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\"Bruce Wayne is Batman no more. With Alfred at his side, Bruce begins a new quest to find Tim Drake's missing father and the only person that may be able to heal his broken body: Shondra Kinsolving. Continuing from Batman: Knightquest: The Crusade Vol. 2, the next chapter in the saga of Bruce Wayne begins in the never before collected, Batman: Knightquest: The Search. Still recovering from his devastating encounter with Bane, and utilizing specially designed accoutrements, Bruce Wayne and Alfred are on the trail of Robin's father and Shondra Kinsolving, both kidnapped by a mysterious new foe lurking in the shadows. Shondra may be the only person on Earth who can repair Bruce's badly damaged body. To rescue her, he will have to push himself mentally and physically before it is too late. Part of a massive 25th anniversary recut of the entire Batman: Knightfall saga.\"-- Provided by publisher.

Significance Diabetes is the leading cause of nontraumatic amputations. There are no effective therapies to prevent diabetic ulcer formation and only modestly effective technologies to help with their healing. To enhance diabetic wound healing we designed a transdermal delivery system containing the FDA-approved small molecule deferoxamine, an iron chelator that increases defective hypoxia inducible factor-1 alpha transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. This system overcomes the challenge of delivering hydrophilic molecules through the normally impermeable stratum corneum and both prevents diabetic ulcer formation and improves the healing of existing diabetic wounds. This represents a prophylactic pharmacological agent to prevent ulcer formation that is rapidly translatable into the clinic and has the potential to ultimately transform the care and prevention of diabetic complications. There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services. We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either 'room temperature' or 'cooled' conditions. Infusate aliquots were assayed at different time-points over 24 hours. Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively. Meropenem infusers are likely to deliver ∼95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with meropenem CIs.

We examined the anthropogenic lead (Pb) burden that accumulated in sediment of lakes in the southeastern USA during the last ~150 years. Mining, smelting, agriculture, and fossil-fuel combustion are known to have contributed to Pb pollution in lakes of other regions. Few studies, however, have examined Pb sequestered in lakes of the southeastern USA, particulary peninsular Florida, which is subject to less continental atmospheric influence than other regions of the eastern USA. We obtained sediment cores from Little Lake Jackson and Little Lake Bonnet in Highlands County, Florida and used Pb isotopes in the records to identify principal sources of Pb contamination. The sediment records showed that changes in Pb concentration and isotope ratios correspond temporally with gasoline consumption in the USA, as well as with changes in lead ores used to produce leaded gasoline. Lead concentrations in the study lakes showed temporal variations that were similar to those found in peat records from east-central Florida. Isotope trends were similar to the mean USA atmospheric Pb deposition record, and to Pb isotope records from Bermuda and Atlantic corals. We modeled the isotopic composition of the anthropogenic Pb in lake sediments and found that the overall trend is controlled by Pb that was released during leaded gasoline combustion. There is, however, additional Pb at each site that comes from sources that are not fully represented by the natural, background Pb. Lead isotope ratios and Pb/arsenic (As) ratios provide evidence that Pb deposition in lakes during the middle 1900s might have been influenced by lead arsenate applications to golf courses, a source that is often ignored in Pb isotope studies. Isotope evidence confirms, however, that following cessation of commercial lead arsenate use in the 1960s, atmospheric alkyl lead was again the primary influence on Pb in sediments of the study lakes.

Purpose. This study aims to identify clinical and imaging prognosticators associated with the successful bridging or downstaging to liver transplantation (LT) in patients undergoing Yttrium-90 radioembolization (Y90-RE) for hepatocellular carcinoma (HCC). Methods. Retrospectively, patients with Y90-RE naïve HCC who were candidates or potential candidates for LT and underwent Y90-RE were included. Patients were then divided into favorable (maintained or achieved Milan criteria (MC) eligibility) or unfavorable (lost eligibility or unchanged MC ineligibility) cohorts based on changes to their MC eligibility after Y90-RE. Penalized logistic regression analysis was performed to identify the significant baseline prognosticators. Results. Between 2013 and 2018, 135 patients underwent Y90-RE treatment. Among the 59 (42%) patients within MC, LT eligibility was maintained in 49 (83%) and lost in 10 (17%) patients. Within the 76 (56%) patients outside MC, eligibility was achieved in 32 (42%) and unchanged in 44 (58%). Among the 81 (60%) patients with a favorable response, 16 (20%) went on to receive LT. Analysis of the baseline characteristics revealed that lower Albumin-Bilirubin score, lower Child–Pugh class, lower Barcelona Clinic Liver Cancer stage, HCC diagnosis using dynamic contrast-enhanced imaging on CT or MRI, normal/higher albumin levels, decreased severity of tumor burden, left lobe HCC disease, and absence of HBV-associated cirrhosis, baseline abdominal pain, or fatigue were all associated with a higher likelihood of bridging or downstaging to LT eligibility (p’s < 0.05). Conclusion. Certain baseline clinical and tumor characteristics are associated with the successful bridging or downstaging of potential LT candidates with HCC undergoing Y90-RE.

BackgroundBiologic therapy (BT) in the treatment of IJD is now well established. The risks and potential complications of this modality of the treatment including infections and interstitial lung pathology have been described previously including in reports from several national registry databases such as the BSRBR. Furthermore the prevalence of lung disease in rheumatoid IJD is estimated at 5%. HRCT scanning for lung disease is therefore an important but under-utilized means of objective assessment of patients with IJD particularly in later stages of disease and when medical treatment is escalated to include immunomodulatory and biologic therapies.ObjectivesOur data examines the role of HRCT in the assessment of IJD patients before and after introduction of biologic therapies to consider the merits of this investigation in the intermediate and long term surveillance of IJD and biologic therapies.MethodsHospital records of patients with IJD under the care of one rheumatologist (MN) submitted for assessment for biologics were assessed. Specific diagnosis, treatment regimens and progression to biologic therapy were documented along with a record of submission for HRCT. Outcome and changes in treatment over time as well as follow up scan results were documented and analysed.ResultsOf the 130 patients assessed for BT in the 5 year period up to 2015, 106 (82%) had HRCT prior to commencing BT. 92 (71%) had normal scans. A total of 116 patients were submitted for BT (93 anti TNF and 23 other) of these 70 (60%) were also on MTX. Thus 10 patients had BT without HRCT. 14 (11%) had abnormal scans (including ground glass change, bronchiectasis, COPD) and were not commenced on anti TNF, Rituximab or other BT. Of the 130 patients 87 (67%) had RA of which 71 (81.6%) were seropositive. Of the 14 with abnormal scans, 8 were seropositive and 8 were on MTX. Of the 93 patients started on Anti TNF, 35 (37.6%) were discontinued/switched to another BT for a variety of reasons including inefficacy and side effects. Of the anti-TNF start-ups, 29 (31%) had progressive changes on repeat HRCT within 0 to 12 months. Of these 14 were switched to Rituximab with no further change in HRCT. Repeat HRCT scan data is available in only 5 of 15 patients switched to a second anti TNF, in three of which progression of lung changes was noted.ConclusionsThese preliminary data reveal the importance of HRCT scanning in the pre-assessment and monitoring of patients requiring BT for IJD. Progression of lung disease was seen in 31% patients on anti TNF. We recommend early repeat scans if any adverse effects are experienced or a change in BT planned due to lack or loss of efficacy. As lung disease is now recognised as the main non-infective cause of mortality in IJD, consideration should be given to routine review HRCT at 12 months after introduction of BT and then at regular (no longer than 3 year) intervals to monitor change even in asymptomatic patients controlled on biologics.Disclosure of InterestNone declared

Paleolimnology combines the disciplines of limnology, geology and ecology, but because of challenges that separate investigators from direct knowledge about past lake conditions, the field is multidisciplinary by necessity. As a result, paleolimnology is influenced continuously by advances in many disciplines. As with limnological studies in recent decades, paleolimnology has diverged largely from the ecological and theoretical focuses of early investigators, but recent studies demonstrate the need for more integration of ecological and paleolimnological research. This paper provides a brief overview of recent paleolimnological investigations that have addressed questions related to theoretical ecology, as well as applied lake-management and climate research issues. We examine the use of transfer function models for estimating past water-quality conditions, and important caveats expressed by investigators about limitations in the development and use of such models. Paleolimnological research has contributed new insights about biological, physical and chemical processes in lakes that have been subject to change because of climate drivers and anthropogenic influences. These findings are relevant to predicting how lakes will respond to climate change, and will require new management approaches in the future. As the range of paleolimnological studies expands, there will be greater need for basic limnological research in order for paleolimnological investigators to better understand how sediments reflect lake processes of those regions.

Background: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). Methods: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan–Meier method and Cox regression. Results: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616–1.089; P= 0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579–0.985; P= 0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan–Meier curves for both end points began to diverge at 6 months. Conclusions: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.