparing 20% vs. 40% velocity-loss resistance training in the back squat and bench press exercises in young men and women (~ 26 years). Maximum strength (1-RM) and submaximal-load mean propulsive velocity (MPV) for low- and high-velocity lifts in squat and bench press, countermovement jump and vastus lateralis cross-sectional area were measured at pre-, mid-, and post-training. Surface EMG of quadriceps measured muscle activity during performance tests.ResultsAll groups increased 1-RM strength in squat and bench press exercises, as well as MPV using submaximal loads and countermovement jump height (P < 0.05). No statistically significant between-group differences were observed, but higher magnitudes following 40% velocity loss in 1-RM (g = 0.60) and in low- (g = 1.42) and high-velocity (g = 0.98) lifts occurred in women. Training-induced improvements were accompanied by increases in surface EMG amplitude and vastus lateralis cross-sectional area.ConclusionSimilar increases in strength and power performance were observed in men and women over 8 weeks of velocity-based resistance training. However, some results suggest that strength and power gains favor using 40% rather than 20% velocity loss in women.

Mangroves are one of the most carbon‐dense forests on the Earth and have been highlighted as key ecosystems for climate change mitigation and adaptation. Hundreds of studies have investigated how mangroves fix, transform, store, and export carbon. Here, we review and synthesize the previously known and emerging carbon pathways in mangroves, including gains (woody biomass accumulation, deadwood accumulation, soil carbon sequestration, root and litterfall production), transformations (food web transfer through herbivory, decomposition), and losses (respiration as CO2 and CH4, litterfall export, particulate and dissolved carbon export). We then review the technologies available to measure carbon fluxes in mangroves, their potential, and their limitations. We also synthesize and compare mangrove net ecosystem productivity (NEP) with terrestrial forests. Finally, we update global estimates of carbon fluxes with the most current values of fluxes and global mangrove area. We found that the contributions of recently investigated fluxes, such as soil respiration as CH4, are minor (<1 Tg C year−1), while the contributions of deadwood accumulation, herbivory, and lateral export are significant (>35 Tg C year−1). Dissolved inorganic carbon exports are an order of magnitude higher than the other processes investigated and were highly variable, highlighting the need for further studies. Gross primary productivity (GPP) and ecosystem respiration (ER) per area of mangroves were within the same order of magnitude as terrestrial forests. However, ER/GPP was lower in mangroves, explaining their higher carbon sequestration. We estimate the global mean mangrove NEP of 109.1 Tg C year−1 (7.4 Mg C ha−1 year−1) or through a budget balance, accounting for lateral losses, a global mean of 66.6 Tg C year−1 (4.5 Mg C ha−1 year−1). Overall, mangroves are highly productive, and despite losses due to respiration and tidal exchange, they are significant carbon sinks.

ObjectiveTo determine the association between joint structure and gait in patients with knee osteoarthritis (OA).MethodsIMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components.ResultsTwo hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12).ConclusionStructural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.